WO2019018841A2

WO2019018841A2 - Compositions and methods for identification of combinatorial immunooncology therapeutics

Info

Publication number: WO2019018841A2
Application number: PCT/US2018/043268
Authority: WO
Inventors: Dan Theodorescu; Mai Tu; Jason DUEX
Original assignee: The Regents Of The University Of Colorado, A Body Corporate
Priority date: 2017-07-21
Filing date: 2018-07-23
Publication date: 2019-01-24
Also published as: WO2019018841A3

Abstract

The present disclosure provides compositions and methods for improving immune-oncology therapies. In certain embodiments, the compositions and methods comprise a combination of a composition that inhibits the activity by reducing the expression level or blocking the function a target gene or protein, and a composition comprising an immune checkpoint blockade (ICB) reagent.

Description

COMPOSITIONS AND METHODS FOR IDENTIFICATION OF

COMBINATORIAL IMMUNOONCOLOGY THERAPEUTICS

RELATED APPLICATIONS

[01] This application claims the benefit of provisional application USSN 62/535,669, filed July 21, 2017 and USSN 62/569,916, filed October 9, 2017, the contents of each of which are herein incorporated by reference in their entirety.

INCORPORATION OF SEQUENCE LISTING

[02] The contents of the text file named "UNCO-021/001WO_SeqList.txt," which was created on July 20, 2018 and is 927 KB in size, are hereby incorporated by reference in their entirety.

FIELD OF THE DISCLOSURE

[03] The disclosure is directed to molecular biology, immunology, oncology and methods of identifying and developing immune-oncology therapeutics as well as compositions comprising combinatorial immune-oncology therapeutics.

SUMMARY

[04] The disclosure provides compositions and methods for improving the effectiveness of immunotherapy in cancer. The disclosure provides a method of identifying a first therapeutic composition comprising a target gene whose reduction in functional activity or depletion of its transcript in combination with a second therapeutic composition that leads to immune checkpoint blockade (ICB), reduces cancer cell viability or induces death of the at least one cancer cell more so than use of ICB alone or reduction in functional activity or depletion of target gene transcript alone. The disclosure also provides a list of target genes obtained by said method that when undergoing depletion of their transcript in combination with ICB, induces death of the at least one cancer cell more than use of ICB alone.

[05] The disclosure provides a method of treating cancer in a subject in need thereof, the method comprising, administering to the subject, (a) a therapeutically-effective amount of a first composition that specifically targets a target gene, (b) a therapeutically-effective amount of a second composition that specifically targets a component of an immune checkpoint or (c) a combination of a therapeutically-effective amount of the composition of (a) and a therapeutically-effective amount of the composition of (b), wherein the administration of (a), (b) or (c) reduces viability of a cancer cell, reduces or inhibits proliferation of a cancer cell or induces death of a cancer cell of the subject. In certain embodiments, the level of expression of the target gene is higher in the cancer cell than the level of expression of the target gene in a non-cancer cell. In certain embodiments, the level of expression of the target gene is lower in the cancer cell than the level of expression of the target gene in a non-cancer cell. In certain embodiments, the non-cancer cell is a healthy cell. In certain embodiments, the cancer cell is in vivo, ex vivo, in vitro or in situ. In certain embodiments, the non-cancer cell is in vivo, ex vivo, in vitro or in situ.

[06] The disclosure provides a method of treating cancer in a subject in need thereof, the method comprising, administering to the subject, (a) a therapeutically-effective amount of a first composition that specifically targets a protein encoded by a target gene, (b) a therapeutically-effective amount of a second composition that specifically targets a component of an immune checkpoint or (c) a combination of a therapeutically-effective amount of the composition of (a) and a therapeutically-effective amount of the composition of (b), wherein the administration of (a), (b) or (c) reduces viability of a cancer cell, reduces or inhibits proliferation of a cancer cell or induces death of a cancer cell of the subject. In certain embodiments, an activity of the protein encoded by the target gene is higher in the cancer cell than the activity of the protein encoded by the target gene in a non-cancer cell. In certain embodiments, an activity of the protein encoded by the target gene is lower in the cancer cell than the activity of the protein encoded by the target gene in a non-cancer cell. In certain embodiments, the non-cancer cell is a healthy cell. In certain embodiments, the cancer cell is in vivo, ex vivo, in vitro or in situ. In certain embodiments, the non-cancer cell is in vivo, ex vivo, in vitro or in situ.

[07] In certain embodiments of the methods of the disclosure, the cancer comprises a solid cancer. In certain embodiments, the cancer comprises a cancer derived from an epithelial cell, a mesenchymal cell, or a neural cell. In certain embodiments, the cancer comprises a lung cancer. In certain embodiments, the cancer is a breast cancer. In certain embodiments, the cancer is a bladder cancer. In certain embodiments, the cancer is a skin cancer.

[08] In certain embodiments of the methods of the disclosure, the cancer comprises a liquid cancer. In certain embodiments, the cancer is a leukemia.

[09] In certain embodiments of the methods of the disclosure, the cancer comprises a stem cell or is derived from a stem cell.

[010] In certain embodiments of the methods of the disclosure, the cancer is metastatic.

[Oil] In certain embodiments of the methods of the disclosure, the target gene is selected from the group consisting of ADAM metallopeptidase domain 10 (ADAM10), alanyl aminopeptidase (ANPEP), carbonic anhydrase (CA1), carbonic anhydrase (CA2), carbonic anhydrase (CA9), C-C motif chemokine ligand 2 (CCL2), cluster of differentiation 37 (CD37), collagen type I alpha 1 chain (COL1A1), C-X-C motif chemokine ligand 12 (CXCL12), C-X-C motif chemokine receptor 4 (CXCR4), discoidin domain receptor tyrosine kinase 2 (DDR2), dipeptidyl peptidase 4 (DPP4), E2F transcription factor 1 (E2F1), erb-b2 receptor tyrosine kinase 2 (ERBB2), coagulation factor III, tissue factor (F3), fatty acid amide hydrolase (FAAH), fibroblast activation protein alpha (FAP), glutathione S-transferase pi 1 (GSTP1), interleukin 7 receptor (IL7R), matrix metallopeptidase 1 (MMP1), matrix metallopeptidase 14 (MMP14), matrix metallopeptidase 2 (MMP2), matrix metallopeptidase 9 (MMP9), MPL proto-oncogene thrombopoietin receptor (MPL), pyruvate dehydrogenase kinase 1 (PDKl), progesterone receptor (PGR), presenilin 1 (PSENl), protein tyrosine kinase 2 beta (PTK2B), ribosomal protein S6 kinase Bl (RPS6KB1), solute carrier family 16 member 1 (SLC16A1), solute carrier family 3 member 2 (SLC3A2), Spl transcription factor (SP1), tyrosinase related protein 1 (TYRP1) and vascular endothelial growth factor C (VEGFC). In certain embodiments of the methods of the disclosure, the target gene is CCL2. In certain embodiments of the methods of the disclosure, the target gene is DDR2.

[012] In certain embodiments of the methods of the disclosure, the composition of (a) comprises a nucleic acid sequence that hybridizes with a coding sequence or non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell. In certain embodiments, the composition of (a) comprises an antisense RNA, a short hairpin RNA (shRNA), an interfering RNA (RNAi), a small interfering RNA (siRNA), a piwi RNA (piRNA), a microRNA (miRNA) or combination thereof that hybridizes with a coding sequence or non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

[013] In certain embodiments of the methods of the disclosure, the composition of (a) comprises a therapeutic nucleic acid sequence that binds to a coding sequence or non-coding sequence associated with the target gene and the binding of the therapeutic nucleic acid sequence to the target sequence reduces a level of expression of the target gene. In certain embodiments, the level of expression of the target gene is a level of transcription of the target gene. In certain embodiments, the level of expression of the target gene is a level of translation of a product of the target gene. In certain embodiments, the composition of (a) comprises an aptamer that specifically binds to a coding sequence or non-coding sequence associated with the target gene. In certain embodiments, the aptamer comprises a DNA sequence.

[014] In certain embodiments of the methods of the disclosure, the composition of (a) comprises a therapeutic nucleic acid sequence that binds to target protein encoded by the target gene and the binding of the therapeutic nucleic acid sequence to the target protein reduces an activity of the target protein encoded by the target gene. In certain embodiments, the composition of (a) comprises an aptamer that specifically binds to the target protein encoded by the target gene. In certain embodiments, the aptamer comprises a DNA sequence.

[015] In certain embodiments of the methods of the disclosure, the composition of (a) comprises a nucleic acid sequence that hybridizes with a coding sequence or non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell. In certain embodiments, the composition of (a) comprises a guide RNA (gRNA) that hybridizes with a coding sequence or a non- coding sequence associated with the target gene. In certain embodiments, the gRNA is a single-stranded gRNA (sgRNA). In certain embodiments, the gRNA is operably linked to an effector. In certain embodiments, the effector comprise a nuclease or a nuclease domain. In certain embodiments, the nuclease or a nuclease domain comprises a sequence isolated or derived from a RNA-guided DNA endonuclease enzyme associated with CRISPR (Clustered Regularly Interspersed Palindromic Repeats), a Transcription activator-like effector nucleases (TALEN), a Zinc-finger nuclease (ZFN), an endonuclease or a Type IIS endonuclease. In certain embodiments, the RNA-guided DNA endonuclease enzyme associated with CRISPR comprises Cas9. In certain embodiments, the nuclease or a nuclease domain induces a single- strand break in a coding sequence or non-coding sequence associated with the target gene. In certain embodiments, the nuclease or a nuclease domain induces a double-strand break in a coding sequence or non-coding sequence associated with the target gene.

[016] In certain embodiments of the methods of the disclosure, the composition of (a) comprises a nucleic acid sequence that hybridizes with a coding sequence or non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell. In certain embodiments, the composition of (a) comprises a short hairpin RNA (shRNA) that hybridizes with a coding sequence or non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

[017] In certain embodiments of the methods of the disclosure, the composition of (a) comprises a protein that binds a coding sequence or non-coding sequence associated with the target gene and wherein the binding of the protein reduces or inhibits transcription or translation of a coding sequence or non-coding sequence associated with the target gene. In certain embodiments, the composition of (a) comprises an antibody, an antibody fragment or an antibody mimetic. In certain embodiments, the antibody comprises a monoclonal antibody. In certain embodiments, the monoclonal antibody is a human monoclonal antibody or a humanized monoclonal antibody. Exemplary antibody mimetics of the disclosure comprise or consist of an organic compound that specifically binds a target sequence and has a structure distinct from a naturally-occurring antibody. Antibody mimetics may comprise or consist of a protein, a nucleic acid, or a small molecule. Antibody mimetics may comprise or consist of an affibody, an afflilin, an affimer, an affitin, an alphabody, an anticalin, an avimer, a DARPin, a Fynomer, a Kunitz domain peptide, or a monobody.

[018] In certain embodiments of the methods of the disclosure, the composition of (a) comprises a therapeutic protein that binds a target protein encoded by the target gene and wherein the binding of the therapeutic protein to the target protein reduces or inhibits an acitivity of the target protein encoded by the target gene. In certain embodiments, the composition of (a) comprises an antibody, an antibody fragment or an antibody mimetic. In certain embodiments, the antibody comprises a monoclonal antibody. In certain

embodiments, the monoclonal antibody is a human monoclonal antibody or a humanized monoclonal antibody. Exemplary antibody mimetics of the disclosure comprise or consist of an organic compound that specifically binds a target sequence and has a structure distinct from a naturally-occurring antibody. Antibody mimetics may comprise or consist of a protein, a nucleic acid, or a small molecule. Antibody mimetics may comprise or consist of an affibody, an afflilin, an affimer, an affitin, an alphabody, an anticalin, an avimer, a DARPin, a Fynomer, a Kunitz domain peptide, or a monobody.

[019] In certain embodiments of the methods of the disclosure, the composition of (a) comprises a small molecule that binds a coding sequence or non-coding sequence associated with the target gene and wherein the binding of the small molecule reduces or inhibits transcription or translation of a coding sequence or non-coding sequence associated with the target gene. In certain embodiments, the small molecule comprises an organic small molecule. In certain embodiments, the small molecule comprises an inorganic small molecule.

[020] In certain embodiments of the methods of the disclosure, the composition of (a) comprises a small molecule that binds a target protein encoded by the target gene and wherein the binding of the small molecule to the target protein reduces or inhibits an activity of the target protein encoded by the target gene. In certain embodiments, the small molecule comprises an organic small molecule. In certain embodiments, the small molecule comprises an inorganic small molecule.In certain embodiments, the small molecule is a kinase inhibitor. In certain embodiments, the kinase inhibitor is abemaciclib, acalabrutinib, afatinib, alectinib, axitinib, baricitinib, binimetinib, bosutinib, brigatinib,cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, encorafenib, erlotinib, everolimus, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, midostaurin, neratinib, nilotinib, nintedanib, osimertinib, palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, ruxolitinib, sirolimus, sorafenib, sunitinib, temsirolimus, tofacitinib, trametinib, vandetanib or vemurafenib. In certain embodiments, the kinase inhibitor is dasatinib.

[021] In certain embodiments of the methods of the disclosure, the composition of (b) comprises an antagonist or an inhibitor of the component of an immune checkpoint, wherein the antagonist or the inhibitor disrupts or blocks an immune checkpoint in an immune cell. As used throughout the disclosure, the term "disrupts or blocks an immune checkpoint in an immune cell" is also meant to describe the disruption or blockade of an interaction on the surface of an immune cell or between an immune cell and a second cell. For example, an antagonist or an inhibitor of the component of an immune checkpoint may disrupts or blocks an immune checkpoint by disrupting or blocking an interaction between an immune cell and an antigen presenting cell. Alternatively, or in addition, an antagonist or an inhibitor of the component of an immune checkpoint may disrupts or blocks an immune checkpoint by disrupting or blocking an interaction between an immune cell and a cancer cell. In certain embodiments of the methods of the disclosure, a cancer cell may be an antigen presenting cell.

[022] In certain embodiments of the methods of the disclosure, the composition of (b) comprises an antagonist or an inhibitor of the component of an immune checkpoint, wherein the antagonist or the inhibitor disrupts or blocks an immune checkpoint in an immune cell. In certain embodiments, the composition of (b) comprises a nucleic acid sequence that hybridizes with a coding sequence or non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell. In certain embodiments, the composition of (b) comprises an antisense RNA, a short hairpin RNA (shRNA), an interfering RNA (RNAi), a small interfering RNA (siRNA), a piwi RNA (piRNA), a microRNA (miRNA) or combination thereof that hybridizes with a coding sequence or non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

[023] In certain embodiments of the methods of the disclosure, the composition of (b) comprises an antagonist or an inhibitor of the component of an immune checkpoint, wherein the antagonist or the inhibitor disrupts or blocks an immune checkpoint in an immune cell. In certain embodiments, the composition of (b) comprises a therapeutic nucleic acid sequence that binds to a coding sequence or non-coding sequence associated with the component of an immune checkpoint and the binding of the therapeutic nucleic acid sequence to the sequence associated with the component of an immune checkpoint reduces a level of expression of the component of an immune checkpoint. In certain embodiments, the level of expression of the component of an immune checkpoint is a level of transcription of the component of an immune checkpoint. In certain embodiments, the level of expression of the component of an immune checkpoint is a level of translation of a product of the component of an immune checkpoint. In certain embodiments, the composition of (b) comprises an aptamer that specifically binds to a coding sequence or non-coding sequence associated with the component of an immune checkpoint. In certain embodiments, the aptamer comprises a DNA sequence.

[024] In certain embodiments of the methods of the disclosure, the composition of (b) comprises an antagonist or an inhibitor of the component of an immune checkpoint, wherein the antagonist or the inhibitor disrupts or blocks an immune checkpoint in an immune cell. In certain embodiments, the composition of (b) comprises a therapeutic nucleic acid sequence that binds to a component of an immune checkpoint and the binding of the therapeutic nucleic acid sequence to the component of an immune checkpoint reduces an activity of the component of an immune checkpoint. In certain embodiments, the composition of (b) comprises an aptamer that specifically binds to the component of an immune checkpoint. In certain embodiments, the aptamer comprises a DNA sequence.

[025] In certain embodiments of the methods of the disclosure, the composition of (b) comprises a nucleic acid sequence that hybridizes with a coding sequence or non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell. In certain embodiments, the composition of (b) comprises a guide RNA (gRNA) that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint. In certain embodiments, the gRNA is a single-stranded gRNA (sgRNA). In certain embodiments, the gRNA is operably linked to an effector. In certain embodiments, the effector comprise a nuclease or a nuclease domain. In certain embodiments, the nuclease or a nuclease domain comprises a sequence isolated or derived from a RNA-guided DNA endonuclease enzyme associated with CRISPR, a transcription activator-like effector nucleases (TALEN), a zinc-finger nuclease (ZFN), an endonuclease or a type IIS

endonuclease. In certain embodiments, the RNA-guided DNA endonuclease enzyme associated with CRISPR comprises Cas9. In certain embodiments, the nuclease or a nuclease domain induces a single-strand break in a coding sequence or non-coding sequence associated with the component of an immune checkpoint. In certain embodiments, the nuclease or a nuclease domain induces a double-strand break in a coding sequence or non- coding sequence associated with the component of an immune checkpoint.

[026] In certain embodiments of the methods of the disclosure, the composition of (b) comprises a nucleic acid sequence that hybridizes with a coding sequence or non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell. In certain embodiments, the composition of (b) comprises a short hairpin RNA (shRNA) that hybridizes with a coding sequence or non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

[027] In certain embodiments of the methods of the disclosure, the composition of (b) comprises a small molecule that binds a coding sequence or non-coding sequence associated with the component of an immune checkpoint and the binding of the small molecule to the sequence associated with the component of an immune checkpoint reduces or inhibits transcription or translation of a coding sequence or non-coding sequence associated with the component of an immune checkpoint. In certain embodiments, the small molecule comprises an organic small molecule. In certain embodiments, the small molecule comprises an inorganic small molecule. [028] In certain embodiments of the methods of the disclosure, the composition of (b) comprises a small molecule that binds a component of an immune checkpoint and the binding of the small molecule to the component of an immune checkpoint reduces or inhibits an activity of the component of an immune checkpoint. In certain embodiments, the small molecule comprises an organic small molecule. In certain embodiments, the small molecule comprises an inorganic small molecule.

[029] In certain embodiments of the methods of the disclosure, the composition of (b) comprises a protein that binds a coding sequence or non-coding sequence associated with the component of an immune checkpoint and the binding of the protein to the sequence associated with the component of an immune checkpoint reduces or inhibits transcription or translation of a coding sequence or non-coding sequence associated with the component of an immune checkpoint. In certain embodiments, the composition of (b) comprises an antibody, an antibody fragment or an antibody mimetic. In certain embodiments, the antibody comprises a monoclonal antibody. In certain embodiments, the monoclonal antibody is a human monoclonal antibody or a humanized monoclonal antibody. Exemplary antibody mimetics of the disclosure comprise or consist of an organic compound that specifically binds a target sequence and has a structure distinct from a naturally-occurring antibody. Antibody mimetics may comprise or consist of a protein, a nucleic acid, or a small molecule. Antibody mimetics may comprise or consist of an affibody, an afflilin, an affimer, an affitin, an alphabody, an anticalin, an avimer, a DARPin, a Fynomer, a Kunitz domain peptide, or a monobody.

[030] In certain embodiments, the composition of (b) comprises a protein that binds the component of an immune checkpoint and the binding of the protein to the component of an immune checkpoint reduces or inhibits an activity of the component of an immune checkpoint. In certain embodiments, the composition of (b) comprises an antibody, an antibody fragment or an antibody mimetic. In certain embodiments, the antibody comprises a monoclonal antibody. In certain embodiments, the monoclonal antibody is a human monoclonal antibody or a humanized monoclonal antibody. Exemplary antibody mimetics of the disclosure comprise or consist of an organic compound that specifically binds a target sequence and has a structure distinct from a naturally-occurring antibody. Antibody mimetics may comprise or consist of a protein, a nucleic acid, or a small molecule. Antibody mimetics may comprise or consist of an affibody, an afflilin, an affimer, an affitin, an alphabody, an anticalin, an avimer, a DARPin, a Fynomer, a Kunitz domain peptide, or a monobody. [031] In certain embodiments of the methods of the disclosure, the component of an immune checkpoint is selected from the group consisting of cytotoxic T-lymphocyte- associated protein 4 (CTLA-4), programmed death-ligand 1 (PD-Ll) and programmed death- 1 (PD-1).

[032] In certain embodiments of the methods of the disclosure, the component of an immune checkpoint is CTLA-4 and the antagonist or the inhibitor of the component of an immune checkpoint comprises Tremelimumab or Ipilumamab. In certain embodiments, the antagonist or the inhibitor of the component of an immune checkpoint comprises

Tremelimumab. In certain embodiments, the antagonist or the inhibitor of the component of an immune checkpoint comprises Ipilumamab.

[033] In certain embodiments of the methods of the disclosure, the component of an immune checkpoint is PD-Ll and the antagonist or the inhibitor of the component of an immune checkpoint comprises Atezolizumab.

[034] In certain embodiments of the compositions of the disclosure, the component of an immune checkpoint is PD-1 and the antagonist or the inhibitor of the component of an immune checkpoint comprises Nivolumab or Pembrolizumab. In certain embodiments, the antagonist or the inhibitor of the component of an immune checkpoint comprises Nivolumab. In certain embodiments, the antagonist or the inhibitor of the component of an immune checkpoint comprises Pembrolizumab.

[035] In certain embodiments, the target gene is DDR2 and the component of the immune checkpoint is PD-1. In certain embodiments, the antagonist or the inhibitor of DDR2 is comprises dasatinib and wherein the antagonist or the inhibitor of PD-1 is comprises an anti- PD-1 antibody.

[036] The disclosure provides a method of identifying a gene as a therapeutic target, comprising, (a) generating a plurality of nucleic acid molecules each comprising a sequence having at least 50% complementarity to a coding sequence or a non-coding sequence associated with at least one target gene, wherein the at least one target gene is expressed in a cancer cell; (b) introducing the plurality of nucleic acid molecules of (a) into at least one cell of a cultured cell line under conditions sufficient to allow for hybridization of at least one nucleic acid molecule of (a) to a sequence encoding a target gene to produce at least one nucleic acid duplex, wherein the formation of the duplex induces a reduction or an elimination of expression of the target gene in the cell, to produce a plurality of transformed cells; (c) introducing the plurality of transformed cells of (b) into a non-human animal to produce a tumor in an in vivo model system; and (d) administering to the non-human animal an amount of a composition comprising an antagonist or an inhibitor of a component of an immune checkpoint, wherein the antagonist or the inhibitor induces an immune checkpoint blockade in at least one cell of the tumor of (c). In certain embodiments, the method further comprises (e) removing the tumor of (c) to produce a biological sample and (f) assaying for the presence or absence of each nucleic acid molecule of the plurality of nucleic acid molecules of (a) obtained from the biological sample of (e), wherein an absence of a nucleic acid molecule of the plurality of nucleic acid molecules of (a) indicates that the nucleic acid molecule hybridized with a sequence associated with at least one target gene and wherein an identity of the absent nucleic acid molecule indicates an identity of the target gene.

[037] The disclosure provides a method of identifying a gene as a therapeutic target, comprising, (a) generating a plurality of nucleic acid molecules each comprising a sequence having at least 50% complementarity to a coding sequence or a non-coding sequence associated with at least one target gene, wherein the at least one target gene is expressed in a cancer cell; (b) introducing the plurality of nucleic acid molecules of (a) into at least one cell of a cultured cell line under conditions sufficient to allow for hybridization of at least one nucleic acid molecule of (a) to a sequence encoding a target gene to produce at least one nucleic acid duplex, wherein the formation of the duplex induces a reduction or an elimination of expression of the target gene in the cell, to produce a plurality of transformed cells; (c) introducing the plurality of transformed cells of (b) into a non-human animal to produce a tumor in an in vivo model system; and (d) administering to the non-human animal an amount of a composition comprising an antagonist or an inhibitor of a component of an immune checkpoint, wherein the antagonist or the inhibitor induces an immune checkpoint blockade in at least one cell of the tumor of (c). In certain embodiments, the method further comprises (e) removing the tumor of (c) to produce a biological sample and (f) assaying for an abundance of each nucleic acid molecule of the plurality of nucleic acid molecules of (a) obtained from the biological sample of (e), wherein a decrease of an abundance of a nucleic acid molecule of the plurality of nucleic acid molecules of (a) in a cancer cell compared to an abundance of the nucleic acid molecule of the plurality of nucleic acid molecules of (a) in a non-cancer cell indicates that the nucleic acid molecule hybridized with a sequence associated with at least one target gene and wherein an identity of the nucleic acid molecule having a decreased abundance indicates an identity of the target gene. Using the method, any nucleic acid molecule that is absent or reduced more profoundly in tumors treated with immune checkpoint blockade compared to tumors treated to a placebo / control substance / carrier reveals the identity of the target gene.

[038] The disclosure provides a method of treating cancer in a subject in need thereof, the method comprising, administering to the subject, (a) a therapeutically-effective amount of a first composition that specifically targets a gene identified according to a method of identifying a gene as a therapeutic target of the disclosure, (b) a therapeutically-effective amount of a second composition that specifically targets a component of an immune checkpoint or (c) a combination of a therapeutically-effective amount of the composition of (a) and a therapeutically-effective amount of the composition of (b), wherein the

administration of (a), (b) or (c) reduces viability of a cancer cell, reduces or inhibits proliferation of a cancer cell or induces death of a cancer cell of the subject.

[039] The disclosure provides a method of producing a cultured cell line, comprising, (a) contacting one or more mutagens and a non-human animal under conditions sufficient for the one or more mutagens to access a nucleic acid sequence of the non-human animal to produce a plurality of transformed cells; (b) isolating the plurality of transformed cells of (a) from the non-human animal; and (c) maintaining the isolated plurality of transformed cells of (b) ex vivo under conditions sufficient to produce a cultured cell line. In certain embodiments, the non-human animal is a mouse. In certain embodiments, the one or more mutagens comprise radiation, a plurality of nanoparticles, an inhibitor of one or more DNA repair pathway(s), a DNA intercalating agent, a nuclease, an endonuclease, a DNase, and an RNase. In certain embodiments, the plurality of nanoparticles comprise a component of or derived from component of a cigarette, a burnt remnant of a cigarette, cigarette smoke or any combination thereof.

[040] The disclosure provides a cultured cell line produced by a method of producing a cultured cell line of the disclosure.

[041] The disclosure provides a method of treating cancer in a subject in need thereof, the method comprising, administering to the subject a therapeutically-effective amount of a composition that specifically targets a target gene, wherein the subject is identified as having an equal or increased expression level of a coding sequence or a non-coding sequence associated with the target gene or an equal or increased activity level of a coding sequence or a non-coding sequence associated with the target gene in a least one cancer cell compared to an expression level of the coding sequence or the non-coding sequence associated with the target gene in at least one non-cancer cell, wherein the composition comprises a nucleic acid, a protein or a small molecule that reduces the expression (e.g. a transcription or a translation) level or the activity of a coding sequence or a non-coding sequence associated with the target gene, and wherein the composition reduces viability of a cancer cell, reduces or inhibits proliferation of a cancer cell or induces death of a cancer cell of the subject. In certain embodiments, the method further comprises administering to the subject a therapeutically - effective amount of a second composition that specifically targets a component of an immune checkpoint, wherein the second composition comprises a nucleic acid, a protein or a small molecule that reduces an expression (e.g. a transcription or a translation) level or an activity of a coding sequence or a non-coding sequence associated with the component of an immune checkpoint, and wherein the second composition reduces viability of a cancer cell, reduces or inhibits proliferation of a cancer cell or induces death of a cancer cell of the subject. In certain embodiments, the method further comprises administering to the subject a therapeutically-effective amount of a second composition that specifically targets a component of an immune checkpoint, wherein the second composition comprises a nucleic acid, a protein or a small molecule that reduces or inhibits an activity of the component of an immune checkpoint, and wherein the second composition reduces viability of a cancer cell, reduces or inhibits proliferation of a cancer cell or induces death of a cancer cell of the subject.

[042] The disclosure provides a method of treating cancer in a subject in need thereof, the method comprising, administering to the subject a therapeutically-effective amount of a composition that specifically targets a target gene, wherein the subject is identified as having an equal or increased expression level of a coding sequence or a non-coding sequence associated with the target gene or an equal or increased activity level of a coding sequence or a non-coding sequence associated with the target gene in a least one cancer cell compared to an expression level of the coding sequence or the non-coding sequence associated with the target gene in at least one non-cancer cell, wherein the composition comprises a nucleic acid, a protein or a small molecule that reduces the activity of the protein encoded by the target gene, and wherein the composition reduces viability of a cancer cell, reduces or inhibits proliferation of a cancer cell or induces death of a cancer cell of the subject. In certain embodiments, the method further comprises administering to the subject a therapeutically- effective amount of a second composition that specifically targets a component of an immune checkpoint, wherein the second composition comprises a nucleic acid, a protein or a small molecule that reduces an expression (e.g. a transcription or a translation) level or an activity of a coding sequence or a non-coding sequence associated with the component of an immune checkpoint, and wherein the second composition reduces viability of a cancer cell, reduces or inhibits proliferation of a cancer cell or induces death of a cancer cell of the subject. In certain embodiments, the method further comprises administering to the subject a therapeutically-effective amount of a second composition that specifically targets a component of an immune checkpoint, wherein the second composition comprises a nucleic acid, a protein or a small molecule that reduces or inhibits an activity of a component of an immune checkpoint, and wherein the second composition reduces viability of a cancer cell, reduces or inhibits proliferation of a cancer cell or induces death of a cancer cell of the subject.

[043] The disclosure provides a method of treating cancer in a subject in need thereof, the method comprising, administering to the subject a therapeutically-effective amount of a first composition that specifically targets a target gene and a second composition that specifically targets a component of an immune checkpoint, wherein the subject is identified as having an equal or an increased expression level of a coding sequence or a non-coding sequence associated with the target gene or an equal or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene in a least one cancer cell compared to an expression level of the coding sequence or the non-coding sequence associated with the target gene in at least one non-cancer cell, and wherein the administering of the first composition and the second composition reduces viability of a cancer cell, reduces or inhibits proliferation of a cancer cell or induces death of a cancer cell of the subject. In certain embodiments, the first composition comprises a nucleic acid, a protein or a small molecule that reduces an expression (e.g. a transcription or a translation) level or an activity of a coding sequence or a non-coding sequence associated with the target gene. In certain embodiments, the first composition comprises a nucleic acid, a protein or a small molecule that reduces an activity of the target protein encoded by the target gene. In certain embodiments, the second composition comprises a nucleic acid, a protein or a small molecule that reduces an expression (e.g. a transcription or a translation) level or an activity of a coding sequence or a non-coding sequence associated with the component of component of an immune checkpoint. In certain embodiments, the second composition comprises a nucleic acid, a protein or a small molecule that reduces an activity of the component of an immune checkpoint.

[044] The disclosure provides a method of treating cancer in a subject in need thereof, the method comprising, administering to the subject a therapeutically-effective amount of a composition that specifically targets a component of an immune checkpoint, wherein the subject is identified as having an equal or a decreased expression level of a coding sequence or a non-coding sequence associated with the target gene or an equal or a decreased activity level of a coding sequence or a non-coding sequence associated with the target gene in a least one cancer cell compared to an expression level of the coding sequence or the non-coding sequence associated with the target gene in at least one non-cancer cell, wherein the composition comprises a nucleic acid, a protein or a small molecule that reduces or inhibits an activity of a component of an immune checkpoint, and wherein the composition reduces viability of a cancer cell, reduces or inhibits proliferation of a cancer cell or induces death of a cancer cell of the subject.

[045] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, an equal activity level of the target protein encoded by the target gene, a decreased level of expression or a decreased activity level of a coding sequence or a non-coding sequence associated with the target gene or an decreased activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the non-cancer cell is a healthy cell. In certain embodiments, the cancer cell is in vivo, ex vivo, in vitro or in situ. In certain embodiments, the non-cancer cell is in vivo, ex vivo, in vitro or in situ.

[046] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, an equal activity level of the target protein encoded by the target gene, a decreased level of expression or a decreased activity level of a coding sequence or a non-coding sequence associated with the target gene or an decreased activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the cancer comprises a solid cancer. In certain embodiments, the cancer comprises a cancer derived from an epithelial cell, a mesenchymal cell, or a neural cell. In certain embodiments, the cancer comprises a lung cancer. In certain embodiments, the cancer is a breast cancer. In certain embodiments, the cancer is a bladder cancer. In certain embodiments, the cancer is a skin cancer.

[047] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, an equal activity level of the target protein encoded by the target gene, a decreased level of expression or a decreased activity level of a coding sequence or a non-coding sequence associated with the target gene or an decreased activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the cancer comprises a liquid cancer. In certain embodiments, the cancer is a leukemia.

[048] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, an equal activity level of the target protein encoded by the target gene, a decreased level of expression or a decreased activity level of a coding sequence or a non-coding sequence associated with the target gene or an decreased activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the cancer comprises a stem cell or is derived from a stem cell.

[049] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, an equal activity level of the target protein encoded by the target gene, a decreased level of expression or a decreased activity level of a coding sequence or a non-coding sequence associated with the target gene or an decreased activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the cancer is metastatic.

[050] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, an equal activity level of the target protein encoded by the target gene, a decreased level of expression or a decreased activity level of a coding sequence or a non-coding sequence associated with the target gene or an decreased activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the target gene is selected from the group consisting of

ADAM 10, ANPEP, CA1, CA2, CA9, CCL2, CD37, COL1A1, CXCL12, CXCR4, DDR2, DPP4, E2F1, ERBB2, F3, FAAH, FAP, GSTP1, IL7R, MMP1, MMP14, MMP2, MMP9, MPL, PDK1, PGR, PSEN1, PTK2B, RPS6KB1, SLC16A1, SLC3A2, SP1, TYRP1 and VEGFC. In certain embodiments the target gene is DDR2.

[051] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, or an equal activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the composition comprises a nucleic acid sequence that hybridizes with a coding sequence or a non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell. In certain embodiments, the composition comprises an antisense RNA, a short hairpin RNA (shRNA), an interfering RNA (RNAi), a small interfering RNA (siRNA), a piwi RNA (piRNA), a microRNA (miRNA) or combination thereof that hybridizes with a coding sequence or a non- coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

[052] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, or an equal activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the composition comprises a nucleic acid sequence that hybridizes with a coding sequence or a non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell. In certain embodiments, the composition comprises a guide RNA (gRNA) that hybridizes with a coding sequence or a non-coding sequence associated with the target gene. In certain embodiments, the gRNA is a single-stranded gRNA (sgRNA). In certain embodiments, the gRNA is operably linked to an effector. In certain embodiments, the effector comprise a nuclease or a nuclease domain. In certain embodiments, the nuclease or a nuclease domain comprises a sequence isolated or derived from a RNA-guided DNA endonuclease enzyme associated with CRISPR, a Transcription activator-like effector nucleases (TALEN), a Zinc-finger nuclease (ZFN), an endonuclease or a Type IIS endonuclease. In certain embodiments, the RNA- guided DNA endonuclease enzyme associated with CRISPR comprises Cas9. In certain embodiments, the nuclease or a nuclease domain induces a single-strand break in a coding sequence or a non-coding sequence associated with the target gene. In certain embodiments, the nuclease or a nuclease domain induces a double-strand break in a coding sequence or a non-coding sequence associated with the target gene.

[053] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, or an equal activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the composition comprises a nucleic acid sequence that hybridizes with a coding sequence or a non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell. In certain embodiments, the composition comprises a guide RNA (gRNA) that hybridizes with a coding sequence or a non-coding sequence associated with the target gene. In certain embodiments, the composition comprises a short hairpin RNA (shRNA) that hybridizes with a coding sequence or a non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

[054] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, or an equal activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the composition comprises a nucleic acid sequence that hybridizes with a coding sequence or a non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, wherein the duplex is depleted from the cancer cell. In certain embodiments, the composition comprises an aptamer that specifically binds to a coding sequence or non-coding sequence associated with the target gene. In certain embodiments, the aptamer comprises a DNA sequence.

[055] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, or an equal activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the composition comprises a nucleic acid sequence that binds to a target protein encoded by the target gene. In certain embodiments, the composition comprises an aptamer that specifically binds to the target protein associated with the target gene. In certain

embodiments, the aptamer comprises a DNA sequence.

[056] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, or an equal activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the composition comprises a protein that binds a coding sequence or non-coding sequence associated with the target gene and wherein the binding of the protein reduces or inhibits transcription or translation of a coding sequence or non-coding sequence associated with the target gene. In certain embodiments, the composition comprises an antibody, an antibody fragment or an antibody mimetic. In certain embodiments, the antibody comprises a monoclonal antibody. In certain embodiments, the monoclonal antibody is a human monoclonal antibody or a humanized monoclonal antibody. Exemplary antibody mimetics of the disclosure comprise or consist of an organic compound that specifically binds a target sequence and has a structure distinct from a naturally-occurring antibody. Antibody mimetics may comprise or consist of a protein, a nucleic acid, or a small molecule. Antibody mimetics may comprise or consist of an affibody, an afflilin, an affimer, an affitin, an alphabody, an anticalin, an avimer, a DARPin, a Fynomer, a Kunitz domain peptide, or a monobody.

[057] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, or an equal activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the composition comprises a protein that binds a target gene encoded by the target gene, wherein the binding of the protein to the target gene reduces or inhibits an activity of the target gene encoded by the target gene. In certain embodiments, the composition comprises an antibody, an antibody fragment or an antibody mimetic. In certain embodiments, the antibody comprises a monoclonal antibody. In certain embodiments, the monoclonal antibody is a human monoclonal antibody or a humanized monoclonal antibody. Exemplary antibody mimetics of the disclosure comprise or consist of an organic compound that specifically binds a target sequence and has a structure distinct from a naturally-occurring antibody. Antibody mimetics may comprise or consist of a protein, a nucleic acid, or a small molecule. Antibody mimetics may comprise or consist of an affibody, an afflilin, an affimer, an affitin, an alphabody, an anticalin, an avimer, a DARPin, a Fynomer, a Kunitz domain peptide, or a monobody.

[058] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, or an equal activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the composition comprises a protein that binds a coding sequence or non-coding sequence associated with the target gene, wherein the binding of the protein to the sequence associated with the target gene reduces or inhibits transcription or translation of a coding sequence or non-coding sequence associated with the target gene. In certain embodiments, the composition comprises an aptamer that specifically binds to a coding sequence or non- coding sequence associated with the target gene. In certain embodiments, the aptamer comprises an amino acid sequence.

[059] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, or an equal activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the composition comprises a protein that binds a target protein encoded by the target gene, wherein the binding of the protein to the target protein encoded by the target gene reduces or inhibits an activity of the target protein encoded by the target gene. In certain embodiments, the composition comprises an aptamer that specifically binds to the target protein encoded by the target gene. In certain embodiments, the aptamer comprises an amino acid sequence.

[060] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, or an equal activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the composition comprises a small molecule that binds a coding sequence or non-coding sequence associated with the target gene and wherein the binding of the small molecule reduces or inhibits transcription or translation of a coding sequence or non-coding sequence associated with the target gene. In certain embodiments, the small molecule comprises an organic small molecule. In certain embodiments, the small molecule comprises an inorganic small molecule. In certain embodiments, the small molecule is a kinase inhibitor. In certain embodiments, the kinase inhibitor is abemaciclib, acalabrutinib, afatinib, alectinib, axitinib, baricitinib, binimetinib, bosutinib, brigatinib,cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, encorafenib, erlotinib, everolimus, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, midostaurin, neratinib, nilotinib, nintedanib, osimertinib, palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, ruxolitinib, sirolimus, sorafenib, sunitinib, temsirolimus, tofacitinib, trametinib, vandetanib or vemurafenib. In certain embodiments, the kinase inhibitor is dasatinib.

[061] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, or an equal activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the composition comprises a small molecule that binds a target protein encoded by the target gene, wherein the binding of the small molecule to the target protein reduces or inhibits an activity of the target protein encoded by the target gene. In certain embodiments, the small molecule comprises an organic small molecule. In certain embodiments, the small molecule comprises an inorganic small molecule.

[062] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, or an equal activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the second composition comprises an antagonist or an inhibitor of the component of an immune checkpoint, wherein the antagonist or the inhibitor disrupts or blocks an immune checkpoint in an immune cell.

[063] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having a decreased level of expression or a decreased activity level of a coding sequence or a non-coding sequence associated with the target gene, a decreased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, or an equal activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the composition comprises an antagonist or an inhibitor of the component of an immune checkpoint, wherein the antagonist or the inhibitor disrupts or blocks an immune checkpoint in an immune cell.

[064] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, or an equal activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the second composition comprises an antagonist or an inhibitor of the component of an immune checkpoint, wherein the antagonist or the inhibitor disrupts or blocks an immune checkpoint in an immune cell.

[065] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having a decreased level of expression or a decreased activity level of a coding sequence or a non-coding sequence associated with the target gene, a decreased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, or an equal activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the composition comprises an antagonist or an inhibitor of the component of an immune checkpoint, wherein the antagonist or the inhibitor disrupts or blocks an immune checkpoint in an immune cell.

[066] In certain embodiments of methods of treating cancer of the disclosure, the antagonist or the inhibitor of the component of an immune checkpoint comprises, the composition comprises, or the second composition comprises a nucleic acid sequence that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, wherein the duplex is depleted from the cancer cell. In certain embodiments, the antagonist or the inhibitor of the component of an immune checkpoint comprises, the composition comprises, or the second composition comprises an antisense RNA, a short hairpin RNA (shRNA), an interfering RNA (RNAi), a small interfering RNA (siRNA), a piwi RNA (piRNA), a microRNA (miRNA) or combination thereof that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or

RNA/DNA duplex, wherein the duplex is depleted from the cancer cell.

[067] In certain embodiments of methods of treating cancer of the disclosure, the antagonist or the inhibitor of the component of an immune checkpoint comprises, the composition comprises, or the second composition comprises a nucleic acid sequence that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, wherein the duplex is depleted from the cancer cell. In certain embodiments, the antagonist or the inhibitor of the component of an immune checkpoint comprises, the composition comprises, or the second composition comprises a guide RNA (gRNA) that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint. In certain embodiments, the gRNA is a single-stranded gRNA (sgRNA). In certain embodiments, the gRNA is operably linked to an effector. In certain embodiments, the effector comprise a nuclease or a nuclease domain. In certain embodiments, the nuclease or a nuclease domain comprises a sequence isolated or derived from a RNA-guided DNA endonuclease enzyme associated with CRISPR, a transcription activator-like effector nucleases (TALEN), a zinc-finger nuclease (ZFN), an endonuclease or a type IIS endonuclease. In certain embodiments, the RNA-guided DNA endonuclease enzyme associated with CRISPR comprises Cas9. In certain

embodiments, the nuclease or a nuclease domain induces a single-strand break in a coding sequence or a non-coding sequence associated with the target gene. In certain embodiments, the nuclease or a nuclease domain induces a double-strand break in a coding sequence or a non-coding sequence associated with the target gene.

[068] In certain embodiments of methods of treating cancer of the disclosure, the antagonist or the inhibitor of the component of an immune checkpoint comprises, the composition comprises, or the second composition comprises a nucleic acid sequence that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, wherein the duplex is depleted from the cancer cell. In certain embodiments, antagonist or the inhibitor of the component of an immune checkpoint comprises, the composition comprises, or the second composition comprises a short hairpin RNA (shRNA) that hybridizes with a coding sequence or a non- coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, wherein the duplex is depleted from the cancer cell.

[069] In certain embodiments of methods of treating cancer of the disclosure, the antagonist or the inhibitor of the component of an immune checkpoint comprises, the composition comprises, or the second composition comprises a small molecule that binds a coding sequence or non-coding sequence associated with the component of an immune checkpoint, wherein the binding of the small molecule to the sequence associated with the component of an immune checkpoint reduces or inhibits transcription or translation of a coding sequence or non-coding sequence associated with the component of an immune checkpoint. In certain embodiments, the small molecule comprises an organic small molecule. In certain embodiments, the small molecule comprises an inorganic small molecule.

[070] In certain embodiments of methods of treating cancer of the disclosure, the antagonist or the inhibitor of the component of an immune checkpoint comprises, the composition comprises, or the second composition comprises a small molecule that binds a component of an immune checkpoint, wherein the binding of the small molecule to the component of an immune checkpoint reduces or inhibits an activity of the component of an immune checkpoint. In certain embodiments, the small molecule comprises an organic small molecule. In certain embodiments, the small molecule comprises an inorganic small molecule.

[071] In certain embodiments of methods of treating cancer of the disclosure, the antagonist or the inhibitor of the component of an immune checkpoint comprises, the composition comprises, or the second composition comprises a protein that binds a coding sequence or non-coding sequence associated with the component of an immune checkpoint, wherein the binding of the protein to the sequence associated with the component of an immune checkpoint reduces or inhibits transcription or translation of a coding sequence or non-coding sequence associated with the component of an immune checkpoint. In certain embodiments, the composition comprises an antibody, an antibody fragment or an antibody mimetic. In certain embodiments, the antibody comprises a monoclonal antibody. In certain embodiments, the monoclonal antibody is a human monoclonal antibody or a humanized monoclonal antibody. Exemplary antibody mimetics of the disclosure comprise or consist of an organic compound that specifically binds a target sequence and has a structure distinct from a naturally-occurring antibody. Antibody mimetics may comprise or consist of a protein, a nucleic acid, or a small molecule. Antibody mimetics may comprise or consist of an affibody, an afflilin, an affimer, an affitin, an alphabody, an anticalin, an avimer, a DARPin, a Fynomer, a Kunitz domain peptide, or a monobody.

[072] In certain embodiments of methods of treating cancer of the disclosure, the antagonist or the inhibitor of the component of an immune checkpoint comprises, the composition comprises, or the second composition comprises a protein that binds the component of an immune checkpoint and wherein the binding of the protein to the component of an immune checkpoint reduces or inhibits an activity of the component of an immune checkpoint. In certain embodiments, the composition or the second composition comprises an antibody, an antibody fragment or an antibody mimetic. In certain embodiments, the antibody comprises a monoclonal antibody. In certain embodiments, the monoclonal antibody is a human monoclonal antibody or a humanized monoclonal antibody. In certain embodiments, the composition comprises an antibody, an antibody fragment or an antibody mimetic.

Exemplary antibody mimetics of the disclosure comprise or consist of an organic compound that specifically binds a target sequence and has a structure distinct from a naturally- occurring antibody. Antibody mimetics may comprise or consist of a protein, a nucleic acid, or a small molecule. Antibody mimetics may comprise or consist of an affibody, an afflilin, an affimer, an affitin, an alphabody, an anticalin, an avimer, a DARPin, a Fynomer, a Kunitz domain peptide, or a monobody.

[073] In certain embodiments of methods of treating cancer of the disclosure, the antagonist or the inhibitor of the component of an immune checkpoint comprises, the composition comprises, or the second composition comprises a protein that binds a coding sequence or non-coding sequence associated with the component of an immune checkpoint, wherein the binding of the protein to the sequence associated with the component of an immune checkpoint reduces or inhibits transcription or translation of a coding sequence or non-coding sequence associated with the component of an immune checkpoint. In certain embodiments, the composition comprises an aptamer. In certain embodiments, the aptamer comprises an amino acid sequence.

[074] In certain embodiments of methods of treating cancer of the disclosure, the antagonist or the inhibitor of the component of an immune checkpoint comprises, the composition comprises, or the second composition comprises a protein that binds the component of an immune checkpoint and wherein the binding of the protein to the component of an immune checkpoint reduces or inhibits an activity of the component of an immune checkpoint. In certain embodiments, the composition comprises an aptamer. In certain embodiments, the aptamer comprises an amino acid sequence.

[075] In certain embodiments of methods of treating cancer of the disclosure, the component of an immune checkpoint is selected from the group consisting of cytotoxic T- lymphocyte-associated protein 4 (CTLA-4), programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1).

[076] In certain embodiments of the methods of the disclosure, the component of an immune checkpoint is CTLA-4 and the antagonist or the inhibitor of the component of an immune checkpoint comprises Tremelimumab or Ipilumamab. In certain embodiments, the antagonist or the inhibitor of the component of an immune checkpoint comprises

[077] In certain embodiments of methods of treating cancer of the disclosure, the component of an immune checkpoint is PD-L1 and the antagonist or the inhibitor of the component of an immune checkpoint comprises Atezolizumab.

[078] In certain embodiments of the compositions of the disclosure, the component of an immune checkpoint is PD-1 and the antagonist or the inhibitor of the component of an immune checkpoint comprises Nivolumab or Pembrolizumab. In certain embodiments, the antagonist or the inhibitor of the component of an immune checkpoint comprises Nivolumab. In certain embodiments, the antagonist or the inhibitor of the component of an immune checkpoint comprises Pembrolizumab.

[079] In certain embodiments of methods of treating cancer of the disclosure, including those wherein the subject is identified as having an increased level of expression or an increased activity level of a coding sequence or a non-coding sequence associated with the target gene, an increased activity level of the target protein encoded by the target gene, an equal level of expression or an equal activity level of a coding sequence or a non-coding sequence associated with the target gene, an equal activity level of the target protein encoded by the target gene, a decreased level of expression or a decreased activity level of a coding sequence or a non-coding sequence associated with the target gene or an decreased activity level of the target protein encoded by the target gene, in at least one cancer cell compared to at least one non-cancer cell, the subject comprises a modification in a coding sequence or a non-coding sequence associated with the target gene. In certain embodiments, the modification is a mutation in the coding sequence or the non-coding sequence associated with the target gene. In certain embodiments, the mutation is a substitution, a deletion, an insertion, an inversion, a translocation or a combination thereof. In certain embodiments, the mutation is an inherited mutation. In certain embodiments, the mutation is a de novo mutation. In certain embodiments, the coding sequence or the non-coding sequence associated with the target gene is a genomic sequence. In certain embodiments, the coding sequence or the non-coding sequence associated with the target gene is a transcript. In certain embodiments, the modification is an epigenetic modification. In certain embodiments, the epigenetic modification is a methylation. In certain embodiments, the modification is a hypomethylation that results in an increased expression of the target gene.

[080] The disclosure provides a composition comprising: a therapeutically-effective amount of a first composition that specifically targets a target gene and a therapeutically-effective amount of a second composition that specifically targets a component of an immune checkpoint.

[081] In certain embodiments of the compositions of the disclosure, the target gene is selected from the group consisting of ADAM 10, ANPEP, CA1, CA2, CA9, CCL2, CD37, COL1A1, CXCL12, CXCR4, DDR2, DPP4, E2F1, ERBB2, F3, FAAH, FAP, GSTP1, IL7R, MMPl, MMPl 4, MMP2, MMP9, MPL, PDKl, PGR, PSENl, TK2B, RPS6KB1, SLC16A1, SLC3A2, SP1, TYRP1 and VEGFC.

[082] In certain embodiments of the compositions of the disclosure, the first composition comprises a nucleic acid sequence that hybridizes with a coding sequence or a non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, wherein the duplex is depleted from the cancer cell.

[083] In certain embodiments of the compositions of the disclosure, the first composition comprises an antisense RNA, a short hairpin RNA (shRNA), an interfering RNA (RNAi), a small interfering RNA (siRNA), a piwi RNA (piRNA), a microRNA (miRNA) or combination thereof that hybridizes with a coding sequence or a non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, wherein the duplex is depleted from the cancer cell.

[084] In certain embodiments of the compositions of the disclosure, the first composition comprises a guide RNA (gRNA) that hybridizes with a coding sequence or a non-coding sequence associated with the target gene. In certain embodiments, the gRNA is a single- stranded gRNA (sgRNA). In certain embodiments, the gRNA is operably linked to an effector. In certain embodiments, the effector comprise a nuclease or a nuclease domain. In certain embodiments, the nuclease or a nuclease domain comprises a sequence isolated or derived from a RNA-guided DNA endonuclease enzyme associated with CRISPR, a

Transcription activator-like effector nucleases (TALEN), a Zinc-finger nuclease (ZFN), an endonuclease or a Type IIS endonuclease. In certain embodiments, the RNA-guided DNA endonuclease enzyme associated with CRISPR comprises Cas9. In certain embodiments, the nuclease or a nuclease domain induces a single-strand break in a coding sequence or a non- coding sequence associated with the target gene. In certain embodiments, the nuclease or a nuclease domain induces a double-strand break in a coding sequence or a non-coding sequence associated with the target gene.

[085] In certain embodiments of the compositions of the disclosure, the first composition comprises a short hairpin RNA (shRNA) that hybridizes with a coding sequence or a non- coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, wherein the duplex is depleted from the cancer cell.

[086] In certain embodiments of the compositions of the disclosure, the first composition comprises an aptamer that specifically binds to a coding sequence or non-coding sequence associated with the target gene. In certain embodiments, the aptamer comprises a DNA sequence.

[087] In certain embodiments of the compositions of the disclosure, the first composition comprises an aptamer that specifically binds to the target protein encoded by the target gene. In certain embodiments, the aptamer comprises a DNA sequence.

[088] In certain embodiments of the compositions of the disclosure, the first composition comprises a protein that binds a coding sequence or non-coding sequence associated with the target gene, wherein the binding of the protein reduces or inhibits transcription or translation of a coding sequence or non-coding sequence associated with the target gene. In certain embodiments, the first composition comprises an antibody, an antibody fragment or an antibody mimetic. In certain embodiments, the antibody comprises a monoclonal antibody. In certain embodiments, the monoclonal antibody is a human monoclonal antibody or a humanized monoclonal antibody. Exemplary antibody mimetics of the disclosure comprise or consist of an organic compound that specifically binds a target sequence and has a structure distinct from a naturally-occurring antibody. Antibody mimetics may comprise or consist of a protein, a nucleic acid, or a small molecule. Antibody mimetics may comprise or consist of an affibody, an afflilin, an affimer, an affitin, an alphabody, an anticalin, an avimer, a DARPin, a Fynomer, a Kunitz domain peptide, or a monobody.

[089] In certain embodiments of the compositions of the disclosure, the first composition comprises a protein that binds a target protein encoded by the target gene, wherein the binding of the protein to the target protein reduces or inhibits an activity of the target protein encoded by the target gene. In certain embodiments, the first composition comprises an antibody, an antibody fragment or an antibody mimetic. In certain embodiments, the antibody comprises a monoclonal antibody. In certain embodiments, the monoclonal antibody is a human monoclonal antibody or a humanized monoclonal antibody. Exemplary antibody mimetics of the disclosure comprise or consist of an organic compound that specifically binds a target sequence and has a structure distinct from a naturally-occurring antibody. Antibody mimetics may comprise or consist of a protein, a nucleic acid, or a small molecule. Antibody mimetics may comprise or consist of an affibody, an afflilin, an affimer, an affitin, an alphabody, an anticalin, an avimer, a DARPin, a Fynomer, a Kunitz domain peptide, or a monobody.

[090] In certain embodiments of the compositions of the disclosure, the first composition comprises a protein that binds a coding sequence or non-coding sequence associated with the target gene, wherein the binding of the protein reduces or inhibits transcription or translation of a coding sequence or non-coding sequence associated with the target gene. In certain embodiments, the first composition comprises an aptamer that specifically binds to a coding sequence or non-coding sequence associated with the target gene. In certain embodiments, the aptamer comprises an amino acid sequence.

[091] In certain embodiments of the compositions of the disclosure, the first composition comprises a protein that binds a target protein encoded by the target gene, wherein the binding of the protein to the target protein reduces or inhibits an activity of the target protein encoded by the target gene. In certain embodiments, the first composition comprises an aptamer that specifically binds to the target protein encoded by the target gene. In certain embodiments, the aptamer comprises an amino acid sequence.

[092] In certain embodiments of the compositions of the disclosure, the first composition comprises a small molecule that binds a coding sequence or a non-coding sequence associated with the target gene, wherein the binding of the small molecule to the sequence associated with the target gene reduces or inhibits transcription or translation of a coding sequence or non-coding sequence associated with the target gene. In certain embodiments, the small molecule comprises an organic small molecule. In certain embodiments, the small molecule comprises an inorganic small molecule.In certain embodiments, the small molecule is a kinase inhibitor. In certain embodiments, the kinase inhibitor is abemaciclib,

acalabrutinib, afatinib, alectinib, axitinib, baricitinib, binimetinib, bosutinib,

brigatinib,cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, encorafenib, erlotinib, everolimus, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, midostaurin, neratinib, nilotinib, nintedanib, osimertinib, palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, ruxolitinib, sirolimus, sorafenib, sunitinib, temsirolimus, tofacitinib, trametinib, vandetanib or vemurafenib. In certain embodiments, the kinase inhibitor is dasatinib.

[093] In certain embodiments of the compositions of the disclosure, the first composition comprises a small molecule that binds a target protein encoded by the target gene, wherein the binding of the small molecule to the target protein reduces or inhibits an activity of the target protein encoded by the target gene. In certain embodiments, the small molecule comprises an organic small molecule. In certain embodiments, the small molecule comprises an inorganic small molecule.

[094] In certain embodiments of the compositions of the disclosure, the second composition comprises an antagonist or an inhibitor of the component of an immune checkpoint, wherein the antagonist or the inhibitor disrupts or blocks an immune checkpoint in an immune cell.

[095] In certain embodiments of the compositions of the disclosure, the second composition comprises a nucleic acid sequence that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, wherein the duplex is depleted from the cancer cell.

[096] In certain embodiments of the compositions of the disclosure, the second composition comprises an antisense RNA, a short hairpin RNA (shRNA), an interfering RNA (RNAi), a small interfering RNA (siRNA), a piwi RNA (piRNA), a microRNA (miRNA) or combination thereof that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or

RNA/DNA duplex, wherein the duplex is depleted from the cancer cell. In certain embodiments, the second composition comprises a guide RNA (gRNA) that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint. In certain embodiments, the gRNA is a single-stranded gRNA (sgRNA).In certain embodiments, the gRNA is operably linked to an effector. In certain embodiments, the effector comprise a nuclease or a nuclease domain. In certain embodiments, the nuclease or a nuclease domain comprises a sequence isolated or derived from a RNA-guided DNA endonuclease enzyme associated with CRISPR, a transcription activator-like effector nucleases (TALEN), a zinc-finger nuclease (ZFN), an endonuclease or a type IIS

endonuclease. In certain embodiments, the RNA-guided DNA endonuclease enzyme associated with CRISPR comprises Cas9. In certain embodiments, the nuclease or a nuclease domain induces a single-strand break in a coding sequence or a non-coding sequence associated with the component of an immune checkpoint. In certain embodiments, the nuclease or a nuclease domain induces a double-strand break in a coding sequence or a non- coding sequence associated with the component of an immune checkpoint.

[097] In certain embodiments of the compositions of the disclosure, the second composition comprises a short hairpin RNA (shRNA) that hybridizes with a coding sequence or a non- coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, wherein the duplex is depleted from the cancer cell.

[098] In certain embodiments of the compositions of the disclosure, the second composition comprises an aptamer that specifically binds to a coding sequence or a non-coding sequence associated with the component of an immune checkpoint. In certain embodiments, the aptamer comprises a DNA sequence.

[099] In certain embodiments of the compositions of the disclosure, the second composition comprises an aptamer that specifically binds to the component of an immune checkpoint. In certain embodiments, the aptamer comprises a DNA sequence.

[0100] In certain embodiments of the compositions of the disclosure, the second composition comprises a protein that binds a coding sequence or a non-coding sequence associated with the component of an immune checkpoint, wherein the binding of the protein to the sequence associated with the component of an immune checkpoint reduces or inhibits transcription or translation of a coding sequence or a non-coding sequence associated with the component of an immune checkpoint. In certain embodiments, the second composition comprises an antibody, an antibody fragment or an antibody mimetic. In certain embodiments, the antibody comprises a monoclonal antibody. In certain embodiments, the monoclonal antibody is a human monoclonal antibody or a humanized monoclonal antibody. Exemplary antibody mimetics of the disclosure comprise or consist of an organic compound that specifically binds a target sequence and has a structure distinct from a naturally-occurring antibody. Antibody mimetics may comprise or consist of a protein, a nucleic acid, or a small molecule. Antibody mimetics may comprise or consist of an affibody, an afflilin, an affimer, an affitin, an alphabody, an anticalin, an avimer, a DARPin, a Fynomer, a Kunitz domain peptide, or a monobody.

[0101] In certain embodiments of the compositions of the disclosure, the second composition comprises a protein that binds the component of an immune checkpoint, wherein the binding of the protein to the component of an immune checkpoint reduces or inhibits an activity of the component of an immune checkpoint. In certain embodiments, the second composition comprises an antibody, an antibody fragment or an antibody mimetic. In certain

embodiments, the antibody comprises a monoclonal antibody. In certain embodiments, the monoclonal antibody is a human monoclonal antibody or a humanized monoclonal antibody. Exemplary antibody mimetics of the disclosure comprise or consist of an organic compound that specifically binds a target sequence and has a structure distinct from a naturally- occurring antibody. Antibody mimetics may comprise or consist of a protein, a nucleic acid, or a small molecule. Antibody mimetics may comprise or consist of an affibody, an afflilin, an affimer, an affitin, an alphabody, an anticalin, an avimer, a DARPin, a Fynomer, a Kunitz domain peptide, or a monobody.

[0102] In certain embodiments of the compositions of the disclosure, the second composition comprises a protein that binds a coding sequence or non-coding sequence associated with the component of an immune checkpoint, wherein the binding of the protein to the sequence associated with the component of an immune checkpoint reduces or inhibits transcription or translation of a coding sequence or a non-coding sequence associated with the sequence associated with the component of an immune checkpoint. In certain embodiments, the second composition comprises an aptamer that specifically binds to a coding sequence or non-coding sequence associated with the sequence associated with the component of an immune checkpoint. In certain embodiments, the aptamer comprises an amino acid sequence.

[0103] In certain embodiments of the compositions of the disclosure, the second composition comprises a protein that binds the component of an immune checkpoint, wherein the binding of the protein to the component of an immune checkpoint reduces or inhibits an activity of the component of an immune checkpoint. In certain embodiments, the second composition comprises an aptamer that specifically binds to the component of an immune checkpoint. In certain embodiments, the aptamer comprises an amino acid sequence. [0104] In certain embodiments of the compositions of the disclosure, the second composition comprises a small molecule that binds a coding sequence or a non-coding sequence associated with the component of an immune checkpoint, wherein the binding of the small molecule to the sequence associated with the component of an immune checkpoint reduces or inhibits transcription or translation of a coding sequence or a non-coding sequence associated with the component of an immune checkpoint. In certain embodiments, the small molecule comprises an organic small molecule. In certain embodiments, the small molecule comprises an inorganic small molecule.

[0105] In certain embodiments of the compositions of the disclosure, the second composition comprises a small molecule that binds a component of an immune checkpoint, wherein the binding of the small molecule to the component of an immune checkpoint reduces or inhibits an activity of the component of an immune checkpoint. In certain embodiments, the small molecule comprises an organic small molecule. In certain embodiments, the small molecule comprises an inorganic small molecule.

[0106] In certain embodiments of the compositions of the disclosure, the component of an immune checkpoint is selected from the group consisting of cytotoxic T-lymphocyte- associated protein 4 (CTLA-4), programmed death-ligand 1 (PD-L1) and programmed death- 1 (PD-1).

[0107] In certain embodiments of the methods of the disclosure, the component of an immune checkpoint is CTLA-4 and the antagonist or the inhibitor of the component of an immune checkpoint comprises Tremelimumab or Ipilumamab. In certain embodiments, the antagonist or the inhibitor of the component of an immune checkpoint comprises

[0108] In certain embodiments of the compositions of the disclosure, the component of an immune checkpoint is PD-L1 and the antagonist or the inhibitor of the component of an immune checkpoint comprises Atezolizumab.

[0109] In certain embodiments of the compositions of the disclosure, the component of an immune checkpoint is PD-1 and the antagonist or the inhibitor of the component of an immune checkpoint comprises Nivolumab or Pembrolizumab. In certain embodiments, the antagonist or the inhibitor of the component of an immune checkpoint comprises Nivolumab. In certain embodiments, the antagonist or the inhibitor of the component of an immune checkpoint comprises Pembrolizumab. [0110] In certain embodiments of the compositions of the disclosure, the first composition or the second composition is administered systemically. In certain embodiments, the first composition or the second composition is administered intravenously. In certain

embodiments, the first composition or the second composition is administered orally.

[0111] In certain embodiments of the compositions of the disclosure, the first composition or the second composition is administered simultaneously. In certain embodiments, the first composition or the second composition is administered sequentially. In certain embodiments, the first composition is administered before the second composition.

BRIEF DESCRIPTION OF THE DRAWINGS

[0112] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0113] Figure 1 A-D is a series of schematic diagrams, photographs and a bar graph showing exemplary steps to derivation of the NA13 cell line. Figure 1A is a schematic of experimental design for assessing bladder tumor incidence. C57BL/6J mice were started on OH-BBN approximately 5 wks after weaning. Figure IB is a series of photographs depicting micro Computed Tomography (mCT) scans, necropsy images, and histological preparations collected at 24 weeks corresponding to the timeline shown in Figure 1A. Arrows represent bladder wall in i-iv and basement membrane in v, L=lumen of bladder. Images i, iii, and v are all of a noninvasive bladder tumor, while ii, iv, and vi are of invasive tumor. Figure 1C is a schematic diagram depicting tumors that were excised and adapted to in vitro cell culture as previously described. The NA13 cell line was derived from an invasive tumor was further developed for experimental studies. Figure ID is a bar graph showing the results of treatment of C57BL/6 mice with NA13 tumors with immune checkpoint blockade. At 8 days post injection 40 mice with measurable tumors were randomized into 4 groups of 10 each and subjected to indicated mAb at 3 day intervals, starting on day 8 (arrows).

[0114] Figure 2 is a schematic diagram depicting an exemplary series of steps taken to identify one or more targets of an immuno-oncology therapeutic of the disclosure.

[0115] Figure 3A-B is a schematic diagram and a corresponding bar graph depicting expression of CCL2 in various tissues in a subject with bladder cancer. Figure 3 A is a schematic diagram depicting an analysis of CCL2 expression in human bladder cancer patient datasets comparing muscle invasive to non-muscle invasive using the Bladder Cancer Biomarker Evaluation Tool (BC-BET). Figure 2B is a bar graph showing CCL2 mRNA expression by qPCR is dramatically increased in bladder tumors relative to normal bladder cells. Values normalized to beta-actin. EB represent SEM.

[0116] Figure 4A-B is a pair of graphs showing that a combination therapy with CCR2 antagonist and aCTLA4 antibody inhibits tumor growth. Treatment of C57BL/6 mice with lxl 0⁶ NA13 tumors with immune checkpoint blockade. Figure 4A depicts the results of a study in which 2mg/kg CCR2 antagonist or vehicle control injected intraperitonally starting from day 0. At 22 days post injection, mice were subsequently treated with 25μg aCTLA or IgG control, as indicated by arrows. Figure 4B depicts the results of a study in which 2mg/kg CCR2 antagonist or vehicle control, and 5C^g aCTLA or IgG control, as indicated by arrows, injected intraperitonally starting from day 14. Mean +/- SD.

[0117] Figure 5A-B is a pair of graphs depicting tumor volume as a function of days post- injection with either vehicle control and IgG or aPD-1 or a CCR2 antagonist and IgG or aPD- 1. lxlO⁶ NA13 bladder cancer cells were injected into the right hind flank of C57BL/6 mice. A combination therapy with CCR2 small molecule antagonist and aPD-1, or a control "therapy" was started on day 14 post injection, once tumors were 3-4mm in diameter. Mice were treated three times with only 5C^g of aPD-1, which is ¼ of the standard 20C^g commonly utilized in murine studies. Arrow indicates the dates in which aPD-1 or IgG were given to the mice. Figure 5A and 5B represent two independent experiments.

[0118] Figure 6A-B is a series of graphs showing an exemplary immune cell profile. Figure 6A depicts an exemplary immune cell profile of splenic and tumor infiltrating lymphocytes and myeloid cells. Figure 6B depicts an exemplary immune cell profile of monocytic myeloid-derived suppressor cells (MDSCs).

[0119] Figure 7A-D is a series of graphs depicting levels of DDR2 expression in samples obtained from subjects having bladder cancer. Figure 7 A depicts a Kaplein-Meyer survival curve comparing bladder cancer patients with high and low DDR2 expression from TCGA dataset. Figure 7B depicts the results of a qPCR analysis of NA13 cells with shRNA - mediated knockdown of DDR2. Figure 7C depicts the results of treatment in a mouse model, lxl 0⁶ shControl or shDDR2 NA13 cells were injected subcutaneously into the hind flank of 7-8 week old female C57BL6/J mice. Starting at day 21, mice were given four treatments of 5C^g of aCTLA4, aPD-1, or aPD-Ll in three day intervals. Figure 7D depicts the results of treatment in a mouse model. lxlO⁶ shDDR cells were injected subcutaneously into the hind flank of 7-8 week old female C57BL6/J mice. Starting at day 21, mice were given four treatments of 5C^g of aCTLA4, aPD-1, or aPD-Ll in three day intervals. Mean +/- SD.

[0120] Figure 8A-B is a series of graphs depicting levels of gene expression in samples obtained from subjects having bladder cancer. Figure 8 A depicts the shRNA -mediated knockdown of Gene B in NA13 bladder cell line quantified by qPCR prior to inoculation of C57BL6/J mice (as shown in Figures 8B and 8C). Figure 8B depicts the results of treatment of a mouse tumor model with control or lxlO⁶ NA13 shControl or shGene B were injected into the right hind flank of C57BL/6 mice. Immunotherapy with 5C^g of aCTLA4, aPD-1, or aPD-Ll was started on day 21 post injection, once tumors were >5mm in diameter. Mice were treated three times with only 5C^g of aCTLA4, aPD-1, or aPD-Ll, which is ¼ of the standard 20C^g commonly utilized in murine studies. Arrow indicates the dates in which immune checkpoint antibodies or IgG were given to the mice.

[0121] Figure 9A is a schematic depicting the use of a lentiviral pool containing the 34 gene druggable shRNA library to identify genes that when knocked-down, confer enhanced response with anti-PD-1 immunotherapy.

[0122] Figure 9B is a graph ranking genes based on the proportion of their reduction in cognate shRNAs relative to the total shRNAs per gene.

[0123] Figure 9C is a graph depicting the normalized fold change of the most-reduced shRNA versus the second-most-reduced shRNA9.

[0124] Figure 9D is a graph depicting the number of shRNAs targeting each gene that are found in the top 15% of most-reduced shRNAs overall9.

[0125] Figure 10A is an image depicting an immunoblot of NA13 cells transduced with two different DDR2 shRNAs with graph showing densitometric analysis of DDR2 protein levelsFigure 10B is a graph depicting subcutaneous tumour growth in syngeneic mice receiving NA13 shDDR2 #1 cells stably expressing shControl or shDDR2 (n = 4-5 mice per group) Mean ± s.e.m. ***P < 0.001, ****P<0.0001.

[0126] Figure IOC is an image depicting an immunoblot of B16F10 cells with shControl or shDDR2 construct.

[0127] Figure 10D are representative images of murine pulmonary lung metastases at 22 days following intravenous (tail vein) inoculation of B16F10 cells.

[0128] Figure 10E is a plot depicting lung weight of mice bearing B16F10 lung metastases (n = 9 mice per group) Mean ± s.e.m. *P < 0.05.

[0129] Figure 10F is an image depicting an immunoblot of E0771 cells with shControl or shDDR2 construct and a graph showing denisitometric analysis. [0130] Figure 10G is a waterfall plot showing change in E0771 mammary fat pad tumour volume compared to baseline prior to treatment.

[0131] Figure 10H is a series of graphs depicting E0771 mammary tumour volume as a function of time for each mouse, (n = 8-9 mice per group).

[0132] Figure 11 A is a graph depicting RNAseq analysis performed comparing shControl and shDDR2 NA13 tumours grown in syngeneic mice treated with anti-PD-1. Summarized GSEA results for significantly (FDR < 0.01) up-regulated, immune-related gene sets from the canonical pathways v6.1 gene set collectionl6. Gene sets are grouped and coloured according to primary function. The coloured tick marks represent a gene for a given gene set. Genes are ranked according to differential expression of the RNA seq data. False discovery rate (FDR) corrected q-values and Normalized Enrichment Scores (NES) are reported for gene set.

[0133] Figure 1 IB is an image depicting PhenoGraph-defined cellular distribution and clustering, as defined by tSNEl and tSNE2, colored by cluster ID for all treatment conditions. The frequency of cluster #15 (defined as CD3+ CD8+ MHCII-) for each experimental condition is shown. Data shows all normalized viable single cells, subjected to the PhenoGraph algorithm.

[0134] Figure 12A is a waterfall plot of NA13 tumour volume in response to dasatinib and anti-PD-1 treatment relative to pre-treatment baseline (prior to anti-PD-1 treatment) (n = 5-6 mice per group).

[0135] Figure 12B is a graph depicting the average MC38 tumour volume in response to dasatinib and anti-PD-1.

[0136] Figure 12C is a graph showing individual tumour volumes of mice shown in b (n = 8 mice per group).

[0137] Figure 12D is a graph depicting PhenoGraph-defined cellular distribution and clustering, as defined by tSNEl and tSNE2, colored by cellular phenotype for all treatment conditions of MC38 tumours. Data shows all normalized viable single cells, subjected to the PhenoGraph algorithm.

[0138] Figure 12E is a series of graphs depicting the frequency of all statistically significant PhenoGraph identified clusters compared to Vehicle + IgG-treated organized according to cluster phenotypic designation. Mean ± s.e.m. *P < 0.05, ***P < 0.001, ****P < 0.0001.

[0139] Figure 12F is a graph depicting TCR clonality in MC38 tumour samples (n = 3 per group), where clonality=0 represents equal distribution across clones, and clonality=l represents total enrichment of only one clone. Mean ± s.e.m. [0140] Figure 12G is a graph depicting relative abundance of tumour-infiltrating immune cell populations determined by the CIBERSORT methodology21 in bladder cancer patients from RNAseq data in the TCGA (n = 433) as a function of DDR2 expression. ***P < 0.001, ****P < 0.0001.

[0141] Figure 13A-C is a series of graphs depicting shRNA-mediated knockdown of DDR2 expression. qPCR analysis of (A) NA13 shControl (shCtrl), and shDDR2 #1 and #2. (B) B16F10 shCtrl and shDDR2. (C) E0771 shCtrl and shDDR2.

[0142] Figure 14 is a series of images depicting histological comparison of lungs from B16F10 tumour-bearing mice. Representative H&E images from the lungs of mice injected intravenously with B16F10 to form pulmonary metastases. T, tumour; N, necrosis; If, inflammation; Br, bronchiole; V, vein.

[0143] Figure 15A is a graph depicting spleen from NA13 tumour-bearing mice analysed using CyTOF with PhenoGraph algorithm. PhenoGraph-defined cellular distribution and clustering, as defined by tSNEl and tSNE2, coloured by phenotype designation for each experimental condition (data pooled from n =5-6 mice per group). Data shows all normalized viable single cells, subjected to the PhenoGraph algorithm.

[0144] Figure 15B is a series of pie charts show the cellular distribution of 29 PhenoGraph defined clusters coloured according to phenotypic designation.

[0145] Figure 15C is a graph depicting the frequency of events across 29 PhenoGraph defined clusters for each experimental condition. Each coloured number represents the phenotype which these clusters fall into.

[0146] Figure 16A is a series of graphs depicting spleen from MC38 tumour-bearing mice analysed using CyTOF with PhenoGraph algorithm. PhenoGraph-defined cellular distribution and clustering, as defined by tSNEl and tSNE2, coloured by cellular phenotype for all treatment conditions (n = 4 mice per group). Data shows all normalized viable single cells, subjected to the PhenoGraph algorithm.

[0147] Figure 16B is a graph depicting frequency of all 29 PhenoGraph identified clusters, colored according to experimental group and cluster's primary phenotype designation.

[0148] Figure 16C is a graph depicting the frequency of all statistically significant

PhenoGraph identified clusters compared to Vehicle + IgG organized according to cluster phenotypic designation. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

[0149] Figure 17A-E is a series of graphs depicting the quantification of immune cell populations in bladder cancer patients with varying DDR2 expression levels. A) Distribution of DDR2 expression in quartiles. B-E) Relative abundance of tumour-infiltrating immune cell populations determined by CIBERSORT methodology21 in bladder cancer patients from RNAseq data in the TCGA (n = 433). DDR2 expression, either low (less than 25%) or high (greater than 75%) is shown as a function of CIBERSORT population estimates at varing scales described below. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. B) From left to right, abundance of tumour-infiltrating immune cell populations is significantly different in DDR2 low versus high expressing Memory B cells (****; Y-axis scale from 0 to 4 in increments of 2), Naive B cells (****; Y-axis scale from 0 to 12 in increments of 3), Naive CD4 T cells (****; Y-axis scale from 0 to 10 in increments of 5), and Memory resting CD4 T cells (****; Y-axis scale from 0 to 4 in increments of 2), C) From left to right, relative abundance of tumour-infiltrating immune cell populations in DDR2 low versus high expressing Resting NK Cells (*, Y-axis scale from 0 to 6 in increments of 2), Gamma Delta T Cells (Y-axis scale from 0 to 60 in increments of 20), Neutrophils (*, Y-axis scale from 0 to 9 in increments of 3), Activated NK Cells (Y-axis scale from 0 to 4 in increments of 2), and Monocytes (Y-axis scale from 0 to 6 in increments of 2), D) From left to right, relative abundance of tumour-infiltrating immune cell populations in DDR2 low versus high expressing Resting Dendritic Cells (Y-axis scale from 0 to 12.5 in increments of 2.5), Activated Mast Cells (Y-axis scale from 0 to 15 in increments of 5), Resting Mast Cells (Y- axis scale from 0 to 10 in increments of 2.5), Eosinophils (Y-axis scale from 0 to 50 in increments of 10), and Memory Activated CD4 T Cells (Y-axis scale from 0 to 15 in increments of 5), and E) From left to right, relative abundance of tumour-infiltrating immune cell populations in DDR2 low versus high expressing Plasma Cells (Y-axis scale from 0 to 6 in increments of 2), M0 Macrophages (Y-axis scale from 0 to 7.5 in increments of 2.5), and Regualtory T Cells (Y-axis scale from 0 to 6 in increments of 2).

DETAILED DESCRIPTION OF THE DISCLOSURE

[0150] The present disclosure provides compositions and methods for improving the effectiveness of immunotherapy in cancer.

[0151] The compositions and methods of the disclosure use functional genomics to discover how to improve the effectiveness of immunotherapy in cancer. Existing therapies, including for example, Immune Checkpoint Blockade (ICB), is associated with only a 35% complete response (CR) rates in, for example, metastatic bladder cancer (BC). Thus, the compositions and methods of the disclosure elucidate one or more mechanisms limiting the effectiveness of existing therapies (including, but not limited to ICBs) to increase the CR rate to at least 95%.

[0152] Treating BC with immunotherapy such as intravesical instillation of Bacillus Calmette Guerin mycobacterium bovis (BCG) has been the standard of care (SOC) since the 1980's. More recently, Atezolizumab (Roche), a PD-L1 inhibiting mAb, was FDA approved in 2016 for patients with platinum-refractory metastatic BC. The PD-1 mAb Nivolumab (Bristol- Myers Squibb (BMS)), currently FDA approved for several tumors, is in Phase III studies for advanced bladder cancer (NCT02632409), and is also being tested in combination with the CTLA-4 mAb, Ipilimumab (BMS). The PD-L1 targeted mAb Durvalumab (AstraZeneca (AZ)) is in trials for bladder cancer with or without the CTLA-4 mAb Tremelimumab (AZ) (NCT02516241). Taken together, the overall CR rate for these existing immunotherapies remains constant at about 35% in metastatic BC, and in most cases, this CR rate is achieved using high mAb doses (e.g., greater than 3 mg/kg), leading to grade 3 and 4 immune-related adverse events.

[0153] The methods of the disclosure apply a functional genomic synthetic lethal screen in vivo and have identified novel genes/pathways that, when blocked in combination with ICB, greatly increase the cure rate in animal models. Methods of the disclosure use lower doses of ICB reagents, which reduces negative side effects of this therapy. The novel genes identified using the methods of the disclosure have never been implicated with response to, or associated with ICB therapy. Since it is very likely that ICB will become first line standard of care (SOC) therapy in most patients with metastatic cancer in the next 3-5 years, the compositions and methods of the disclosure have fundamental ramifications for cancer medicine.

[0154] Using the compositions and methods of the disclosure, 34 gene targets have been identified, that when genetically depleted (by, for example, short hairpin RNA (shRNA)) in conjunction with ICB, enhance cellular destruction of cancer. Two of these genes are used for more detailed examples because drugs that block their function are publicly available from companies that also market ICB reagents (both owned by Bristol Myers Squibb). Thus, the data provided in this disclosure can be translated to the clinic very rapidly. These two genes are DDR2 (Discoidin Domain Receptor Tyrosine Kinase 2) and CCL2 (C-C motif ligand 2).

[0155] DDR2 is inhibited by Dasatinib, a drug that inhibits several kinases. The data provided herein indicate that administration of a composition comprising a therapeutically effective amount of Dasatinib and a composition comprising a therapeutically effective amount of an ICB would raise the cure rate from 35% to at least 95% for subjects having metastatic bladder cancer. The data provided herein are translatable to other common tumor types such as breast, lung, colon and the neuroendocrine subtype of prostate cancer (the most aggressive and lethal form), each of which often have DDR2 alterations (overexpression, amplification and mutations), and I which DDR2 may be a driver of an aggressive phenotype of each tumor.

[0156] To assess tumor responses in an immune competent animal, several new cell line models of murine BC derived from chemically induced C57BL/6 tumors that are known to have molecular characteristics similar to those found in human BC were generated. Tumors were excised from BBN-treated mice and adapted to in vitro cell culture to generate the NA13 cell line (Fig. 1 A-C). The NA13 line generated using the methods of the disclosure has several advantages over the two other commonly used mouse syngeneic BC lines (MB49 and MBT2): 1) slow growth kinetics consistent with human bladder cancer; 2) large inoculate (2- 5 million cells) required for tumor formation allowing for excellent coverage when using functional genomic libraries; 3) sensitivity to ICB; 4) poor vascularization which limits contaminating blood immune cells that can confound analyses; 5) solid and uniform tumor architecture allowing for better multiplexed IHC. NA13 tumors are not T cell inflamed, a finding similar to human BC, with less than 1% of cells being positive for T cell markers (CD3 by IHC and CD4/CD8 by FACS). Treatment of established NA13 tumors with ICB (mAb PD-1, PD-L1, CTLA-4) led to a CR in about 40% of mice (Fig. ID).

[0157] Using NA13 and other syngeneic BC models generated by the methods of the disclosure, in vivo synthetic lethal screens were performed to identify genes whose depletion, using short hairpin RNA (shRNA) technology, leads to enhanced immune-mediated cell death when used in combination with ICB.

[0158] To develop a therapeutically actionable shRNA library, a listing of all cancer clinical trials available in clinicaltrials.gov (Fig. 2) was generated. Using the portal below, the word "cancer" was entered in the "Condition/Disease" field. A resultant list of 52,502 trials/entries were downloaded from clinicaltrials.gov. The name of the drug used in each trial was bioinformatically extracted and the target type of each drug (e.g., protein, DNA, protein complex) was then determined through a literature search. Drugs which targeted an individual protein were filtered, and a list of those unique individual proteins (and their corresponding genes) was generated (614 genes). Next, to generate the most clinically relevant library, the mRNA expression level of each gene was analyzed in 8 bladder cancer patient datasets (N=>500 patients). Genes whose high expression had at least one negative association with clinical outcome (e.g., tumor vs normal, stage, grade, and survival (HR>1)) were moved forward. The top 200 genes from this filter, the genes with the highest frequency of negative associations, were designated as the gene candidates for the shRNA library. Of these, 192 had a mouse ortholog and mouse versions of the shRNAs available and these 192 gene candidates were used to make the library with 3-5 shRNA per gene (Fig. 2).

[0159] Each shRNA was then introduced into lentiviral vectors and a pooled lentivirus inoculum was used to infect NA13 cells in vitro. NA13 cells selected for harboring this 'drug target' shRNA library were injected subcutaneously into mice and when tumors were detected, treated with ICB mAb. Any NA13 cells which contain a shRNA which is synthetic lethal with ICB should be lost from the tumor mass. Through examination of the excised tumors after ICB with next generation sequencing (NGS), it was determined which shRNAs are present in isotype controls but have been lost because of ICB. From this initial screen, 34 of the 192 genes were identified as being synthetic lethal with ICB. To confirm the synthetic lethal role of these genes in combination with ICB, a shRNA sub-library targeting these 34 genes was constructed. This library was used to repeat the experiment described above with the 192 gene shRNA library. Following these confirmatory experiments, two gene targets, CCL2 and DDR2, were chosen for a more in-depth investigation because of their broad relevance and implication in growth and progression of multiple tumor types. Furthermore, these two genes have drugs that block the function of the corresponding proteins in clinical trials or in clinical use. Of equal importance, one of the companies that also has ICB reagents, Bristol Myers Squibb, has both CCL2 and DDR2 targeting agents and thus, this data can be translated to the clinic very rapidly.

[0160] CCL2 is a chemokine which interacts with the CCR2 receptor present on the cell surface of immune cells. It plays a crucial role in regulating the migration and infiltration of monocytes/macrophages, basophils, memory T cells, and NK cells. The CCL2-CCR2 interaction has a pro-tumorigenic role in various cancers due to their ability to recruit suppressive immune subsets such as tumor-associated macrophages (TAMs) and myeloid- derived suppressor cells (MDSCs). Furthermore, they are also involved in the preferential differentiation of precursor immune cells into the immunosuppressive M2 macrophages and Treg cells. CCL2 is upregulated in patients with locally advanced BC in all 12 patient data sets (average 2.48 fold increase; p=0.007) available through BC-BET, an online diagnostic and prognostic gene expression biomarker tool for bladder cancer (Fig. 3A). Expression analysis of NA13 and MB49 tumors also revealed a dramatic increase in CCL2 expression relative to normal bladder (Fig. 3B) and that depletion of CCL2 from MB49 cells or blocking the cognate receptor on macrophages suppresses the ability of MB49 cells to colonize mouse lungs. Of note, in vivo growth enhances CCL2 upregulation, suggesting that interaction with the tumor microenvironment leads to enhanced upregulation, compared to in vitro baseline levels. Preliminary data from combination therapy of RS504393, a CCR2 antagonist, and aCTLA4 revealed a synergistic effect (Fig. 4A and B), providing strong support for combining anti-CCL2 therapy with ICB. The double control and single treatment groups showed minimal differences in tumor growth hindrance. In contrast, treatment with both a CCL2 antagonist and aCTLA antibody reduced tumor growth rate and size at comparable dates. Immune profiling of tumor infiltrating lymphocytes and myeloid cells reveals that combination therapy leads to a more immune active microenvironment with statistically significant increases in the anti-tumor NK cell population and trending increases in Ml macrophages, while at the same time decreasing the pro-tumor M2 macrophages (Fig 6A). These differences are not observed in the splenic population suggesting that the response is specific to the tumor microenvironment and not systemic. There is also a trending decrease in the percentage of immunosuppressive monocytic MDSCs within the tumor (Fig. 6B).

[0161] Another gene of interest from this screen is DDR2, discoidin domain receptor tyrosine kinase 2, which plays a role in cell communication and is involved in cell growth, differentiation and metabolism. Clinically, high expression of DDR2 is associated with worse overall survival in bladder cancer patients (Fig. 7 A). NA13 cells with shRNA-mediated knockdown of DDR2 (Fig. 7B) were injected into mice and treated with combination ICB therapy of 5C^g aCTLA4, aPD-1, or aPD-Ll (Fig. 7C-D). Treatment with any of the three ICB reagents resulted in drastic reductions in tumor growth, compared to IgG control and treatment of shControl cells. Very importantly, the ICB dose of 5C^g used in this study is significantly lower than the commonly reported 20C^g used in murine studies. At such low dose, no effect is seen in shControl cells, but is greatly enhanced when DDR2 expression is knocked-down. These observations suggest a strong synergism with tremendous potential for patients who are non-responsive to ICB, exhibit intolerance or develop autoimmunity to current dosing regimens, or are unable to complete treatment programs due to the severity of their immune-related adverse events.

[0162] Single gene validation of two of our synthetic lethal gene hits from our library screen have proven to be synergistic with ICB and allow for reduced dosing of ICB reagents required for tumor cure. This data indicates that the 34 genes identified herein exhibit similarly favorable therapeutic characteristics.

[0163] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference.

Targeting DDR2 enhances tumour response to anti-PD-1 immunotherapy

[0164] Targeting antibodies to programmed cell death protein- 1 (PD-1) has proven to be an effective treatment for a range of cancer types, including bladder cancer. While increased overall survival and durable responses are observed in a subset of patients, the majority still do not benefit from these treatment modalities. Furthermore, immune related adverse events (irAEs) occur in a subset of patients, stemming from an over-stimulation of the immune system and result in patient morbidity. Utilizing an shRNA-based screen of select druggable targets for which there are FDA-approved drugs, genes were identified whose knockdown in tumours were able to potentiate response to anti-PD-1 immunotherapy. The top gene identified through this screen was Discoidin Domain Receptor 2 (DDR2), a collagen receptor, which when activated, triggers a signalling cascade involving SHP-2, SRC and MAP kinases. Both shRNA-mediated knockdown and pharmacologic inhibition of DDR2, when combined with anti-PD-1 leads to tumour shrinkage and clearance in multiple cancer models.

[0165] Using NA13, an in vivo screen was performed by subcutaneously injecting NA13 cells containing a pooled 34-gene shRNA library (5 shRNAs per gene) into syngeneic immune-competent mice. To identify candidate genes whose depletion led to enhanced cell death mediated by the immune-activating anti-PD-1, shRNA constructs in tumour samples using next-generation sequencing were quantified, then prioritized genes that were preferentially lost in the anti-PD-1 -treated compared to IgG-treated group. DDR2 was identified as the top ranked gene.

[0166] A combination of DDR2 depletion and treatment with anti-PD-1 antibodies was highly effective in controlling NA13 tumours and displayed a synergistic effect on tumor volume (Fig 10B). Anti-PD-1 treatment of mice was effective at reducing pulmonary metastases only in shDDR2 B16F10 cells. This analysis revealed a strong immune response in the shDDR2 tumours treated with anti-PD-1. Upregulation of immune-related pathways was specific to the shDDR2 tumours treated with anti-PD-1 compared to IgG treatment; we did not find this strong immune response in shControl tumours treated with anti-PD-1. A strong T cell signature was also observed with multiple T cell receptor (TCR) signaling pathways significantly enriched in the former group.

Cancer [0167] The compositions and methods of the disclosure treat a cancer or a cell proliferative disease. In certain embodiments, cancer is a type of a cell proliferative disease.

[0168] A "cancer cell" or "cancerous cell" is a cell manifesting a cell proliferative disorder that is a cancer. Any reproducible means of measurement may be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological typing or grading of a tissue sample (e.g., a biopsy sample). Cancer cells or precancerous cells can be identified through the use of appropriate molecular markers.

[0169] Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS- related cancers, AIDS-related lymphoma, anal cancer, anorectal cancer, cancer of the anal canal, appendix cancer, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodeimal tumors, visual pathway and hypothalamic glioma, breast cancer, bronchial adenomas/carcinoids, carcinoid tumor, gastrointestinal, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasm, mycosis fungoides, Seziary Syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, ovariant germ cell tumor, gestational trophoblastic tumor glioma, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, ocular cancer, islet cell tumors (endocrine pancreas), Kaposi Sarcoma, kidney cancer, renal cancer, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, lip and oral cavity cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-related lymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma, Waldenstram macroglobulinemia, medulloblastoma, melanoma, intraocular (eye) melanoma, merkel cell carcinoma, mesothelioma malignant, mesothelioma, metastatic squamous neck cancer, mouth cancer, cancer of the tongue, multiple endocrine neoplasia syndrome, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/

myeloproliferative diseases, chronic myelogenous leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal cancer,

neuroblastoma, oral cancer, oral cavity cancer, oropharyngeal cancer, ovariant cancer, ovariant epithelial cancer, ovariant low malignant potential tumor, pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing family of sarcoma tumors, Kaposi Sarcoma, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), merkel cell skin carcinoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter and other urinary organs, gestational trophoblastic tumor, urethral cancer, endometrial uterine cancer, uterine sarcoma, uterine corpus cancer, vaginal cancer, vulvar cancer, and Wilm's Tumor.

[0170] A "cell proliferative disorder of the hematologic system" is a cell proliferative disorder involving cells of the hematologic system. A cell proliferative disorder of the hematologic system can include lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoid papulosis, polycythemia vera, chronic myelocytic leukemia, agnogenic myeloid metaplasia, and essential thrombocythemia. A cell proliferative disorder of the hematologic system can include hyperplasia, dysplasia, and metaplasia of cells of the hematologic system. Preferably, compositions of the disclosure may be used to treat a cancer selected from the group consisting of a hematologic cancer of the disclosure or a hematologic cell proliferative disorder of the disclosure. A hematologic cancer of the disclosure can include multiple myeloma, lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas of lymphocytic and cutaneous origin), leukemia (including childhood leukemia, hairy-cell leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, and mast cell leukemia), myeloid neoplasms and mast cell neoplasms.

Therapeutic Methods

[0171] As used herein, "contacting a cell" refers to a condition in which a compound or other composition of matter is in direct contact with a cell, or is close enough to induce a desired biological effect in a cell. As used herein, "contacting a non-human animal" refers to a condition in which a compound or other composition of matter is in direct contact with a non- human animal, or is close enough to induce a desired biological effect in a non-human animal.

[0172] As used herein, "treating" or "treat" describes the management and care of a subject for the purpose of combating a disease, condition, or disorder and includes the administration of a composition of the disclosure, or a pharmaceutical composition to alleviate the symptoms or complications of cancer or to eliminate the cancer. Pharmaceutical

compositions of the disclosure comprise a composition of the disclosure and a

pharmaceutically-acceptable carrier.

[0173] By treating, a composition or method of the disclosure may alleviate a sign or symptom of a disease (e.g. cancer). As used herein, the term "alleviate" is meant to describe a process by which the severity of a sign or symptom of cancer is decreased. Importantly, a sign or symptom can be alleviated without being eliminated. In a preferred embodiment, the administration of pharmaceutical compositions of the disclosure leads to the elimination of a sign or symptom, however, elimination is not required. Effective dosages are expected to decrease the severity of a sign or symptom. For instance, a sign or symptom of a disorder such as cancer, which can occur in multiple locations, is alleviated if the severity of the cancer is decreased within at least one of multiple locations.

[0174] As used herein, the term "severity" is meant to describe the potential of cancer to transform from a precancerous, or benign, state into a malignant state. Alternatively, or in addition, severity is meant to describe a cancer stage, for example, according to the TNM system (accepted by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC)) or by other art-recognized methods. Cancer stage refers to the extent or severity of the cancer, based on factors such as the location of the primary tumor, tumor size, number of tumors, and lymph node involvement (spread of cancer into lymph nodes). Alternatively, or in addition, severity is meant to describe the tumor grade by art- recognized methods (see, National Cancer Institute, www.cancer.gov). Tumor grade is a system used to classify cancer cells in terms of how abnormal they look under a microscope and how quickly the tumor is likely to grow and spread. Many factors are considered when determining tumor grade, including the structure and growth pattem of the cells. The specific factors used to determine tumor grade vary with each type of cancer. Severity also describes a histologic grade, also called differentiation, which refers to how much the tumor cells resemble normal cells of the same tissue type (see, National Cancer Institute,

www.cancer.gov). Furthermore, severity describes a nuclear grade, which refers to the size and shape of the nucleus in tumor cells and the percentage of tumor cells that are dividing (see, National Cancer Institute, cancer.gov).

[0175] In another aspect of the disclosure, severity describes the degree to which a tumor has secreted growth factors, degraded the extracellular matrix, become vascularized, lost adhesion to juxtaposed tissues, or metastasized. Moreover, severity describes the number of locations to which a primary tumor has metastasized. Finally, severity includes the difficulty of treating tumors of varying types and locations. For example, inoperable tumors, those cancers which have greater access to multiple body systems (hematological and

immunological tumors), and those which are the most resistant to traditional treatments are considered most severe. In these situations, prolonging the life expectancy of the subject and/or reducing pain, decreasing the proportion of cancerous cells or restricting cells to one system, and improving cancer stage/tumor grade/histological grade/nuclear grade are considered alleviating a sign or symptom of the cancer.

[0176] As used herein the term "symptom" is defined as an indication of disease, illness, injury, or that something is not right in the body. Symptoms are felt or noticed by the individual experiencing the symptom, but may not easily be noticed by others. Others are defined as non-health-care professionals.

[0177] As used herein the term "sign" is also defined as an indication that something is not right in the body. But signs are defined as things that can be seen by a doctor, nurse, or other health care professional.

[0178] Cancer is a group of diseases that may cause almost any sign or symptom. The signs and symptoms will depend on where the cancer is, the size of the cancer, and how much it affects the nearby organs or structures. If a cancer spreads (metastasizes), then symptoms may appear in different parts of the body.

[0179] As a cancer grows, it begins to push on nearby organs, blood vessels, and nerves. This pressure creates some of the signs and symptoms of cancer. Cancers may form in places where it does not cause any symptoms until the cancer has grown quite large.

[0180] Cancer may also cause symptoms such as fever, fatigue, or weight loss. This may be because cancer cells use up much of the body's energy supply or release substances that change the body's metabolism. Or the cancer may cause the immune system to react in ways that produce these symptoms. While the signs and symptoms listed above are the more common ones seen with cancer, there are many others that are less common and are not listed here. However, all art-recognized signs and symptoms of cancer are contemplated and encompassed by the disclosure.

[0181] Treating cancer may result in a reduction in size of a tumor. A reduction in size of a tumor may also be referred to as "tumor regression". Preferably, after treatment according to the methods of the disclosure, tumor size is reduced by 5% or greater relative to its size prior to treatment; more preferably, tumor size is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater. Size of a tumor may be measured by any reproducible means of measurement. The size of a tumor may be measured as a diameter of the tumor.

[0182] Treating cancer may result in a reduction in tumor volume. Preferably, after treatment according to the methods of the disclosure, tumor volume is reduced by 5% or greater relative to its size prior to treatment; more preferably, tumor volume is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater. Tumor volume may be measured by any reproducible means of measurement.

[0183] Treating cancer may result in a decrease in number of tumors. Preferably, after treatment, tumor number is reduced by 5% or greater relative to number prior to treatment; more preferably, tumor number is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%. Number of tumors may be measured by any reproducible means of measurement. The number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification. Preferably, the specified magnification is 2x, 3x, 4x, 5x, lOx, or 50x. [0184] Treating cancer may result in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site. Preferably, after treatment according to the methods of the disclosure, the number of metastatic lesions is reduced by 5% or greater relative to number prior to treatment; more preferably, the number of metastatic lesions is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%. The number of metastatic lesions may be measured by any reproducible means of measurement. The number of metastatic lesions may be measured by counting metastatic lesions visible to the naked eye or at a specified magnification. Preferably, the specified magnification is 2x, 3x, 4x, 5x, lOx, or 50x.

Target Genes

[0185] Compositions of the disclosure may comprise a nucleic acid, protein or small molecule that hybridizes or binds to a sequence of a target gene. Exemplary, not nonlimiting, sequences for target genes of the disclosure are provided below.

[0186] An exemplary nucleic acid sequence encoding AD AMI 0 (GenBank Accession No:

AF009615.1 (mRNA complete cds)) comprises or consists of:

1 gaattcgagg atccgggtac catgggcggc ggcaggccta gcagcacggg aaccgtcccc 61 cgcgcgcatg cgcgcgcccc tgaagcgcct gggggacggg tatgggcggg aggtaggggc 121 gcggctccgc gtgccagttg ggtgcccgcg cgtcacgtgg tgaggaagga ggcggaggtc 181 tgagtttcga gggagggggg gagagaagag ggaacgagca agggaaggaa agcggggaaa 241 ggaggaagga aacgaacgag ggggagggag gtccctgttt tggaggagct aggagcgttg 301 ccggcccctg aagtggagcg agagggaggt gcttcgccgt ttctcctgcc aggggaggtc 361 ccggcttccc gtggaggctc cggaccaagc cccttcagct tctccctccg gatcgatgtg 421 ctgctgttaa cccgtgagga ggcggcggcg gcggcagcgg cagcggaaga tggtgttgct 481 gagagtgtta attctgctcc tctcctgggc ggcggggatg ggaggtcagt atgggaatcc 541 tttaaataaa tatatcagac attatgaagg attatcttac aatgtggatt cattacacca 601 aaaacaccag cgtgccaaaa gagcagtctc acatgaagac caatttttac gtctagattt 661 ccatgcccat ggaagacatt tcaacctacg aatgaagagg gacacttccc ttttcagtga 721 tgaatttaaa gtagaaacat caaataaagt acttgattat gatacctctc atatttacac 781 tggacatatt tatggtgaag aaggaagttt tagccatggg tctgttattg atggaagatt 841 tgaaggattc atccagactc gtggtggcac attttatgtt gagccagcag agagatatat 901 taaagaccga actctgccat ttcactctgt catttatcat gaagatgata ttaactatcc 961 ccataaatac ggtcctcagg ggggctgtgc agatcattca gtatttgaaa gaatgaggaa 1021 ataccagatg actggtgtag aggaagtaac acagatacct caagaagaac atgctgctaa 1081 tggtccagaa cttctgagga aaaaacgtac aacttcagct gaaaaaaata cttgtcagct 1141 ttatattcag actgatcatt tgttctttaa atattacgga acacgagaag ctgtgattgc 1201 ccagatatcc agtcatgtta aagcgattga tacaatttac cagaccacag acttctccgg 1261 aatccgtaac atcagtttca tggtgaaacg cataagaatc aatacaactg ctgatgagaa 1321 ggaccctaca aatcctttcc gtttcccaaa tattggtgtg gagaagtttc tggaattgaa 1381 ttctgagcag aatcatgatg actactgttt ggcctatgtc ttcacagacc gagattttga 1441 tgatggcgta cttggtctgg cttgggttgg agcaccttca ggaagctctg gaggaatatg 1501 tgaaaaaagt aaactctatt cagatggtaa gaagaagtcc ttaaacactg gaattattac 1561 tgttcagaac tatgggtctc atgtacctcc caaagtctct cacattactt ttgctcacga 1621 agttggacat aactttggat ccccacatga ttctggaaca gagtgcacac caggagaatc 1681 taagaatttg ggtcaaaaag aaaatggcaa ttacatcatg tatgcaagag caacatctgg 1741 ggacaaactt aacaacaata aattctcact ctgtagtatt agaaatataa gccaagttct 1801 tgagaagaag agaaacaact gttttgttga atctggccaa cctatttgtg gaaatggaat 1861 ggtagaacaa ggtgaagaat gtgattgtgg ctatagtgac cagtgtaaag atgaatgctg 1921 cttcgatgca aatcaaccag agggaagaaa atgcaaactg aaacctggga aacagtgcag 1981 tccaagtcaa ggtccttgtt gtacagcaca gtgtgcattc aagtcaaagt ctgagaagtg 2041 tcgggatgat tcagactgtg caagggaagg aatatgtaat ggcttcacag ctctctgccc 2101 agcatctgac cctaaaccaa acttcacaga ctgtaatagg catacacaag tgtgcattaa 2161 tgggcaatgt gcaggttcta tctgtgagaa atatggctta gaggagtgta cgtgtgccag 2221 ttctgatggc aaagatgata aagaattatg ccatgtatgc tgtatgaaga aaatggaccc 2281 atcaacttgt gccagtacag ggtctgtgca gtggagtagg cacttcagtg gtcgaaccat 2341 caccctgcaa cctggatccc cttgcaacga ttttagaggt tactgtgatg ttttcatgcg 2401 gtgcagatta gtagatgctg atggtcctct agctaggctt aaaaaagcaa tttttagtcc 2461 agagctctat gaaaacattg ctgaatggat tgtggctcat tggtgggcag tattacttat 2521 gggaattgct ctgatcatgc taatggctgg atttattaag atatgcagtg ttcatactcc 2581 aagtagtaat ccaaagttgc ctcctcctaa accacttcca ggcactttaa agaggaggag 2641 acctccacag cccattcagc aaccccagcg tcagcggccc cgagagagtt atcaaatggg 2701 acacatgaga cgctaactgc agcttttgcc ttggttcttc ctagtgccta caatgggaaa 2761 acttcactcc aaagagaaac ctattaagtc atcatctcca aactaaaccc tcacaagtaa 2821 cagttgaaga aaaaatggca agagatcata tcctcagacc aggtggaatt acttaaattt 2881 taaagcctga aaattccaat ttgggggtgg gaggtggaaa aggaacccaa ttttcttatg 2941 aacagatatt tttaacttaa tggcacaaag tcttagaata ttattatgtg ccccgtgttc 3001 cctgttcttc gttgctgcat tttcttcact tgcaggcaaa cttggctctc aataaacttt 3061 taccacaaat tgaaataaat atattttttt caactgccaa tcaaggctag gaggctcgac 3121 cacctcaaca ttggagacat cacttgccaa tgtacatacc ttgttatatg cagacatgta 3181 tttcttacgt acactgtact tctgtgtgca attgtaaaca gaaattgcaa tatggatgtt 3241 tctttgtatt ataaaatttt tccgctctta attaaaaatt actgtttaat tgacatactc 3301 aggataacag agaatggtgg tattcagtgg tccaggattc tgtaatgctt tacacaggca 3361 gttttgaaat gaaaatcaat ttaccccatg gtacccggat cctcgaattc (SEQ ID

NO:

[0187] An exemplary nucleic acid sequence encoding AD AMI 0 (GenBank Accession No:

NM_001110.3 (transcript variant 1)) comprises or consists of:

1 gcggcggcag gcctagcagc acgggaaccg tcccccgcgc gcatgcgcgc gcccctgaag 61 cgcctggggg acgggtaggg gcgggaggta ggggcgcggc tccgcgtgcc agttgggtgc 121 ccgcgcgtca cgtggtgagg aaggaggcgg aggtctgagt ttcgaaggag ggggggagag 181 aagagggaac gagcaaggga aggaaagcgg ggaaaggagg aaggaaacga acgaggggga 241 gggaggtccc tgttttggag gagctaggag cgttgccggc ccctgaagtg gagcgagagg 301 gaggtgcttc gccgtttctc ctgccagggg aggtcccggc ttcccgtgga ggctccggac 361 caagcccctt cagcttctcc ctccggatcg atgtgctgct gttaacccgt gaggaggcgg 421 cggcggcggc agcggcagcg gaagatggtg ttgctgagag tgttaattct gctcctctcc 481 tgggcggcgg ggatgggagg tcagtatggg aatcctttaa ataaatatat cagacattat 541 gaaggattat cttacaatgt ggattcatta caccaaaaac accagcgtgc caaaagagca 601 gtctcacatg aagaccaatt tttacgtcta gatttccatg cccatggaag acatttcaac 661 ctacgaatga agagggacac ttcccttttc agtgatgaat ttaaagtaga aacatcaaat 721 aaagtacttg attatgatac ctctcatatt tacactggac atatttatgg tgaagaagga 781 agttttagcc atgggtctgt tattgatgga agatttgaag gattcatcca gactcgtggt 841 ggcacatttt atgttgagcc agcagagaga tatattaaag accgaactct gccatttcac 901 tctgtcattt atcatgaaga tgatattaac tatccccata aatacggtcc tcaggggggc 961 tgtgcagatc attcagtatt tgaaagaatg aggaaatacc agatgactgg tgtagaggaa 1021 gtaacacaga tacctcaaga agaacatgct gctaatggtc cagaacttct gaggaaaaaa 1081 cgtacaactt cagctgaaaa aaatacttgt cagctttata ttcagactga tcatttgttc 1141 tttaaatatt acggaacacg agaagctgtg attgcccaga tatccagtca tgttaaagcg 1201 attgatacaa tttaccagac cacagacttc tccggaatcc gtaacatcag tttcatggtg 1261 aaacgcataa gaatcaatac aactgctgat gagaaggacc ctacaaatcc tttccgtttc 1321 ccaaatattg gtgtggagaa gtttctggaa ttgaattctg agcagaatca tgatgactac 1381 tgtttggcct atgtcttcac agaccgagat tttgatgatg gcgtacttgg tctggcttgg 1441 gttggagcac cttcaggaag ctctggagga atatgtgaaa aaagtaaact ctattcagat 1501 ggtaagaaga agtccttaaa cactggaatt attactgttc agaactatgg gtctcatgta 1561 cctcccaaag tctctcacat tacttttgct cacgaagttg gacataactt tggatcccca 1621 catgattctg gaacagagtg cacaccagga gaatctaaga atttgggtca aaaagaaaat 1681 ggcaattaca tcatgtatgc aagagcaaca tctggggaca aacttaacaa caataaattc 1741 tcactctgta gtattagaaa tataagccaa gttcttgaga agaagagaaa caactgtttt 1801 gttgaatctg gccaacctat ttgtggaaat ggaatggtag aacaaggtga agaatgtgat 1861 tgtggctata gtgaccagtg taaagatgaa tgctgcttcg atgcaaatca accagaggga 1921 agaaaatgca aactgaaacc tgggaaacag tgcagtccaa gtcaaggtcc ttgttgtaca 1981 gcacagtgtg cattcaagtc aaagtctgag aagtgtcggg atgattcaga ctgtgcaagg 2041 gaaggaatat gtaatggctt cacagctctc tgcccagcat ctgaccctaa accaaacttc 2101 acagactgta ataggcatac acaagtgtgc attaatgggc aatgtgcagg ttctatctgt 2161 gagaaatatg gcttagagga gtgtacgtgt gccagttctg atggcaaaga tgataaagaa 2221 ttatgccatg tatgctgtat gaagaaaatg gacccatcaa cttgtgccag tacagggtct 2281 gtgcagtgga gtaggcactt cagtggtcga accatcaccc tgcaacctgg atccccttgc 2341 aacgatttta gaggttactg tgatgttttc atgcggtgca gattagtaga tgctgatggt 2401 cctctagcta ggcttaaaaa agcaattttt agtccagagc tctatgaaaa cattgctgaa 2461 tggattgtgg ctcattggtg ggcagtatta cttatgggaa ttgctctgat catgctaatg 2521 gctggattta ttaagatatg cagtgttcat actccaagta gtaatccaaa gttgcctcct 2581 cctaaaccac ttccaggcac tttaaagagg aggagacctc cacagcccat tcagcaaccc 2641 cagcgtcagc ggccccgaga gagttatcaa atgggacaca tgagacgcta actgcagctt 2701 ttgccttggt tcttcctagt gcctacaatg ggaaaacttc actccaaaga gaaacctatt 2761 aagtcatcat ctccaaacta aaccctcaca agtaacagtt gaagaaaaaa tggcaagaga 2821 tcatatcctc agaccaggtg gaattactta aattttaaag cctgaaaatt ccaatttggg 2881 ggtgggaggt ggaaaaggaa cccaattttc ttatgaacag atatttttaa cttaatggca 2941 caaagtctta gaatattatt atgtgccccg tgttccctgt tcttcgttgc tgcattttct 3001 tcacttgcag gcaaacttgg ctctcaataa acttttacca caaattgaaa taaatatatt 3061 tttttcaact gccaatcaag gctaggaggc tcgaccacct caacattgga gacatcactt 3121 gccaatgtac ataccttgtt atatgcagac atgtatttct tacgtacact gtacttctgt 3181 gtgcaattgt aaacagaaat tgcaatatgg atgtttcttt gtattataaa atttttccgc 3241 tcttaattaa aaattactgt ttaattgaca tactcaggat aacagagaat ggtggtattc 3301 agtggtccag gattctgtaa tgctttacac aggcagtttt gaaatgaaaa tcaatttacc 3361 tttctgttac gatggagttg gttttgatac tcattttttc tttatcacat ggctgctacg 3421 ggcacaagtg actatactga agaacacagt taagtgttgt gcaaactgga catagcagca 3481 catactactt cagagttcat gatgtagatg tctggtttct gcttacgtct tttaaacttt 3541 ctaattcaat tccatttttc aattaatagg tgaaatttta ttcatgcttt gatagaaatt 3601 atgtcaatga aatgattctt tttatttgta gcctacttat ttgtgttttt catatatctg 3661 aaatatgcta attatgtttt ctgtctgata tggaaaagaa aagctgtgtc tttatcaaaa 3721 tatttaaacg gttttttcag catatcatca ctgatcattg gtaaccacta aagatgagta 3781 atttgcttaa gtagtagtta aaattgtaga taggccttct gacatttttt ttcctaaaat 3841 ttttaacagc attgaaggtg aaacagcaca atgtcccatt ccaaatttat ttttgaaaca 3901 gatgtaaata attggcattt taaagagaaa gcaaaaacat ttaatgtatt aacaggctta 3961 ttgctatgca ggaaatagaa ggggcattac aaaaattgaa gcttgtgaca tatttattgc 4021 ttctgttttc caactacatc acttcaacta gaagtaaagc tatgattttc ctgacttcac 4081 ataggaggca aatttagaga aagttgtaaa gatttctatg ttttgggttt ttttttttcc 4141 tttttttttt taagagtata aggtttacac aatcattctc ataatgtgac gcaagccagc 4201 aaggccaaaa atgctagaga aaataacggg atctcttcct tgtaaacttg tacagtatgt 4261 ggtgactttt tcaaaataca gctttttgta catgatttag agacaaattt tgtacatgaa 4321 accccagata gactataaat aattctaaac aaacaagtag gtagatatgt atgtaattgc 4381 ttttaaatca tttaaatgcc tttgtttttg gactgtgcaa aggttggaag tgggtttgca 4441 tttctaaaat ggtgactttt attctgcaag agttcttagt aacttcttga gtgtggtaga 4501 ctttggaaca tgtaaatttt ttgcttgtaa tgttatcctg tggtaggatt ttggcaggta 4561 cacacactgc cctattttat tttgagtcta agttaaatgt tttctgaaaa gagatacatg 4621 cactgaactc tttccactgc gaatcaagat gtggtaatat aaaaggatca agacaaatga 4681 gatctaatac tactgtcagt tttaatgtcc actgtgtttt atacagtatc tttttttgtt 4741 cactttggaa atttttacta aaaattgcaa aaaataaagt attgtgcaaa gatgtaaggt 4801 tttttgaaac ttgaaatgca ttaataaata gacgattaaa tcaacttgaa ggttctatac 4861 tctttgaact ctgagaacta tcacaagaag cttcccacaa ggcagtgttt tcttacagtt 4921 gtctcttcct acaaaagtat agattatctt tattcttaat actttggaat ccatgtagaa 4981 aatttccagt tagatactct gcgtacacac aataaacctt tttaaaacac ccaaaaaaaa 5041 aaaaaaaaaa (SEQ ID NO 2) .

[0188] An exemplary amino acid sequence encoding ADAMIO (GenBank Accession No:

NP_001101.1, isoform 1 pre-protein) comprises or consists of: MVLLRVLILLLSWAAGMGGQYGNPLNKYIRHYEGLSYNVDSLHQKHQRAKRAVSHEDQFLRLDFHAHGRHFNLRM KRDTSLFSDEFKVETSNKVLDYDTSHIYTGHIYGEEGSFSHGSVIDGRFEGFIQTRGGTFYVEPAERYIKDRTLP FHSVIYHEDDINYPHKYGPQGGCADHSVFERMRKYQMTGVEEVTQIPQEEHAANGPELLRKKRTTSAEKNTCQLY IQTDHLFFKYYGTREAVIAQISSHVKAIDTIYQTTDFSGIRNISFMVKRIRINTTADEKDPTNPFRFPNIGVEKF LELNSEQNHDDYCLAYVFTDRDFDDGVLGLA VGAPSGSSGGICEKSKLYSDGKKKSLNTGI ITVQNYGSHVPPK VSHITFAHEVGHNFGSPHDSGTECTPGESKNLGQKENGNYIMYARATSGDKLNNNKFSLCSIRNISQVLEKKRNN CFVESGQPICGNGMVEQGEECDCGYSDQCKDECCFDANQPEGRKCKLKPGKQCSPSQGPCCTAQCAFKSKSEKCR DDSDCAREGICNGFTALCPASDPKPNFTDCNRHTQVCINGQCAGSICEKYGLEECTCASSDGKDDKELCHVCCMK KMDPSTCASTGSVQWSRHFSGRTITLQPGSPCNDFRGYCDVFMRCRLVDADGPLARLKKAIFSPELYENIAEWIV AHWWAVLLMGIALIMLMAGFIKICSVHTPSSNPKLPPPKPLPGTLKRRRPPQPIQQPQRQRPRESYQMGHMRR

(SEQ ID NO: 3) .

[0189] An exemplary nucleic acid sequence encoding AD AMI 0 (GenBank Accession No:

NM_001320570.1, transcript variant 2) comprises or consists of:

1 gcggcggcag gcctagcagc acgggaaccg tcccccgcgc gcatgcgcgc gcccctgaag 61 cgcctggggg acgggtaggg gcgggaggta ggggcgcggc tccgcgtgcc agttgggtgc 121 ccgcgcgtca cgtggtgagg aaggaggcgg aggtctgagt ttcgaaggag ggggggagag 181 aagagggaac gagcaaggga aggaaagcgg ggaaaggagg aaggaaacga acgaggggga 241 gggaggtccc tgttttggag gagctaggag cgttgccggc ccctgaagtg gagcgagagg 301 gaggtgcttc gccgtttctc ctgccagggg aggtcccggc ttcccgtgga ggctccggac 361 caagcccctt cagcttctcc ctccggatcg atgtgctgct gttaacccgt gaggaggcgg 421 cggcggcggc agcggcagcg gaagatggtg ttgctgagag tgttaattct gctcctctcc 481 tgggcggcgg ggatgggagg tcagtatggg aatcctttaa ataaatatat cagacattat 541 gaaggattat cttacaatgt ggattcatta caccaaaaac accagcgtgc caaaagagca 601 gtctcacatg aagaccaatt tttacgtcta gatttccatg cccatggaag acatttcaac 661 ctacgaatga agagggacac ttcccttttc agtgatgaat ttaaagtaga aacatcaaat 721 aaagtacttg attatgatac ctctcatatt tacactggac atatttatgg tgaagaagga 781 agttttagcc atgggtctgt tattgatgga agatttgaag gattcatcca gactcgtggt 841 ggcacatttt atgttgagcc agcagagaga tatattaaag accgaactct gccatttcac 901 tctgtcattt atcatgaaga tgatattaac tatccccata aatacggtcc tcaggggggc 961 tgtgcagatc attcagtatt tgaaagaatg aggaaatacc agatgactgg tgtagaggaa 1021 gtaacacaga tacctcaaga agaacatgct gctaatggtc cagaacttct gaggaaaaaa 1081 cgtacaactt cagctgaaaa aaatacttgt cagctttata ttcagactga tcatttgttc 1141 tttaaatatt acggaacacg agaagctgtg attgcccaga tcaatacaac tgctgatgag 1201 aaggacccta caaatccttt ccgtttccca aatattggtg tggagaagtt tctggaattg 1261 aattctgagc agaatcatga tgactactgt ttggcctatg tcttcacaga ccgagatttt 1321 gatgatggcg tacttggtct ggcttgggtt ggagcacctt caggaagctc tggaggaata 1381 tgtgaaaaaa gtaaactcta ttcagatggt aagaagaagt ccttaaacac tggaattatt 1441 actgttcaga actatgggtc tcatgtacct cccaaagtct ctcacattac ttttgctcac 1501 gaagttggac ataactttgg atccccacat gattctggaa cagagtgcac accaggagaa 1561 tctaagaatt tgggtcaaaa agaaaatggc aattacatca tgtatgcaag agcaacatct 1621 ggggacaaac ttaacaacaa taaattctca ctctgtagta ttagaaatat aagccaagtt 1681 cttgagaaga agagaaacaa ctgttttgtt gaatctggcc aacctatttg tggaaatgga 1741 atggtagaac aaggtgaaga atgtgattgt ggctatagtg accagtgtaa agatgaatgc 1801 tgcttcgatg caaatcaacc agagggaaga aaatgcaaac tgaaacctgg gaaacagtgc 1861 agtccaagtc aaggtccttg ttgtacagca cagtgtgcat tcaagtcaaa gtctgagaag 1921 tgtcgggatg attcagactg tgcaagggaa ggaatatgta atggcttcac agctctctgc 1981 ccagcatctg accctaaacc aaacttcaca gactgtaata ggcatacaca agtgtgcatt 2041 aatgggcaat gtgcaggttc tatctgtgag aaatatggct tagaggagtg tacgtgtgcc 2101 agttctgatg gcaaagatga taaagaatta tgccatgtat gctgtatgaa gaaaatggac 2161 ccatcaactt gtgccagtac agggtctgtg cagtggagta ggcacttcag tggtcgaacc 2221 atcaccctgc aacctggatc cccttgcaac gattttagag gttactgtga tgttttcatg 2281 cggtgcagat tagtagatgc tgatggtcct ctagctaggc ttaaaaaagc aatttttagt 2341 ccagagctct atgaaaacat tgctgaatgg attgtggctc attggtgggc agtattactt 2401 atgggaattg ctctgatcat gctaatggct ggatttatta agatatgcag tgttcatact 2461 ccaagtagta atccaaagtt gcctcctcct aaaccacttc caggcacttt aaagaggagg 2521 agacctccac agcccattca gcaaccccag cgtcagcggc cccgagagag ttatcaaatg 2581 ggacacatga gacgctaact gcagcttttg ccttggttct tcctagtgcc tacaatggga 2641 aaacttcact ccaaagagaa acctattaag tcatcatctc caaactaaac cctcacaagt 2701 aacagttgaa gaaaaaatgg caagagatca tatcctcaga ccaggtggaa ttacttaaat 2761 tttaaagcct gaaaattcca atttgggggt gggaggtgga aaaggaaccc aattttctta 2821 tgaacagata tttttaactt aatggcacaa agtcttagaa tattattatg tgccccgtgt 2881 tccctgttct tcgttgctgc attttcttca cttgcaggca aacttggctc tcaataaact 2941 tttaccacaa attgaaataa atatattttt ttcaactgcc aatcaaggct aggaggctcg 3001 accacctcaa cattggagac atcacttgcc aatgtacata ccttgttata tgcagacatg 3061 tatttcttac gtacactgta cttctgtgtg caattgtaaa cagaaattgc aatatggatg 3121 tttctttgta ttataaaatt tttccgctct taattaaaaa ttactgttta attgacatac 3181 tcaggataac agagaatggt ggtattcagt ggtccaggat tctgtaatgc tttacacagg 3241 cagttttgaa atgaaaatca atttaccttt ctgttacgat ggagttggtt ttgatactca 3301 ttttttcttt atcacatggc tgctacgggc acaagtgact atactgaaga acacagttaa 3361 gtgttgtgca aactggacat agcagcacat actacttcag agttcatgat gtagatgtct 3421 ggtttctgct tacgtctttt aaactttcta attcaattcc atttttcaat taataggtga 3481 aattttattc atgctttgat agaaattatg tcaatgaaat gattcttttt atttgtagcc 3541 tacttatttg tgtttttcat atatctgaaa tatgctaatt atgttttctg tctgatatgg 3601 aaaagaaaag ctgtgtcttt atcaaaatat ttaaacggtt ttttcagcat atcatcactg 3661 atcattggta accactaaag atgagtaatt tgcttaagta gtagttaaaa ttgtagatag 3721 gccttctgac attttttttc ctaaaatttt taacagcatt gaaggtgaaa cagcacaatg 3781 tcccattcca aatttatttt tgaaacagat gtaaataatt ggcattttaa agagaaagca 3841 aaaacattta atgtattaac aggcttattg ctatgcagga aatagaaggg gcattacaaa 3901 aattgaagct tgtgacatat ttattgcttc tgttttccaa ctacatcact tcaactagaa 3961 gtaaagctat gattttcctg acttcacata ggaggcaaat ttagagaaag ttgtaaagat 4021 ttctatgttt tgggtttttt tttttccttt ttttttttaa gagtataagg tttacacaat 4081 cattctcata atgtgacgca agccagcaag gccaaaaatg ctagagaaaa taacgggatc 4141 tcttccttgt aaacttgtac agtatgtggt gactttttca aaatacagct ttttgtacat 4201 gatttagaga caaattttgt acatgaaacc ccagatagac tataaataat tctaaacaaa 4261 caagtaggta gatatgtatg taattgcttt taaatcattt aaatgccttt gtttttggac 4321 tgtgcaaagg ttggaagtgg gtttgcattt ctaaaatggt gacttttatt ctgcaagagt 4381 tcttagtaac ttcttgagtg tggtagactt tggaacatgt aaattttttg cttgtaatgt 4441 tatcctgtgg taggattttg gcaggtacac acactgccct attttatttt gagtctaagt 4501 taaatgtttt ctgaaaagag atacatgcac tgaactcttt ccactgcgaa tcaagatgtg 4561 gtaatataaa aggatcaaga caaatgagat ctaatactac tgtcagtttt aatgtccact 4621 gtgttttata cagtatcttt ttttgttcac tttggaaatt tttactaaaa attgcaaaaa 4681 ataaagtatt gtgcaaagat gtaaggtttt ttgaaacttg aaatgcatta ataaatagac 4741 gattaaatca acttgaaggt tctatactct ttgaactctg agaactatca caagaagctt 4801 cccacaaggc agtgttttct tacagttgtc tcttcctaca aaagtataga ttatctttat 4861 tcttaatact ttggaatcca tgtagaaaat ttccagttag atactctgcg tacacacaat 4921 aaaccttttt aaaacaccca a (SEQ ID NO: 4) .

[0190] An exemplary amino acid sequence encoding ADAM10 (GenBank Accession No: NP_001307499.1, isoform 2 precursor) comprises or consists of:

MVLLRVLILLLSWAAGMGGQYGNPLNKYIRHYEGLSYNVDSLHQKHQRAKRAVSHEDQFLRLDFHAHGRHFNLRM KRDTSLFSDEFKVETSNKVLDYDTSHIYTGHIYGEEGSFSHGSVIDGRFEGFIQTRGGTFYVEPAERYIKDRTLP FHSVIYHEDDINYPHKYGPQGGCADHSVFERMRKYQMTGVEEVTQIPQEEHAANGPELLRKKRTTSAEKNTCQLY IQTDHLFFKYYGTREAVIAQINTTADEKDPTNPFRFPNIGVEKFLELNSEQNHDDYCLAYVFTDRDFDDGVLGLA VGAPSGSSGGICEKSKLYSDGKKKSLNTGI ITVQNYGSHVPPKVSHITFAHEVGHNFGSPHDSGTECTPGESKN LGQKENGNYIMYARATSGDKLNNNKFSLCSIRNISQVLEKKRNNCFVESGQPICGNGMVEQGEECDCGYSDQCKD ECCFDANQPEGRKCKLKPGKQCSPSQGPCCTAQCAFKSKSEKCRDDSDCAREGICNGFTALCPASDPKPNFTDCN RHTQVCINGQCAGSICEKYGLEECTCASSDGKDDKELCHVCCMKKMDPSTCASTGSVQWSRHFSGRTITLQPGSP CNDFRGYCDVFMRCRLVDADGPLARLKKAIFSPELYENIAEWIVAHWWAVLLMGIALIMLMAGFIKICSVHTPSS NPKLPPPKPLPGTLKRRRPPQPIQQPQRQRPRESYQMGHMRR (SEQ ID NO: 5) .

[0191] An exemplary nucleic acid sequence encoding ANPEP (GenBank Accession No:

NM_001150.2) comprises or consists of:

1 gggacggcgg cggcgcagct cggaacccgc cagggtccag ggtccaggtt ccagcgcccg 61 gcggcccagg caccccccga gcccagctcc acacaccgtt cctggatctc ctctccccag 121 gcggagcgtg cccctgccca gtccagtgac cttcgcctgt tggagccctg gttaattttt 181 gcccagtctg cctgttgtgg ggctcctccc ctttggggat ataagcccgg cctggggctg 241 ctccgttctc tgcctggcct gaggctccct gagccgcctc cccaccatca ccatggccaa 301 gggcttctat atttccaagt ccctgggcat cctggggatc ctcctgggcg tggcagccgt 361 gtgcacaatc atcgcactgt cagtggtgta ctcccaggag aagaacaaga acgccaacag 421 ctcccccgtg gcctccacca ccccgtccgc ctcagccacc accaaccccg cctcggccac 481 caccttggac caaagtaaag cgtggaatcg ttaccgcctc cccaacacgc tgaaacccga 541 ttcctaccgg gtgacgctga gaccgtacct cacccccaat gacaggggcc tgtacgtttt 601 taagggctcc agcaccgtcc gtttcacctg caaggaggcc actgacgtca tcatcatcca 661 cagcaagaag ctcaactaca ccctcagcca ggggcacagg gtggtcctgc gtggtgtggg 721 aggctcccag ccccccgaca ttgacaagac tgagctggtg gagcccaccg agtacctggt 781 ggtgcacctc aagggctccc tggtgaagga cagccagtat gagatggaca gcgagttcga 841 gggggagttg gcagatgacc tggcgggctt ctaccgcagc gagtacatgg agggcaatgt 901 cagaaaggtg gtggccacta cacagatgca ggctgcagat gcccggaagt ccttcccatg 961 cttcgatgag ccggccatga aggccgagtt caacatcacg cttatccacc ccaaggacct 1021 gacagccctg tccaacatgc ttcccaaagg tcccagcacc ccacttccag aagaccccaa 1081 ctggaatgtc actgagttcc acaccacgcc caagatgtcc acgtacttgc tggccttcat 1141 tgtcagtgag ttcgactacg tggagaagca ggcatccaat ggtgtcttga tccggatctg 1201 ggcccggccc agtgccattg cggcgggcca cggcgattat gccctgaacg tgacgggccc 1261 catccttaac ttctttgctg gtcattatga cacaccctac ccactcccaa aatcagacca 1321 gattggcctg ccagacttca acgccggcgc catggagaac tggggactgg tgacctaccg 1381 ggagaactcc ctgctgttcg accccctgtc ctcctccagc agcaacaagg agcgggtggt 1441 cactgtgatt gctcatgagc tggcccacca gtggttcggg aacctggtga ccatagagtg 1501 gtggaatgac ctgtggctga acgagggctt cgcctcctac gtggagtacc tgggtgctga 1561 ctatgcggag cccacctgga acttgaaaga cctcatggtg ctgaatgatg tgtaccgcgt 1621 gatggcagtg gatgcactgg cctcctccca cccgctgtcc acacccgcct cggagatcaa 1681 cacgccggcc cagatcagtg agctgtttga cgccatctcc tacagcaagg gcgcctcagt 1741 cctcaggatg ctctccagct tcctgtccga ggacgtattc aagcagggcc tggcgtccta 1801 cctccacacc tttgcctacc agaacaccat ctacctgaac ctgtgggacc acctgcagga 1861 ggctgtgaac aaccggtcca tccaactccc caccaccgtg cgggacatca tgaaccgctg 1921 gaccctgcag atgggcttcc cggtcatcac ggtggatacc agcacgggga ccctttccca 1981 ggagcacttc ctccttgacc ccgattccaa tgttacccgc ccctcagaat tcaactacgt 2041 gtggattgtg cccatcacat ccatcagaga tggcagacag cagcaggact actggctgat 2101 agatgtaaga gcccagaacg atctcttcag cacatcaggc aatgagtggg tcctgctgaa 2161 cctcaatgtg acgggctatt accgggtgaa ctacgacgaa gagaactgga ggaagattca 2221 gactcagctg cagagagacc actcggccat ccctgtcatc aatcgggcac agatcattaa 2281 tgacgccttc aacctggcca gtgcccataa ggtccctgtc actctggcgc tgaacaacac 2341 cctcttcctg attgaagaga gacagtacat gccctgggag gccgccctga gcagcctgag 2401 ctacttcaag ctcatgtttg accgctccga ggtctatggc cccatgaaga actacctgaa 2461 gaagcaggtc acacccctct tcattcactt cagaaataat accaacaact ggagggagat 2521 cccagaaaac ctgatggacc agtacagcga ggttaatgcc atcagcaccg cctgctccaa 2581 cggagttcca gagtgtgagg agatggtctc tggccttttc aagcagtgga tggagaaccc 2641 caataataac ccgatccacc ccaacctgcg gtccaccgtc tactgcaacg ctatcgccca 2701 gggcggggag gaggagtggg acttcgcctg ggagcagttc cgaaatgcca cactggtcaa 2761 tgaggctgac aagctccggg cagccctggc ctgcagcaaa gagttgtgga tcctgaacag 2821 gtacctgagc tacaccctga acccggactt aatccggaag caggacgcca cctctaccat 2881 catcagcatt accaacaacg tcattgggca aggtctggtc tgggactttg tccagagcaa 2941 ctggaagaag ctttttaacg attatggtgg tggctcgttc tccttctcca acctcatcca 3001 ggcagtgaca cgacgattct ccaccgagta tgagctgcag cagctggagc agttcaagaa 3061 ggacaacgag gaaacaggct tcggctcagg cacccgggcc ctggagcaag ccctggagaa 3121 gacgaaagcc aacatcaagt gggtgaagga gaacaaggag gtggtgctcc agtggttcac 3181 agaaaacagc aaatagtccc cagcccttga agtcacccgg cccccatgca aggtgcccac

3241 atgtgtccat cccagcggct ggtgcagggc ctccattcct ggagcccgag gcaccagtgt

3301 cctcccctca aggacaaagt ctccagccca cgttctctct gcctgtgagc cagtctagtt

3361 cctgatgacc caggctgcct gagcacctcc cagcccctgc ccctcatgcc aaccccgccc

3421 taggcctggc atggcacctg tcgcccagtg ccctggggct gatctcaggg aagcccagct

3481 ccagggccag atgagcagaa gctctcgatg gacaatgaac ggccttgctg ggggccgccc

3541 tgtaccctct ttcacctttc cctaaagacc ctaaatctga ggaatcaaca gggcagcaga

3601 tctgtatatt tttttctaag agaaaatgta aataaaggat ttctagatga aaaaaaaaaa

3661 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

3721 aaaaaaaaaa aaaaaaaaaa (SEQ ID NO: 6).

[0192] An exemplary amino acid sequence encoding ANPEP (GenBank Accession No: NP_001 141.2) comprises or consists of:

MAKGFYISKSLGILGILLGVAAVCTI IALSWYSQEKNKNANSSPVASTTPSASATTNPASATTLDQSKAWNRYR LPNTLKPDSYRVTLRPYLTPNDRGLYVFKGSSTVRFTCKEATDVI IIHSKKLNYTLSQGHRWLRGVGGSQPPDI DKTELVEPTEYLWHLKGSLVKDSQYEMDSEFEGELADDLAGFYRSEYMEGNVRKWATTQMQAADARKSFPCFD EPAMKAEFNITLIHPKDLTALSNMLPKGPSTPLPEDPNWNVTEFHTTPKMSTYLLAFIVSEFDYVEKQASNGVLI RIWARPSAIAAGHGDYALNVTGPILNFFAGHYDTPYPLPKSDQIGLPDFNAGAMENWGLVTYRENSLLFDPLSSS SSNKERWTVIAHELAHQWFGNLVTIEWWNDLWLNEGFASYVEYLGADYAEPTWNLKDLMVLNDVYRVMAVDALA SSHPLSTPASEINTPAQISELFDAISYSKGASVLRMLSSFLSEDVFKQGLASYLHTFAYQNTIYLNLWDHLQEAV NNRSIQLPTTVRDIMNRWTLQMGFPVITVDTSTGTLSQEHFLLDPDSNVTRPSEFNYVWIVPITSIRDGRQQQDY WLIDVRAQNDLFSTSGNE VLLNLNVTGYYRVNYDEENWRKIQTQLQRDHSAIPVINRAQIINDAFNLASAHKVP VTLALNNTLFLIEERQYMPWEAALSSLSYFKLMFDRSEVYGPMKNYLKKQVTPLFIHFRNNTNNWREIPENLMDQ YSE AISTACSNGVPECEEMVSGLFKQWMENPNNNPIHPNLRSTVYCNAIAQGGEEEWDFAWEQFRNATLVNEA DKLRAALACSKELWILNRYLSYTLNPDLIRKQDATSTIISITNNVIGQGLVWDFVQSNWKKLFNDYGGGSFSFSN LIQAVTRRFSTEYELQQLEQFKKDNEETGFGSGTRALEQALEKTKANIK VKENKEWLQWFTENSK (SEQ ID NO: 7) .

[0193] An exemplary nucleic acid sequence encoding CA1 (GenBank Accession No:

NM_001128829.3, transcript variant 1) comprises or consists of:

1 cctttttgct gtacataagc tgcccattcc ccctccagcc tgtggtaccc agtcctcagg 61 tgcaaccccc tgcgtggtcc tctgtggcag ccttctctca ttcagagcta aatagaaggg 121 aggaggacct attttgttcc atcctgtagg ctgatccttt acacctagga ctggaagaaa 181 taagaaaaag aaaactcagt agaagataat ggcaagtcca gactggggat atgatgacaa 241 aaatggtcct gaacaatgga gcaagctgta tcccattgcc aatggaaata accagtcccc 301 tgttgatatt aaaaccagtg aaaccaaaca tgacacctct ctgaaaccta ttagtgtctc 361 ctacaaccca gccacagcca aagaaattat caatgtgggg cattccttcc atgtaaattt 421 tgaggacaac gataaccgat cagtgctgaa aggtggtcct ttctctgaca gctacaggct 481 ctttcagttc cattttcact ggggcagtac aaatgagcat ggttcagaac atacagtgga 541 tggagtcaaa tattctgccg agcttcacgt agctcactgg aattctgcaa agtactccag 601 ccttgctgaa gctgcctcaa aggctgatgg tttggcagtt attggtgttt tgatgaaggt 661 tggtgaggcc aacccaaagc tgcagaaagt acttgatgcc ctccaagcaa ttaaaaccaa 721 gggcaaacga gccccattca caaattttga cccctctact ctccttcctt catccctgga 781 tttctggacc taccctggct ctctgactca tcctcctctt tatgagagtg taacttggat 841 catctgtaag gagagcatca gtgtcagctc agagcagctg gcacaattcc gcagccttct 901 atcaaatgtt gaaggtgata acgctgtccc catgcagcac aacaaccgcc caacccaacc 961 tctgaagggc agaacagtga gagcttcatt ttgatgattc tgagaagaaa cttgtccttc 1021 ctcaagaaca cagccctgct tctgacataa tccagtaaaa taataatttt taagaaataa 1081 atttatttca atattagcaa gacagcatgc cttcaaatca atctgtaaaa ctaagaaact 1141 taaattttag ttcttactgc ttaattcaaa taataattag taagctagca aatagtaatc 1201 tgtaagcata agcttatgct taaattcaag tttagtttga ggaattcttt aaaattacaa 1261 ctaagtgatt tgtatgtcta tttttttcag tttatttgaa ccaataaaat aattttatct 1321 ctttcaaaaa aaaaaaaaaa (SEQ ID NO: 8).

[0194] An exemplary nucleic acid sequence encoding CAl (GenBank Accession No:

NM_001738.4 , transcript variant 2) comprises or consists of:

1 cctttttgct gtacataagc tgcccattcc ccctccagcc tgtggtaccc agtcctcagg

61 tgcaaccccc tgcgtggtcc tctgtggcag ccttctctca ttcagagctg ttttccacag

121 aggtagtgaa aagaactgga ttttcaagtt cactttgcaa gagaaaaaga aaactcagta

181 gaagataatg gcaagtccag actggggata tgatgacaaa aatggtcctg aacaatggag

241 caagctgtat cccattgcca atggaaataa ccagtcccct gttgatatta aaaccagtga

301 aaccaaacat gacacctctc tgaaacctat tagtgtctcc tacaacccag ccacagccaa

361 agaaattatc aatgtggggc attccttcca tgtaaatttt gaggacaacg ataaccgatc

421 agtgctgaaa ggtggtcctt tctctgacag ctacaggctc tttcagttcc attttcactg

481 gggcagtaca aatgagcatg gttcagaaca tacagtggat ggagtcaaat attctgccga

541 gcttcacgta gctcactgga attctgcaaa gtactccagc cttgctgaag ctgcctcaaa

601 ggctgatggt ttggcagtta ttggtgtttt gatgaaggtt ggtgaggcca acccaaagct

661 gcagaaagta cttgatgccc tccaagcaat taaaaccaag ggcaaacgag ccccattcac

721 aaattttgac ccctctactc tccttccttc atccctggat ttctggacct accctggctc

781 tctgactcat cctcctcttt atgagagtgt aacttggatc atctgtaagg agagcatcag

841 tgtcagctca gagcagctgg cacaattccg cagccttcta tcaaatgttg aaggtgataa

901 cgctgtcccc atgcagcaca acaaccgccc aacccaacct ctgaagggca gaacagtgag

961 agcttcattt tgatgattct gagaagaaac ttgtccttcc tcaagaacac agccctgctt

1021 ctgacataat ccagtaaaat aataattttt aagaaataaa tttatttcaa tattagcaag

1081 acagcatgcc ttcaaatcaa tctgtaaaac taagaaactt aaattttagt tcttactgct

1141 taattcaaat aataattagt aagctagcaa atagtaatct gtaagcataa gcttatgctt

1201 aaattcaagt ttagtttgag gaattcttta aaattacaac taagtgattt gtatgtctat

1261 ttttttcagt ttatttgaac caataaaata attttatctc tttcaaaaaa aaaaaaaaa

ID NO: 9) .

[0195] An exemplary nucleic acid sequence encoding CAl (GenBank Accession No:

NM_001128830.3 , transcript variant 3) comprises or consists of:

cctttttgct gtacataagc tgcccattcc ccctccagcc tgtggtaccc agtcctcagg

61 tgcaaccccc tgcgtggtcc tctgtggcag ccttctctca ttcagagctg ggttgcagca

121 gctcagacaa tccttaccat gtgaaaggag gaatgactgt catggcatga aaaaagcatc

181 actatgaaaa agaaaactca gtagaagata atggcaagtc cagactgggg atatgatgac

241 aaaaatggtc ctgaacaatg gagcaagctg tatcccattg ccaatggaaa taaccagtcc

301 cctgttgata ttaaaaccag tgaaaccaaa catgacacct ctctgaaacc tattagtgtc

361 tcctacaacc cagccacagc caaagaaatt atcaatgtgg ggcattcctt ccatgtaaat

421 tttgaggaca acgataaccg atcagtgctg aaaggtggtc ctttctctga cagctacagg

481 ctctttcagt tccattttca ctggggcagt acaaatgagc atggttcaga acatacagtg

541 gatggagtca aatattctgc cgagcttcac gtagctcact ggaattctgc aaagtactcc

601 agccttgctg aagctgcctc aaaggctgat ggtttggcag ttattggtgt tttgatgaag

661 gttggtgagg ccaacccaaa gctgcagaaa gtacttgatg ccctccaagc aattaaaacc

721 aagggcaaac gagccccatt cacaaatttt gacccctcta ctctccttcc ttcatccctg

781 gatttctgga cctaccctgg ctctctgact catcctcctc tttatgagag tgtaacttgg

841 atcatctgta aggagagcat cagtgtcagc tcagagcagc tggcacaatt ccgcagcctt

901 ctatcaaatg ttgaaggtga taacgctgtc cccatgcagc acaacaaccg cccaacccaa

961 cctctgaagg gcagaacagt gagagcttca ttttgatgat tctgagaaga aacttgtcct

1021 tcctcaagaa cacagccctg cttctgacat aatccagtaa aataataatt tttaagaaat

1081 aaatttattt caatattagc aagacagcat gccttcaaat caatctgtaa aactaagaaa

1141 cttaaatttt agttcttact gcttaattca aataataatt agtaagctag caaatagtaa

1201 tctgtaagca taagcttatg cttaaattca agtttagttt gaggaattct ttaaaattac

1261 aactaagtga tttgtatgtc tatttttttc agtttatttg aaccaataaa ataattttat

1321 ctctttcaaa aaaaaaaaaa aa (SEQ ID NO: 10) .

[0196] An exemplary nucleic acid sequence encoding CAl (GenBank Accession No: NM_001128831.3, transcript variant 4) comprises or consists of:

1 cctttttgct gtacataagc tgcccattcc ccctccagcc tgtggtaccc agtcctcagg 61 tgcaaccccc tgcgtggtcc tctgtggcag ccttctctca ttcagagcta aaaagaaaac 121 tcagtagaag ataatggcaa gtccagactg gggatatgat gacaaaaatg gtcctgaaca 181 atggagcaag ctgtatccca ttgccaatgg aaataaccag tcccctgttg atattaaaac 241 cagtgaaacc aaacatgaca cctctctgaa acctattagt gtctcctaca acccagccac 301 agccaaagaa attatcaatg tggggcattc cttccatgta aattttgagg acaacgataa 361 ccgatcagtg ctgaaaggtg gtcctttctc tgacagctac aggctctttc agttccattt 421 tcactggggc agtacaaatg agcatggttc agaacataca gtggatggag tcaaatattc 481 tgccgagctt cacgtagctc actggaattc tgcaaagtac tccagccttg ctgaagctgc 541 ctcaaaggct gatggtttgg cagttattgg tgttttgatg aaggttggtg aggccaaccc 601 aaagctgcag aaagtacttg atgccctcca agcaattaaa accaagggca aacgagcccc 661 attcacaaat tttgacccct ctactctcct tccttcatcc ctggatttct ggacctaccc 721 tggctctctg actcatcctc ctctttatga gagtgtaact tggatcatct gtaaggagag 781 catcagtgtc agctcagagc agctggcaca attccgcagc cttctatcaa atgttgaagg 841 tgataacgct gtccccatgc agcacaacaa ccgcccaacc caacctctga agggcagaac 901 agtgagagct tcattttgat gattctgaga agaaacttgt ccttcctcaa gaacacagcc 961 ctgcttctga cataatccag taaaataata atttttaaga aataaattta tttcaatatt 1021 agcaagacag catgccttca aatcaatctg taaaactaag aaacttaaat tttagttctt 1081 actgcttaat tcaaataata attagtaagc tagcaaatag taatctgtaa gcataagctt 1141 atgcttaaat tcaagtttag tttgaggaat tctttaaaat tacaactaag tgatttgtat 1201 gtctattttt ttcagtttat ttgaaccaat aaaataattt tatctctttc aaaaaaaaaa 1261 aaaaa (SEQ ID NO: 11)

[0197] An exemplary nucleic acid sequence encoding CAl (GenBank Accession No:

NM_001164830.1 , transcript variant 5) comprises or consists of:

1 atctcctgca tgcacagttg cagttagtta ttccaggtat tatttttgtt ttcagaaaaa 61 gaaaactcag tagaagataa tggcaagtcc agactgggga tatgatgaca aaaatggtcc 121 tgaacaatgg agcaagctgt atcccattgc caatggaaat aaccagtccc ctgttgatat 181 taaaaccagt gaaaccaaac atgacacctc tctgaaacct attagtgtct cctacaaccc 241 agccacagcc aaagaaatta tcaatgtggg gcattccttc catgtaaatt ttgaggacaa 301 cgataaccga tcagtgctga aaggtggtcc tttctctgac agctacaggc tctttcagtt 361 ccattttcac tggggcagta caaatgagca tggttcagaa catacagtgg atggagtcaa 421 atattctgcc gagcttcacg tagctcactg gaattctgca aagtactcca gccttgctga 481 agctgcctca aaggctgatg gtttggcagt tattggtgtt ttgatgaagg ttggtgaggc 541 caacccaaag ctgcagaaag tacttgatgc cctccaagca attaaaacca agggcaaacg 601 agccccattc acaaattttg acccctctac tctccttcct tcatccctgg atttctggac 661 ctaccctggc tctctgactc atcctcctct ttatgagagt gtaacttgga tcatctgtaa 721 ggagagcatc agtgtcagct cagagcagct ggcacaattc cgcagccttc tatcaaatgt 781 tgaaggtgat aacgctgtcc ccatgcagca caacaaccgc ccaacccaac ctctgaaggg 841 cagaacagtg agagcttcat tttgatgatt ctgagaagaa acttgtcctt cctcaagaac 901 acagccctgc ttctgacata atccagtaaa ataataattt ttaagaaata aatttatttc 961 aatattagca agacagcatg ccttcaaatc aatctgtaaa actaagaaac ttaaatttta 1021 gttcttactg cttaattcaa ataataatta gtaagctagc aaatagtaat ctgtaagcat 1081 aagcttatgc ttaaattcaa gtttagtttg aggaattctt taaaattaca actaagtgat 1141 ttgtatgtct atttttttca gtttatttga accaataaaa taattttatc tctttcaaaa 1201 aaaaaaaaaa a (SEQ ID NO: 12) .

[0198] An exemplary nucleic acid sequence encoding CAl (GenBank Accession No:

NM_001291967.1 , transcript variant 6) comprises or consists of:

1 cctttttgct gtacataagc tgcccattcc ccctccagcc tgtggtaccc agtcctcagg

61 tgcaaccccc tgcgtggtcc tctgtggcag ccttctctca ttcagagcta aaaagaaaac

121 tcagtagaag ataatggcaa gtccagactg gggatatgat gacaaaaatg tgctgaaagg

181 tggtcctttc tctgacagct acaggctctt tcagttccat tttcactggg gcagtacaaa

241 tgagcatggt tcagaacata cagtggatgg agtcaaatat tctgccgagc ttcacgtagc

301 tcactggaat tctgcaaagt actccagcct tgctgaagct gcctcaaagg ctgatggttt

361 ggcagttatt ggtgttttga tgaaggttgg tgaggccaac ccaaagctgc agaaagtact 421 tgatgccctc caagcaatta aaaccaaggg caaacgagcc ccattcacaa attttgaccc

48 1 ctctactctc cttccttcat ccctggattt ctggacctac cctggctctc tgactcatcc

54 1 tcctctttat gagagtgtaa cttggatcat ctgtaaggag agcatcagtg tcagctcaga

60 1 gcagctggca caattccgca gccttctatc aaatgttgaa ggtgataacg ctgtccccat

66 1 gcagcacaac aaccgcccaa cccaacctct gaagggcaga acagtgagag cttcattttg

72 1 atgattctga gaagaaactt gtccttcctc aagaacacag ccctgcttct gacataatcc

78 1 agtaaaataa taatttttaa gaaataaatt tatttcaata ttagcaagac agcatgcctt

84 1 caaatcaatc tgtaaaacta agaaacttaa attttagttc ttactgctta attcaaataa

90 1 taattagtaa gctagcaaat agtaatctgt aagcataagc ttatgcttaa attcaagttt

96 1 agtttgagga attctttaaa attacaacta agtgatttgt atgtctattt ttttcagttt

102 1 atttgaacca ataaaataat tttatctctt tcaaaaaaaa aaaaaaa ( S . IQ ID NO:

13)

[0199] An exemplary nucleic acid sequence encoding CA1 (GenBank Accession No:

NM_001291968.1 , transcript variant 7) comprises or consists of:

1 cctttttgct gtacataagc tgcccattcc ccctccagcc tgtggtaccc agtcctcagg

61 tgcaaccccc tgcgtggtcc tctgtggcag ccttctctca ttcagagcta aaaagaaaac

121 tcagtagaag ataatggcaa gtccagactg gggatatgat gacaaaaatg cttcacgtag

181 ctcactggaa ttctgcaaag tactccagcc ttgctgaagc tgcctcaaag gctgatggtt

241 tggcagttat tggtgttttg atgaaggttg gtgaggccaa cccaaagctg cagaaagtac

301 ttgatgccct ccaagcaatt aaaaccaagg gcaaacgagc cccattcaca aattttgacc

361 cctctactct ccttccttca tccctggatt tctggaccta ccctggctct ctgactcatc

421 ctcctcttta tgagagtgta acttggatca tctgtaagga gagcatcagt gtcagctcag

481 agcagctggc acaattccgc agccttctat caaatgttga aggtgataac gctgtcccca

541 tgcagcacaa caaccgccca acccaacctc tgaagggcag aacagtgaga gcttcatttt

601 gatgattctg agaagaaact tgtccttcct caagaacaca gccctgcttc tgacataatc

661 cagtaaaata ataattttta agaaataaat ttatttcaat attagcaaga cagcatgcct

721 tcaaatcaat ctgtaaaact aagaaactta aattttagtt cttactgctt aattcaaata

781 ataattagta agctagcaaa tagtaatctg taagcataag cttatgctta aattcaagtt

841 tagtttgagg aattctttaa aattacaact aagtgatttg tatgtctatt tttttcagtt

901 tatttgaacc aataaaataa ttttatctct ttcaaaaaaa aaaaaaaa (SEQ ID NO:

14) .

[0200] An exemplary amino acid sequence encoding CA1 (GenBank Accession No:

NP_001 122301.1, isoform a corresponding to transcript variants 1, 2, 3, 4, and 5) comprises or consists of:

MASPDWGYDDKNGPEQWSKLYPIANGNNQSPVDIKTSETKHDTSLKPISVSYNPATAKEI INVGHSFHVNFEDND NRSVLKGGPFSDSYRLFQFHFHWGSTNEHGSEHTVDGVKYSAELHVAHWNSAKYSSLAEAASKADGLAVIGVLMK VGEANPKLQKVLDALQAIKTKGKRAPFTNFDPSTLLPSSLDFWTYPGSLTHPPLYESVTWIICKESISVSSEQLA QFRSLLSNVEGDNAVPMQHNNRPTQPLKGRTVRASF (SEQ ID NO: 15) .

[0201] An exemplary amino acid sequence encoding CA1 (GenBank Accession No:

NP_001278896.1 , isoform b corresponding to transcript variant 6) comprises or consists of:

MASPDWGYDDKNVLKGGPFSDSYRLFQFHFHWGSTNEHGSEHTVDGVKYSAELHVAHWNSAKYSSLAEAASKADG LAVIGVLMKVGEANPKLQKVLDALQAIKTKGKRAPFTNFDPSTLLPSSLDFWTYPGSLTHPPLYESVTWI ICKES ISVSSEQLAQFRSLLSNVEGDNAVPMQHNNRPTQPLKGRTVRASF (SEQ ID NO: 16) .

[0202] An exemplary amino acid sequence encoding CA1 (GenBank Accession No:

NP_001278897.1 , isoform c corresponding to transcript variant 7) comprises or consists of: MTKMLHVAHWNSAKYSSLAEAASKADGLAVIGVLMKVGEANPKLQKVLDALQAIKTKGKRAPFTNFDPSTLLPS SLDFWTYPGSLTHPPLYESVTWIICKESISVSSEQLAQFRSLLSNVEGDNAVPMQHNNRPTQPLKGRTVRASF

(SEQ ID NO: 17) .

[0203] An exemplary nucleic acid sequence encoding CA2 (GenBank Accession No:

NM_000067.2 , transcript variant 1) comprises or consists of:

1 cctccccttg tcgcctaggt ccacccgagc cccctccccc gggccgcccc cgagcacgaa 61 gttggcggga gcctataaaa gctggtgccg gcgcgacccg cggacacaca gtgcaggcgc 121 ccaagccgcc gccgccagat cggtgccgat tcctgccctg ccccgaccgc cagcgcgacc 181 atgtcccatc actgggggta cggcaaacac aacggacctg agcactggca taaggacttc 241 cccattgcca agggagagcg ccagtcccct gttgacatcg acactcatac agccaagtat 301 gacccttccc tgaagcccct gtctgtttcc tatgatcaag caacttccct gaggatcctc 361 aacaatggtc atgctttcaa cgtggagttt gatgactctc aggacaaagc agtgctcaag 421 ggaggacccc tggatggcac ttacagattg attcagtttc actttcactg gggttcactt 481 gatggacaag gttcagagca tactgtggat aaaaagaaat atgctgcaga acttcacttg 541 gttcactgga acaccaaata tggggatttt gggaaagctg tgcagcaacc tgatggactg 601 gccgttctag gtattttttt gaaggttggc agcgctaaac cgggccttca gaaagttgtt 661 gatgtgctgg attccattaa aacaaagggc aagagtgctg acttcactaa cttcgatcct 721 cgtggcctcc ttcctgaatc cttggattac tggacctacc caggctcact gaccacccct 781 cctcttctgg aatgtgtgac ctggattgtg ctcaaggaac ccatcagcgt cagcagcgag 841 caggtgttga aattccgtaa acttaacttc aatggggagg gtgaacccga agaactgatg 901 gtggacaact ggcgcccagc tcagccactg aagaacaggc aaatcaaagc ttccttcaaa 961 taagatggtc ccatagtctg tatccaaata atgaatcttc gggtgtttcc ctttagctaa 1021 gcacagatct accttggtga tttggaccct ggttgctttg tgtctagttt tctagaccct 1081 tcatctctta cttgatagac ttactaataa aatgtgaaga ctagaccaat tgtcatgctt 1141 gacacaactg ctgtggctgg ttggtgcttt gtttatggta gtagtttttc tgtaacacag 1201 aatataggat aagaaataag aataaagtac cttgactttg ttcacagcat gtagggtgat 1261 gagcactcac aattgttgac taaaatgctg cttttaaaac ataggaaagt agaatggttg 1321 agtgcaaatc catagcacaa gataaattga gctagttaag gcaaatcagg taaaatagtc 1381 atgattctat gtaatgtaaa ccagaaaaaa taaatgttca tgatttcaag atgttatatt 1441 aaagaaaaac tttaaaaatt attatatatt tatagcaaag ttatcttaaa tatgaattct 1501 gttgtaattt aatgactttt gaattacaga gatataaatg aagtattatc tgtaaaaatt 1561 gttataatta gagttgtgat acagagtata tttccattca gacaatatat cataacttaa 1621 taaatattgt attttagata tattctctaa taaaattcag aattct (SEQ ID NO:

18)

[0204] An exemplary amino acid sequence encoding CA2 (GenBank Accession No:

NP_000058.1 , isoform 1, corresponding to transcript variant 1) comprises or consists of:

MSHHWGYGKHNGPEHWHKDFPIAKGERQSPVDIDTHTAKYDPSLKPLSVSYDQATSLRILNNGHAFNVEFDDSQD KAVLKGGPLDGTYRLIQFHFHWGSLDGQGSEHTVDKKKYAAELHLVHWNTKYGDFGKAVQQPDGLAVLGIFLKVG SAKPGLQKWDVLDSIKTKGKSADFTNFDPRGLLPESLDYWTYPGSLTTPPLLECVTWIVLKEPISVSSEQVLKF RKLNFNGEGEPEELMVDNWRPAQPLKNRQIKASFK (SEQ ID NO: 19) .

[0205] An exemplary nucleic acid sequence encoding CA2 (GenBank Accession No:

NM_001293675.1 , transcript variant 2) comprises or consists of:

1 cctccccttg tcgcctaggt ccacccgagc cccctccccc gggccgcccc cgagcacgaa

61 gttggcggga gcctataaaa gctggtgccg gcgcgacccg cggacacaca gtgcaggcgc

121 ccaagccgcc gccgccagat cggtgccgat tcctgccctg ccccgaccgc cagcgcgacc

181 atgtcccatc actgggggta cggcaaacac aacggacctg agcactggca taaggacttc

241 cccattgcca agggagagcg ccagtcccct gttgacatcg acactcatac agccaagtat

301 gacccttccc tgaagcccct gtctgtttcc tatgatcaag caacttccct gaggatcctc 361 aacaatggtc atgctttcaa cgtggagttt gatgactctc aggacaaagc agcttcactt 421 ggttcactgg aacaccaaat atggggattt tgggaaagct gtgcagcaac ctgatggact 481 ggccgttcta ggtatttttt tgaaggttgg cagcgctaaa ccgggccttc agaaagttgt 541 tgatgtgctg gattccatta aaacaaaggg caagagtgct gacttcacta acttcgatcc 601 tcgtggcctc cttcctgaat ccttggatta ctggacctac ccaggctcac tgaccacccc 661 tcctcttctg gaatgtgtga cctggattgt gctcaaggaa cccatcagcg tcagcagcga 721 gcaggtgttg aaattccgta aacttaactt caatggggag ggtgaacccg aagaactgat 781 ggtggacaac tggcgcccag ctcagccact gaagaacagg caaatcaaag cttccttcaa 841 ataagatggt cccatagtct gtatccaaat aatgaatctt cgggtgtttc cctttagcta 901 agcacagatc taccttggtg atttggaccc tggttgcttt gtgtctagtt ttctagaccc 961 ttcatctctt acttgataga cttactaata aaatgtgaag actagaccaa ttgtcatgct 1021 tgacacaact gctgtggctg gttggtgctt tgtttatggt agtagttttt ctgtaacaca 1081 gaatatagga taagaaataa gaataaagta ccttgacttt gttcacagca tgtagggtga 1141 tgagcactca caattgttga ctaaaatgct gcttttaaaa cataggaaag tagaatggtt 1201 gagtgcaaat ccatagcaca agataaattg agctagttaa ggcaaatcag gtaaaatagt 1261 catgattcta tgtaatgtaa accagaaaaa ataaatgttc atgatttcaa gatgttatat 1321 taaagaaaaa ctttaaaaat tattatatat ttatagcaaa gttatcttaa atatgaattc 1381 tgttgtaatt taatgacttt tgaattacag agatataaat gaagtattat ctgtaaaaat 1441 tgttataatt agagttgtga tacagagtat atttccattc agacaatata tcataactta 1501 ataaatattg tattttagat atattctcta ataaaattca gaattct (SEQ ID NO:

20)

[0206] An exemplary amino acid sequence encoding CA2 (GenBank Accession No:

NP_001280604.1 , isoform 2, corresponding to transcript variant 2) comprises or consists of:

MVMLSTWSLMTLRTKQLHLVHWNTKYGDFGKAVQQPDGLAVLGIFLKVGSAKPGLQKWDVLDSIKTKGKSADFT NFDPRGLLPESLDYWTYPGSLTTPPLLECVTWIVLKEPISVSSEQVLKFRKLNFNGEGEPEELMVDNWRPAQPLK NRQIKASFK (SEQ ID NO: 21) .

[0207] An exemplary nucleic acid sequence encoding CA9 (GenBank Accession No:

NM_001216.2 , mRNA) comprises or consists of:

i gcccgtacac accgtgtgct gggacacccc acagtcagcc gcatggctcc cctgtgcccc

61 agcccctggc tccctctgtt gatcccggcc cctgctccag gcctcactgt gcaactgctg 121 ctgtcactgc tgcttctggt gcctgtccat ccccagaggt tgccccggat gcaggaggat 181 tcccccttgg gaggaggctc ttctggggaa gatgacccac tgggcgagga ggatctgccc 241 agtgaagagg attcacccag agaggaggat ccacccggag aggaggatct acctggagag 301 gaggatctac ctggagagga ggatctacct gaagttaagc ctaaatcaga agaagagggc 361 tccctgaagt tagaggatct acctactgtt gaggctcctg gagatcctca agaaccccag 421 aataatgccc acagggacaa agaaggggat gaccagagtc attggcgcta tggaggcgac 481 ccgccctggc cccgggtgtc cccagcctgc gcgggccgct tccagtcccc ggtggatatc 541 cgcccccagc tcgccgcctt ctgcccggcc ctgcgccccc tggaactcct gggcttccag 601 ctcccgccgc tcccagaact gcgcctgcgc aacaatggcc acagtgtgca actgaccctg 661 cctcctgggc tagagatggc tctgggtccc gggcgggagt accgggctct gcagctgcat 721 ctgcactggg gggctgcagg tcgtccgggc tcggagcaca ctgtggaagg ccaccgtttc 781 cctgccgaga tccacgtggt tcacctcagc accgcctttg ccagagttga cgaggccttg 841 gggcgcccgg gaggcctggc cgtgttggcc gcctttctgg aggagggccc ggaagaaaac 901 agtgcctatg agcagttgct gtctcgcttg gaagaaatcg ctgaggaagg ctcagagact 961 caggtcccag gactggacat atctgcactc ctgccctctg acttcagccg ctacttccaa 1021 tatgaggggt ctctgactac accgccctgt gcccagggtg tcatctggac tgtgtttaac 1081 cagacagtga tgctgagtgc taagcagctc cacaccctct ctgacaccct gtggggacct 1141 ggtgactctc ggctacagct gaacttccga gcgacgcagc ctttgaatgg gcgagtgatt 1201 gaggcctcct tccctgctgg agtggacagc agtcctcggg ctgctgagcc agtccagctg 1261 aattcctgcc tggctgctgg tgacatccta gccctggttt ttggcctcct ttttgctgtc 1321 accagcgtcg cgttccttgt gcagatgaga aggcagcaca gaaggggaac caaagggggt 1381 gtgagctacc gcccagcaga ggtagccgag actggagcct agaggctgga tcttggagaa 1441 tgtgagaagc cagccagagg catctgaggg ggagccggta actgtcctgt cctgctcatt 1501 atgccacttc cttttaactg ccaagaaatt ttttaaaata aatatttata ataaaaaaaa 1561 a (SEQ ID NO: 22) .

[0208] An exemplary amino acid sequence encoding CA9 (GenBank Accession No:

NP_001207.2 ) comprises or consists of:

MAPLCPSPWLPLLIPAPAPGLTVQLLLSLLLLVPVHPQRLPRMQEDSPLGGGSSGEDDPLGEEDLPSEEDSPREE DPPGEEDLPGEEDLPGEEDLPEVKPKSEEEGSLKLEDLPTVEAPGDPQEPQNNAHRDKEGDDQSHWRYGGDPPWP RVSPACAGRFQSPVDIRPQLAAFCPALRPLELLGFQLPPLPELRLRNNGHSVQLTLPPGLEMALGPGREYRALQL HLHWGAAGRPGSEHTVEGHRFPAEIHWHLSTAFARVDEALGRPGGLAVLAAFLEEGPEENSAYEQLLSRLEEIA EEGSETQVPGLDISALLPSDFSRYFQYEGSLTTPPCAQGVIWTVFNQTVMLSAKQLHTLSDTLWGPGDSRLQLNF RATQPLNGRVIEASFPAGVDSSPRAAEPVQLNSCLAAGDILALVFGLLFAVTSVAFLVQMRRQHRRGTKGGVSYR PAEVAETGA (SEQ ID NO: 23) .

[0209] An exemplary nucleic acid sequence encoding CA9 (GenBank Accession No:

KU177953.1 ) comprises or consists of:

1 atggctcccc tgtgccccag cccctggctc cctctgttga tcccggcccc tgctccaggc 61 ctcactgtgc aactgctgct gtcactgctg cttctggtgc ctgtccatcc ccagaggttg 121 ccccggatgc aggaggattc ccccttggga ggaggctctt ctggggaaga tgacccactg 181 ggcgaggagg atctgcccag tgaagaggat tcacccagag aggaggatcc acccggagag 241 gaggatctac ctggagagga ggatctacct ggagaggagg atctacctga agttaagcct 301 aaatcagaag aagagggctc cctgaagtta gaggatctac ctactgttga ggctcctgga 361 gatcctcaag aaccccagaa taatgcccac agggacaaag aaggggatga ccagagtcat 421 tggcgctatg gaggcgaccc gccctggccc cgggtgtccc cagcctgcgc gggccgcttc 481 cagtccccgg tggatatccg cccccagctc gccgccttct gcccggccct gcgccccctg 541 gaactcctgg gcttccagct cccgccgctc ccagaactgc gcctgcgcaa caatggccac 601 agtgtgcaac tgaccctgcc tcctgggcta gagatggctc tgggtcccgg gcgggagtac 661 cgggctctgc agctgcatct gcactggggg gctgcaggtc gtccgggctc ggagcacact 721 gtggaaggcc accgtttccc tgccgagatc cacgtggttc acctcagcac cgcctttgcc 781 agagttgacg aggccttggg gcgcccggga ggcctggccg tgttggccgc ctttctggag 841 cattctcaga gctgaggaat gggagaggtc tatgggaacc ccccttcatg ttccggcctt 901 cagccatggc cctggataca tgcactcatc tgtcttacaa tgtcatcccc caggagggcc 961 cggaagaaaa cagtgcctat gagcagttgc tgtctcgctt ggaagaaatc gctgaggaag 1021 gctcagagac tcaggtccca ggactggaca tatctgcact cctgccctct gacttcagcc 1081 gctacttcca atatgagggg tctctgacta caccgccctg tgcccagggt gtcatctgga 1141 ctgtgtttaa ccagacagtg atgctgagtg ctaagcagct ccacaccctc tctgacaccc 1201 tgtggggacc tggtgactct cggctacagc tgaacttccg agcgacgcag cctttgaatg 1261 ggcgagtgat tgaggcctcc ttccctgctg gagtggacag cagtcctcgg gctgctgagc 1321 cagtccagct gaattcctgc ctggctgctg gtgacatcct agccctggtt tttggcctcc 1381 tttttgctgt caccagcgtc gcgttccttg tgcagatgag aaggcagcac agaaggggaa 1441 ccaaaggggg tgtgagctac cgcccagcag aggtagccga gactggagcc (SEQ ID

NO: 24) .

[0210] An exemplary amino acid sequence encoding CA9 (GenBank Accession No:

ALQ33411.1 ) comprises or consists of:

MAPLCPSPWLPLLIPAPAPGLTVQLLLSLLLLVPVHPQRLPRMQEDSPLGGGSSGEDDPLGEEDLPSEEDSPREE DPPGEEDLPGEEDLPGEEDLPEVKPKSEEEGSLKLEDLPTVEAPGDPQEPQNNAHRDKEGDDQSHWRYGGDPPWP RVSPACAGRFQSPVDIRPQLAAFCPALRPLELLGFQLPPLPELRLRNNGHSVQLTLPPGLEMALGPGREYRALQL HLHWGAAGRPGSEHTVEGHRFPAEIHWHLSTAFARVDEALGRPGGLAVLAAFLEHSQS (SEQ ID NO: 25) . [0211] An exemplary nucleic acid sequence encoding CA9 (GenBank Accession No:

GU570447.1. promoter region ) comprises or consists of:

i gcagaattca tctctcttcc ctcaatatga tgatattgac agggtttgcc ctcactcact

61 agattgtgag ctgctcaggg caggtagcgt tttttgtttt tgtttttgtt tttctttttt 121 gagacagggt cttgctctgt cacccaggcc agagtgcaat ggtacagtct cagctcactg 181 cagcctcaac cgcctcggct caaaccatca tcccatttca gcctcctgag tagctgggac 241 tacaggcaca tgccattaca cctggctaat ttttttgtat ttctagtaga gacagggttt 301 ggccatgttg cccgggctgg tctcgaactc ctggactcaa gcaatccacc cacctcagcc 361 tcccaaaatg agggaccgtg tcttattcat ttccatgtcc ctagtccata gcccagtgct 421 ggacctatgg tagtactaaa taaatatttg ttgaatgcaa tagtaaatag catttcaggg 481 agcaagaact agattaacaa aggtggtaaa aggtttggag aaaaaaataa tagtttaatt 541 tggctagagt atgagggaga gtagtaggag acaagatgga aaggtctctt gggcaaggtt 601 ttgaaggaag ttggaagtca gaagtacaca atgtgcatat cgtggcaggc agtggggagc 661 caatgaaggc ttttgagcag gagagtaatg tgttgaaaaa taaatatagg ttaaacctat 721 cagagcccct ctgacacata cacttgcttt tcattcaagc tcaagtttgt ctcccacata 781 cccattactt aactcaccct cgggctcccc tagcagcctg ccctacctct ttacctgctt 841 cctggtggag tcagggatgt atacatgagc tgctttccct ctcagccaga ggacatgggg 901 ggccccagct cccctgcctt tccccttctg tgcctggagc tgggaagcag gccagggtta 961 gctgaggctg gctggcaagc agctgggtgg tgccagggag agcctgcata gtgccaggtg 1021 gtgccttggg ttccaagcta gtccatggcc ccgataacct tctgcctgtg cacacacctg 1081 cccctcactc cacccccatc ctagctttgg tatgggggag agggcacagg gccagacaaa 1141 cctgtgagac tttggctcca tctctgcaaa agggcgctct gtgagtcagc ctgctcccct 1201 ccaggcttgc tcctccccca cccagctctc gtttccaatg cacgtacagc ccgtacacac 1261 cgtgtgctgg gacaccccac agtcag (SEQ ID NO: 26)

[0212] An exemplary nucleic acid sequence encoding CCL2 (GenBank Accession No:

NM_002982.3, mRNA) comprises or consists of:

1 gaggaaccga gaggctgaga ctaacccaga aacatccaat tctcaaactg aagctcgcac

61 tctcgcctcc agcatgaaag tctctgccgc ccttctgtgc ctgctgctca tagcagccac 121 cttcattccc caagggctcg ctcagccaga tgcaatcaat gccccagtca cctgctgtta 181 taacttcacc aataggaaga tctcagtgca gaggctcgcg agctatagaa gaatcaccag 241 cagcaagtgt cccaaagaag ctgtgatctt caagaccatt gtggccaagg agatctgtgc 301 tgaccccaag cagaagtggg ttcaggattc catggaccac ctggacaagc aaacccaaac 361 tccgaagact tgaacactca ctccacaacc caagaatctg cagctaactt attttcccct 421 agctttcccc agacaccctg ttttatttta ttataatgaa ttttgtttgt tgatgtgaaa 481 cattatgcct taagtaatgt taattcttat ttaagttatt gatgttttaa gtttatcttt 541 catggtacta gtgtttttta gatacagaga cttggggaaa ttgcttttcc tcttgaacca 601 cagttctacc cctgggatgt tttgagggtc tttgcaagaa tcattaatac aaagaatttt 661 ttttaacatt ccaatgcatt gctaaaatat tattgtggaa atgaatattt tgtaactatt 721 acaccaaata aatatatttt tgtacaaaaa aaaaaaaaaa (SEQ ID NO 27) .

[0213] An exemplary amino acid sequence encoding CCL2 (GenBank Accession No:

NP_002973.1) comprises or consists of:

MKVSAALLCLLLIAATFIPQGLAQPDAINAPVTCCYNFTNRKISVQRLASYRRITSSKCPKEAVIFKTIVAKEIC ADPKQK VQDSMDHLDKQTQTPKT (SEQ ID NO: 28) .

[0214] An exemplary nucleic acid sequence encoding CD37 (NM_001774.2, transcript variant 1 , mRNA ) comprises or consists of:

1 ttcctttctc tctcagctct ccgtctctct ttctctctca gcctctttct ttctccctgt

61 ctcccccact gtcagcacct cttctgtgtg gtgagtggac cgcttacccc actaggtgaa

121 gatgtcagcc caggagagct gcctcagcct catcaagtac ttcctcttcg ttttcaacct

181 cttcttcttc gtcctcggca gcctgatctt ctgcttcggc atctggatcc tcattgacaa

241 gaccagcttc gtgtcctttg tgggcttggc cttcgtgcct ctgcagatct ggtccaaagt 301 cctggccatc tcaggaatct tcaccatggg catcgccctc ctgggttgtg tgggggccct 361 caaggagctc cgctgcctcc tgggcctgta ttttgggatg ctgctgctcc tgtttgccac 421 acagatcacc ctgggaatcc tcatctccac tcagcgggcc cagctggagc gaagcttgcg 481 ggacgtcgta gagaaaacca tccaaaagta cggcaccaac cccgaggaga ccgcggccga 541 ggagagctgg gactatgtgc agttccagct gcgctgctgc ggctggcact acccgcagga 601 ctggttccaa gtcctcatcc tgagaggtaa cgggtcggag gcgcaccgcg tgccctgctc 661 ctgctacaac ttgtcggcga ccaacgactc cacaatccta gataaggtga tcttgcccca 721 gctcagcagg cttggacacc tggcgcggtc cagacacagt gcagacatct gcgctgtccc 781 tgcagagagc cacatctacc gcgagggctg cgcgcagggc ctccagaagt ggctgcacaa 841 caaccttatt tccatagtgg gcatttgcct gggcgtcggc ctactcgagc tcgggttcat 901 gacgctctcg atattcctgt gcagaaacct ggaccacgtc tacaaccggc tcgctcgata 961 ccgttaggcc ccgccctccc caaagtcccg ccccgccccc gtcacgtgcg ctgggcactt 1021 ccctgctgcc tgtaaatatt tgtttaatcc ccagttcgcc tggagccctc cgccttcaca 1081 ttcccctggg gacccacgtg gctgcgtgcc cctgctgctg tcacctctcc cacgggacct 1141 ggggctttcg tccacagctt cctgtcccca tctgtcggcc taccaccacc cacaagatta 1201 tttttcaccc aaacctcaaa taaatcccct gcgtttttgg taaaaaaaaa aaaaaaaaaa 1261 aaa (SEQ ID NO: 29) .

[0215] An exemplary amino acid sequence encoding CD37 (NP_001765.1 , isoform A (corresponding to tanscript variant 1) comprises or consists of:

MSAQESCLSLIKYFLFVFNLFFFVLGSLIFCFGIWILIDKTSFVSFVGLAFVPLQIWSKVLAISGIFTMGIALLG CVGALKELRCLLGLYFGMLLLLFATQITLGILISTQRAQLERSLRDWEKTIQKYGTNPEETAAEESWDYVQFQL RCCGWHYPQDWFQVLILRGNGSEAHRVPCSCYNLSATNDSTILDKVILPQLSRLGHLARSRHSADICAVPAESHI YREGCAQGLQKWLHNNLISIVGICLGVGLLELGFMTLSIFLCRNLDHVYNRLARYR (SEQ ID NO: 30) .

[0216] An exemplary nucleic acid sequence encoding CD37 (NM_001040031.1 , transcript variant 2, mRNA) comprises or consists of:

1 ttcctttctc tctcagctct ccgtctctct ttctctctca gcctctttct ttctccctgt 61 ctcccccact gtcagcacct cttctgtgtg gtgagtggac cgcttacccc actaggtgaa 121 gatgtcagcc caggagagct gcctcagcct catcaagtcc tcggcagcct gatcttctgc 181 ttcggcatct ggatcctcat tgacaagacc agcttcgtgt cctttgtggg cttggccttc 241 gtgcctctgc agatctggtc caaagtcctg gccatctcag gaatcttcac catgggcatc 301 gccctcctgg gttgtgtggg ggccctcaag gagctccgct gcctcctggg cctgtatttt 361 gggatgctgc tgctcctgtt tgccacacag atcaccctgg gaatcctcat ctccactcag 421 cgggcccagc tggagcgaag cttgcgggac gtcgtagaga aaaccatcca aaagtacggc 481 accaaccccg aggagaccgc ggccgaggag agctgggact atgtgcagtt ccagctgcgc 541 tgctgcggct ggcactaccc gcaggactgg ttccaagtcc tcatcctgag aggtaacggg 601 tcggaggcgc accgcgtgcc ctgctcctgc tacaacttgt cggcgaccaa cgactccaca 661 atcctagata aggtgatctt gccccagctc agcaggcttg gacacctggc gcggtccaga 721 cacagtgcag acatctgcgc tgtccctgca gagagccaca tctaccgcga gggctgcgcg 781 cagggcctcc agaagtggct gcacaacaac cttatttcca tagtgggcat ttgcctgggc 841 gtcggcctac tcgagctcgg gttcatgacg ctctcgatat tcctgtgcag aaacctggac 901 cacgtctaca accggctcgc tcgataccgt taggccccgc cctccccaaa gtcccgcccc 961 gcccccgtca cgtgcgctgg gcacttccct gctgcctgta aatatttgtt taatccccag 1021 ttcgcctgga gccctccgcc ttcacattcc cctggggacc cacgtggctg cgtgcccctg 1081 ctgctgtcac ctctcccacg ggacctgggg ctttcgtcca cagcttcctg tccccatctg 1141 tcggcctacc accacccaca agattatttt tcacccaaac ctcaaataaa tcccctgcgt 1201 ttttggtaaa aaaaaaaaaa aaaaaaaaa (SEQ ID NO: 31) .

[0217] An exemplary amino acid sequence encoding CD37 (NP_001035120.1, isoform B, corresponding to isoform 2) comprises or consists of:

MGIALLGCVGALKELRCLLGLYFGMLLLLFATQITLGILISTQRAQLERSLRDWEKTIQKYGTNPEETAAEESW DYVQFQLRCCGWHYPQDWFQVLILRGNGSEAHRVPCSCYNLSATNDSTILDKVILPQLSRLGHLARSRHSADICA VPAESHIYREGCAQGLQKWLHNNLISIVGICLGVGLLELGFMTLSIFLCRNLDHVYNRLARYR (SEQ ID NO: 32) .

[0218] An exemplary nucleic acid sequence encoding COLlAl (NM_000088.3 mRNA) comprises or consists of:

1 tcgtcggagc agacgggagt ttctcctcgg ggtcggagca ggaggcacgc ggagtgtgag 61 gccacgcatg agcggacgct aaccccctcc ccagccacaa agagtctaca tgtctagggt 121 ctagacatgt tcagctttgt ggacctccgg ctcctgctcc tcttagcggc caccgccctc 181 ctgacgcacg gccaagagga aggccaagtc gagggccaag acgaagacat cccaccaatc 241 acctgcgtac agaacggcct caggtaccat gaccgagacg tgtggaaacc cgagccctgc 301 cggatctgcg tctgcgacaa cggcaaggtg ttgtgcgatg acgtgatctg tgacgagacc 361 aagaactgcc ccggcgccga agtccccgag ggcgagtgct gtcccgtctg ccccgacggc 421 tcagagtcac ccaccgacca agaaaccacc ggcgtcgagg gacccaaggg agacactggc 481 ccccgaggcc caaggggacc cgcaggcccc cctggccgag atggcatccc tggacagcct 541 ggacttcccg gaccccccgg accccccgga cctcccggac cccctggcct cggaggaaac 601 tttgctcccc agctgtctta tggctatgat gagaaatcaa ccggaggaat ttccgtgcct 661 ggccccatgg gtccctctgg tcctcgtggt ctccctggcc cccctggtgc acctggtccc 721 caaggcttcc aaggtccccc tggtgagcct ggcgagcctg gagcttcagg tcccatgggt 781 ccccgaggtc ccccaggtcc ccctggaaag aatggagatg atggggaagc tggaaaacct 841 ggtcgtcctg gtgagcgtgg gcctcctggg cctcagggtg ctcgaggatt gcccggaaca 901 gctggcctcc ctggaatgaa gggacacaga ggtttcagtg gtttggatgg tgccaaggga 961 gatgctggtc ctgctggtcc taagggtgag cctggcagcc ctggtgaaaa tggagctcct 1021 ggtcagatgg gcccccgtgg cctgcctggt gagagaggtc gccctggagc ccctggccct 1081 gctggtgctc gtggaaatga tggtgctact ggtgctgccg ggccccctgg tcccaccggc 1141 cccgctggtc ctcctggctt ccctggtgct gttggtgcta agggtgaagc tggtccccaa 1201 gggccccgag gctctgaagg tccccagggt gtgcgtggtg agcctggccc ccctggccct 1261 gctggtgctg ctggccctgc tggaaaccct ggtgctgatg gacagcctgg tgctaaaggt 1321 gccaatggtg ctcctggtat tgctggtgct cctggcttcc ctggtgcccg aggcccctct 1381 ggaccccagg gccccggcgg ccctcctggt cccaagggta acagcggtga acctggtgct 1441 cctggcagca aaggagacac tggtgctaag ggagagcctg gccctgttgg tgttcaagga 1501 ccccctggcc ctgctggaga ggaaggaaag cgaggagctc gaggtgaacc cggacccact 1561 ggcctgcccg gaccccctgg cgagcgtggt ggacctggta gccgtggttt ccctggcgca 1621 gatggtgttg ctggtcccaa gggtcccgct ggtgaacgtg gttctcctgg ccctgctggc 1681 cccaaaggat ctcctggtga agctggtcgt cccggtgaag ctggtctgcc tggtgccaag 1741 ggtctgactg gaagccctgg cagccctggt cctgatggca aaactggccc ccctggtccc 1801 gccggtcaag atggtcgccc cggaccccca ggcccacctg gtgcccgtgg tcaggctggt 1861 gtgatgggat tccctggacc taaaggtgct gctggagagc ccggcaaggc tggagagcga 1921 ggtgttcccg gaccccctgg cgctgtcggt cctgctggca aagatggaga ggctggagct 1981 cagggacccc ctggccctgc tggtcccgct ggcgagagag gtgaacaagg ccctgctggc 2041 tcccccggat tccagggtct ccctggtcct gctggtcctc caggtgaagc aggcaaacct 2101 ggtgaacagg gtgttcctgg agaccttggc gcccctggcc cctctggagc aagaggcgag 2161 agaggtttcc ctggcgagcg tggtgtgcaa ggtccccctg gtcctgctgg tccccgaggg 2221 gccaacggtg ctcccggcaa cgatggtgct aagggtgatg ctggtgcccc tggagctccc 2281 ggtagccagg gcgcccctgg ccttcaggga atgcctggtg aacgtggtgc agctggtctt 2341 ccagggccta agggtgacag aggtgatgct ggtcccaaag gtgctgatgg ctctcctggc 2401 aaagatggcg tccgtggtct gactggcccc attggtcctc ctggccctgc tggtgcccct 2461 ggtgacaagg gtgaaagtgg tcccagcggc cctgctggtc ccactggagc tcgtggtgcc 2521 cccggagacc gtggtgagcc tggtcccccc ggccctgctg gctttgctgg cccccctggt 2581 gctgacggcc aacctggtgc taaaggcgaa cctggtgatg ctggtgctaa aggcgatgct 2641 ggtccccctg gccctgccgg acccgctgga ccccctggcc ccattggtaa tgttggtgct 2701 cctggagcca aaggtgctcg cggcagcgct ggtccccctg gtgctactgg tttccctggt 2761 gctgctggcc gagtcggtcc tcctggcccc tctggaaatg ctggaccccc tggccctcct 2821 ggtcctgctg gcaaagaagg cggcaaaggt ccccgtggtg agactggccc tgctggacgt 2881 cctggtgaag ttggtccccc tggtccccct ggccctgctg gcgagaaagg atcccctggt 2941 gctgatggtc ctgctggtgc tcctggtact cccgggcctc aaggtattgc tggacagcgt 3001 ggtgtggtcg gcctgcctgg tcagagagga gagagaggct tccctggtct tcctggcccc 3061 tctggtgaac ctggcaaaca aggtccctct ggagcaagtg gtgaacgtgg tccccctggt 3121 cccatgggcc cccctggatt ggctggaccc cctggtgaat ctggacgtga gggggctcct 3181 ggtgccgaag gttcccctgg acgagacggt tctcctggcg ccaagggtga ccgtggtgag 3241 accggccccg ctggaccccc tggtgctcct ggtgctcctg gtgcccctgg ccccgttggc 3301 cctgctggca agagtggtga tcgtggtgag actggtcctg ctggtcccgc cggtcctgtc 3361 ggccctgttg gcgcccgtgg ccccgccgga ccccaaggcc cccgtggtga caagggtgag 3421 acaggcgaac agggcgacag aggcataaag ggtcaccgtg gcttctctgg cctccagggt 3481 ccccctggcc ctcctggctc tcctggtgaa caaggtccct ctggagcctc tggtcctgct 3541 ggtccccgag gtccccctgg ctctgctggt gctcctggca aagatggact caacggtctc 3601 cctggcccca ttgggccccc tggtcctcgc ggtcgcactg gtgatgctgg tcctgttggt 3661 ccccccggcc ctcctggacc tcctggtccc cctggtcctc ccagcgctgg tttcgacttc 3721 agcttcctgc cccagccacc tcaagagaag gctcacgatg gtggccgcta ctaccgggct 3781 gatgatgcca atgtggttcg tgaccgtgac ctcgaggtgg acaccaccct caagagcctg 3841 agccagcaga tcgagaacat ccggagccca gagggcagcc gcaagaaccc cgcccgcacc 3901 tgccgtgacc tcaagatgtg ccactctgac tggaagagtg gagagtactg gattgacccc 3961 aaccaaggct gcaacctgga tgccatcaaa gtcttctgca acatggagac tggtgagacc 4021 tgcgtgtacc ccactcagcc cagtgtggcc cagaagaact ggtacatcag caagaacccc 4081 aaggacaaga ggcatgtctg gttcggcgag agcatgaccg atggattcca gttcgagtat 4141 ggcggccagg gctccgaccc tgccgatgtg gccatccagc tgaccttcct gcgcctgatg 4201 tccaccgagg cctcccagaa catcacctac cactgcaaga acagcgtggc ctacatggac 4261 cagcagactg gcaacctcaa gaaggccctg ctcctccagg gctccaacga gatcgagatc 4321 cgcgccgagg gcaacagccg cttcacctac agcgtcactg tcgatggctg cacgagtcac 4381 accggagcct ggggcaagac agtgattgaa tacaaaacca ccaagacctc ccgcctgccc 4441 atcatcgatg tggccccctt ggacgttggt gccccagacc aggaattcgg cttcgacgtt 4501 ggccctgtct gcttcctgta aactccctcc atcccaacct ggctccctcc cacccaacca 4561 actttccccc caacccggaa acagacaagc aacccaaact gaaccccctc aaaagccaaa 4621 aaatgggaga caatttcaca tggactttgg aaaatatttt tttcctttgc attcatctct 4681 caaacttagt ttttatcttt gaccaaccga acatgaccaa aaaccaaaag tgcattcaac 4741 cttaccaaaa aaaaaaaaaa aaaaagaata aataaataac tttttaaaaa aggaagcttg 4801 gtccacttgc ttgaagaccc atgcgggggt aagtcccttt ctgcccgttg ggcttatgaa 4861 accccaatgc tgccctttct gctcctttct ccacaccccc cttggggcct cccctccact 4921 ccttcccaaa tctgtctccc cagaagacac aggaaacaat gtattgtctg cccagcaatc 4981 aaaggcaatg ctcaaacacc caagtggccc ccaccctcag cccgctcctg cccgcccagc 5041 acccccaggc cctgggggac ctggggttct cagactgcca aagaagcctt gccatctggc 5101 gctcccatgg ctcttgcaac atctcccctt cgtttttgag ggggtcatgc cgggggagcc 5161 accagcccct cactgggttc ggaggagagt caggaagggc cacgacaaag cagaaacatc 5221 ggatttgggg aacgcgtgtc aatcccttgt gccgcagggc tgggcgggag agactgttct 5281 gttccttgtg taactgtgtt gctgaaagac tacctcgttc ttgtcttgat gtgtcaccgg 5341 ggcaactgcc tgggggcggg gatgggggca gggtggaagc ggctccccat tttataccaa 5401 aggtgctaca tctatgtgat gggtggggtg gggagggaat cactggtgct atagaaattg 5461 agatgccccc ccaggccagc aaatgttcct ttttgttcaa agtctatttt tattccttga 5521 tatttttctt tttttttttt tttttttgtg gatggggact tgtgaatttt tctaaaggtg 5581 ctatttaaca tgggaggaga gcgtgtgcgg ctccagccca gcccgctgct cactttccac 5641 cctctctcca cctgcctctg gcttctcagg cctctgctct ccgacctctc tcctctgaaa 5701 ccctcctcca cagctgcagc ccatcctccc ggctccctcc tagtctgtcc tgcgtcctct 5761 gtccccgggt ttcagagaca acttcccaaa gcacaaagca gtttttcccc ctaggggtgg 5821 gaggaagcaa aagactctgt acctattttg tatgtgtata ataatttgag atgtttttaa 5881 ttattttgat tgctggaata aagcatgtgg aaatgaccca aacataa (SEQ ID NO:

33)

[0219] An exemplary amino acid sequence encoding COL1A1 (NP_000079.2) comprises or consists of:

MFSFVDLRLLLLLAATALLTHGQEEGQVEGQDEDIPPITCVQNGLRYHDRDVWKPEPCRICVCDNGKVLCDDVIC DETKNCPGAEVPEGECCPVCPDGSESPTDQETTGVEGPKGDTGPRGPRGPAGPPGRDGIPGQPGLPGPPGPPGPP GPPGLGGNFAPQLSYGYDEKSTGGISVPGPMGPSGPRGLPGPPGAPGPQGFQGPPGEPGEPGASGPMGPRGPPGP PGKNGDDGEAGKPGRPGERGPPGPQGARGLPGTAGLPGMKGHRGFSGLDGAKGDAGPAGPKGEPGSPGENGAPGQ MGPRGLPGERGRPGAPGPAGARGNDGATGAAGPPGPTGPAGPPGFPGAVGAKGEAGPQGPRGSEGPQGVRGEPGP PGPAGAAGPAGNPGADGQPGAKGANGAPGIAGAPGFPGARGPSGPQGPGGPPGPKGNSGEPGAPGSKGDTGAKGE PGPVGVQGPPGPAGEEGKRGARGEPGPTGLPGPPGERGGPGSRGFPGADGVAGPKGPAGERGSPGPAGPKGSPGE AGRPGEAGLPGAKGLTGSPGSPGPDGKTGPPGPAGQDGRPGPPGPPGARGQAGVMGFPGPKGAAGEPGKAGERGV PGPPGAVGPAGKDGEAGAQGPPGPAGPAGERGEQGPAGSPGFQGLPGPAGPPGEAGKPGEQGVPGDLGAPGPSGA RGERGFPGERGVQGPPGPAGPRGANGAPGNDGAKGDAGAPGAPGSQGAPGLQGMPGERGAAGLPGPKGDRGDAGP KGADGSPGKDGVRGLTGPIGPPGPAGAPGDKGESGPSGPAGPTGARGAPGDRGEPGPPGPAGFAGPPGADGQPGA KGEPGDAGAKGDAGPPGPAGPAGPPGPIGNVGAPGAKGARGSAGPPGATGFPGAAGRVGPPGPSGNAGPPGPPGP AGKEGGKGPRGETGPAGRPGEVGPPGPPGPAGEKGSPGADGPAGAPGTPGPQGIAGQRGWGLPGQRGERGFPGL PGPSGEPGKQGPSGASGERGPPGPMGPPGLAGPPGESGREGAPGAEGSPGRDGSPGAKGDRGETGPAGPPGAPGA PGAPGPVGPAGKSGDRGETGPAGPAGPVGPVGARGPAGPQGPRGDKGETGEQGDRGIKGHRGFSGLQGPPGPPGS PGEQGPSGASGPAGPRGPPGSAGAPGKDGLNGLPGPIGPPGPRGRTGDAGPVGPPGPPGPPGPPGPPSAGFDFSF LPQPPQEKAHDGGRYYRADDANWRDRDLEVDTTLKSLSQQIENIRSPEGSRKNPARTCRDLKMCHSDWKSGEYW IDPNQGCNLDAIKVFCNMETGETCVYPTQPSVAQKNWYISKNPKDKRHVWFGESMTDGFQFEYGGQGSDPADVAI QLTFLRLMSTEASQNITYHCKNSVAYMDQQTGNLKKALLLQGSNEIEIRAEGNSRFTYSVTVDGCTSHTGAWGKT VIEYKTTKTSRLPI IDVAPLDVGAPDQEFGFDVGPVCFL (SEQ ID NO: 34) .

[0220] An exemplary nucleic acid sequence encoding CXCL12 (NM 199168.3, variant 1) comprises or consists of:

1 gccgcacttt cactctccgt cagccgcatt gcccgctcgg cgtccggccc ccgacccgcg 61 ctcgtccgcc cgcccgcccg cccgcccgcg ccatgaacgc caaggtcgtg gtcgtgctgg 121 tcctcgtgct gaccgcgctc tgcctcagcg acgggaagcc cgtcagcctg agctacagat 181 gcccatgccg attcttcgaa agccatgttg ccagagccaa cgtcaagcat ctcaaaattc 241 tcaacactcc aaactgtgcc cttcagattg tagcccggct gaagaacaac aacagacaag 301 tgtgcattga cccgaagcta aagtggattc aggagtacct ggagaaagct ttaaacaagt 361 aagcacaaca gccaaaaagg actttccgct agacccactc gaggaaaact aaaaccttgt 421 gagagatgaa agggcaaaga cgtgggggag ggggccttaa ccatgaggac caggtgtgtg 481 tgtggggtgg gcacattgat ctgggatcgg gcctgaggtt tgccagcatt tagaccctgc 541 atttatagca tacggtatga tattgcagct tatattcatc catgccctgt acctgtgcac 601 gttggaactt ttattactgg ggtttttcta agaaagaaat tgtattatca acagcatttt 661 caagcagtta gttccttcat gatcatcaca atcatcatca ttctcattct cattttttaa 721 atcaacgagt acttcaagat ctgaatttgg cttgtttgga gcatctcctc tgctcccctg 781 gggagtctgg gcacagtcag gtggtggctt aacagggagc tggaaaaagt gtcctttctt 841 cagacactga ggctcccgca gcagcgcccc tcccaagagg aaggcctctg tggcactcag 901 ataccgactg gggctgggcg ccgccactgc cttcacctcc tctttcaacc tcagtgattg 961 gctctgtggg ctccatgtag aagccactat tactgggact gtgctcagag acccctctcc 1021 cagctattcc tactctctcc ccgactccga gagcatgctt aatcttgctt ctgcttctca 1081 tttctgtagc ctgatcagcg ccgcaccagc cgggaagagg gtgattgctg gggctcgtgc 1141 cctgcatccc tctcctccca gggcctgccc cacagctcgg gccctctgtg agatccgtct 1201 ttggcctcct ccagaatgga gctggccctc tcctggggat gtgtaatggt ccccctgctt 1261 acccgcaaaa gacaagtctt tacagaatca aatgcaattt taaatctgag agctcgcttt 1321 gagtgactgg gttttgtgat tgcctctgaa gcctatgtat gccatggagg cactaacaaa 1381 ctctgaggtt tccgaaatca gaagcgaaaa aatcagtgaa taaaccatca tcttgccact 1441 accccctcct gaagccacag cagggtttca ggttccaatc agaactgttg gcaaggtgac 1501 atttccatgc ataaatgcga tccacagaag gtcctggtgg tatttgtaac tttttgcaag 1561 gcattttttt atatatattt ttgtgcacat ttttttttac gtttctttag aaaacaaatg 1621 tatttcaaaa tatatttata gtcgaacaat tcatatattt gaagtggagc catatgaatg 1681 tcagtagttt atacttctct attatctcaa actactggca atttgtaaag aaatatatat 1741 gatatataaa tgtgattgca gcttttcaat gttagccaca gtgtattttt tcacttgtac 1801 taaaattgta tcaaatgtga cattatatgc actagcaata aaatgctaat tgtttcatgg 1861 tataaacgtc ctactgtatg tgggaattta tttacctgaa ataaaattca ttagttgtta 1921 gtgatggagc ttaaaaaaaa (SEQ ID NO 35) . [0221] An exemplary amino acid sequence encoding CXCL12 (NP 954637.1, isoform alpha, corresponding to transcript variant 1) comprises or consists of:

MNAKWWLVLVLTALCLSDGKPVSLSYRCPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNRQVCIDPK LKWIQEYLEKALNK (SEQ ID NO: 36) .

[0222] An exemplary nucleic acid sequence encoding CXCL12 (NM_000609.6 transcript variant 2) comprises or consists of:

1 gccgcacttt cactctccgt cagccgcatt gcccgctcgg cgtccggccc ccgacccgcg 61 ctcgtccgcc cgcccgcccg cccgcccgcg ccatgaacgc caaggtcgtg gtcgtgctgg 121 tcctcgtgct gaccgcgctc tgcctcagcg acgggaagcc cgtcagcctg agctacagat 181 gcccatgccg attcttcgaa agccatgttg ccagagccaa cgtcaagcat ctcaaaattc 241 tcaacactcc aaactgtgcc cttcagattg tagcccggct gaagaacaac aacagacaag 301 tgtgcattga cccgaagcta aagtggattc aggagtacct ggagaaagct ttaaacaaga 361 ggttcaagat gtgagagggt cagacgcctg aggaaccctt acagtaggag cccagctctg 421 aaaccagtgt tagggaaggg cctgccacag cctcccctgc cagggcaggg ccccaggcat 481 tgccaagggc tttgttttgc acactttgcc atattttcac catttgatta tgtagcaaaa 541 tacatgacat ttatttttca tttagtttga ttattcagtg tcactggcga cacgtagcag 601 cttagactaa ggccattatt gtacttgcct tattagagtg tctttccacg gagccactcc 661 tctgactcag ggctcctggg ttttgtattc tctgagctgt gcaggtgggg agactgggct 721 gagggagcct ggccccatgg tcagccctag ggtggagagc caccaagagg gacgcctggg 781 ggtgccagga ccagtcaacc tgggcaaagc ctagtgaagg cttctctctg tgggatggga 841 tggtggaggg ccacatggga ggctcacccc cttctccatc cacatgggag ccgggtctgc 901 ctcttctggg agggcagcag ggctaccctg agctgaggca gcagtgtgag gccagggcag 961 agtgagaccc agccctcatc ccgagcacct ccacatcctc cacgttctgc tcatcattct 1021 ctgtctcatc catcatcatg tgtgtccacg actgtctcca tggccccgca aaaggactct 1081 caggaccaaa gctttcatgt aaactgtgca ccaagcagga aatgaaaatg tcttgtgtta 1141 cctgaaaaca ctgtgcacat ctgtgtcttg tttggaatat tgtccattgt ccaatcctat 1201 gtttttgttc aaagccagcg tcctcctctg tgaccaatgt cttgatgcat gcactgttcc 1261 ccctgtgcag ccgctgagcg aggagatgct ccttgggccc tttgagtgca gtcctgatca 1321 gagccgtggt cctttggggt gaactacctt ggttccccca ctgatcacaa aaacatggtg 1381 ggtccatggg cagagcccaa gggaattcgg tgtgcaccag ggttgacccc agaggattgc 1441 tgccccatca gtgctccctc acatgtcagt accttcaaac tagggccaag cccagcactg 1501 cttgaggaaa acaagcattc acaacttgtt tttggttttt aaaacccagt ccacaaaata 1561 accaatcctg gacatgaaga ttctttccca attcacatct aacctcatct tcttcaccat 1621 ttggcaatgc catcatctcc tgccttcctc ctgggccctc tctgctctgc gtgtcacctg 1681 tgcttcgggc ccttcccaca ggacatttct ctaagagaac aatgtgctat gtgaagagta 1741 agtcaacctg cctgacattt ggagtgttcc ccttccactg agggcagtcg atagagctgt 1801 attaagccac ttaaaatgtt cacttttgac aaaggcaagc acttgtgggt ttttgttttg 1861 tttttcattc agtcttacga atacttttgc cctttgatta aagactccag ttaaaaaaaa 1921 ttttaatgaa gaaagtggaa aacaaggaag tcaaagcaag gaaactatgt aacatgtagg 1981 aagtaggaag taaattatag tgatgtaatc ttgaattgta actgttcttg aatttaataa 2041 tctgtagggt aattagtaac atgtgttaag tattttcata agtatttcaa attggagctt 2101 catggcagaa ggcaaaccca tcaacaaaaa ttgtccctta aacaaaaatt aaaatcctca 2161 atccagctat gttatattga aaaaatagag cctgagggat ctttactagt tataaagata 2221 cagaactctt tcaaaacctt ttgaaattaa cctctcacta taccagtata attgagtttt 2281 cagtggggca gtcattatcc aggtaatcca agatatttta aaatctgtca cgtagaactt 2341 ggatgtacct gcccccaatc catgaaccaa gaccattgaa ttcttggttg aggaaacaaa 2401 catgacccta aatcttgact acagtcagga aaggaatcat ttctatttct cctccatggg 2461 agaaaataga taagagtaga aactgcaggg aaaattattt gcataacaat tcctctacta 2521 acaatcagct ccttcctgga gactgcccag ctaaagcaat atgcatttaa atacagtctt 2581 ccatttgcaa gggaaaagtc tcttgtaatc cgaatctctt tttgctttcg aactgctagt 2641 caagtgcgtc cacgagctgt ttactaggga tccctcatct gtccctccgg gacctggtgc 2701 tgcctctacc tgacactccc ttgggctccc tgtaacctct tcagaggccc tcgctgccag 2761 ctctgtatca ggacccagag gaaggggcca gaggctcgtt gactggctgt gtgttgggat 2821 tgagtctgtg ccacgtgttt gtgctgtggt gtgtccccct ctgtccaggc actgagatac 2881 cagcgaggag gctccagagg gcactctgct tgttattaga gattacctcc tgagaaaaaa 2941 ggttccgctt ggagcagagg ggctgaatag cagaaggttg cacctccccc aaccttagat 3001 gttctaagtc tttccattgg atctcattgg acccttccat ggtgtgatcg tctgactggt 3061 gttatcaccg tgggctccct gactgggagt tgatcgcctt tcccaggtgc tacacccttt 3121 tccagctgga tgagaatttg agtgctctga tccctctaca gagcttccct gactcattct 3181 gaaggagccc cattcctggg aaatattccc tagaaacttc caaatcccct aagcagacca 3241 ctgataaaac catgtagaaa atttgttatt ttgcaacctc gctggactct cagtctctga 3301 gcagtgaatg attcagtgtt aaatgtgatg aatactgtat tttgtattgt ttcaattgca 3361 tctcccagat aatgtgaaaa tggtccagga gaaggccaat tcctatacgc agcgtgcttt 3421 aaaaaataaa taagaaacaa ctctttgaga aacaacaatt tctactttga agtcatacca 3481 atgaaaaaat gtatatgcac ttataatttt cctaataaag ttctgtactc aaatgtagcc 3541 accaacagt (SEQ ID NO: 37) .

[0223] An exemplary amino acid sequence encoding CXCL12 (NP_000600.1, isoform beta, corresponding to transcript variant 2) comprises or consists of:

MNAKWWLVLVLTALCLSDGKPVSLSYRCPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNRQVCIDPK LKWIQEYLEKALNKRFKM (SEQ ID NO: 38) .

[0224] An exemplary nucleic acid sequence encoding CXCL12 (NM_001033886.2 transcript variant 3) comprises or consists of:

1 gccgcacttt cactctccgt cagccgcatt gcccgctcgg cgtccggccc ccgacccgcg

61 ctcgtccgcc cgcccgcccg cccgcccgcg ccatgaacgc caaggtcgtg gtcgtgctgg

121 tcctcgtgct gaccgcgctc tgcctcagcg acgggaagcc cgtcagcctg agctacagat

181 gcccatgccg attcttcgaa agccatgttg ccagagccaa cgtcaagcat ctcaaaattc

241 tcaacactcc aaactgtgcc cttcagattg tagcccggct gaagaacaac aacagacaag

301 tgtgcattga cccgaagcta aagtggattc aggagtacct ggagaaagct ttaaacaagg

361 ggcgcagaga agaaaaagtg gggaaaaaag aaaagatagg aaaaaagaag cgacagaaga

421 agagaaaggc tgcccagaaa aggaaaaact agttatctgc cacctcgaga tggaccacag

481 ttcacttgct ctcggcgctt tgtaaatttg ctcgatcctc ctcc (SEQ ID NO: 39) .

[0225] An exemplary amino acid sequence encoding CXCL12 (NP_001029058.1 , isoform gamma, corresponding to transcript variant 3) comprises or consists of:

MNAKWWLVLVLTALCLSDGKPVSLSYRCPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNRQVCIDPK LKWIQEYLEKALNKGRREEKVGKKEKIGKKKRQKKRKAAQKRKN (SEQ ID NO: 40) .

[0226] An exemplary nucleic acid sequence encoding CXCL12 (NM_001 178134.1 transcript variant 4) comprises or consists of:

1 gccgcacttt cactctccgt cagccgcatt gcccgctcgg cgtccggccc ccgacccgcg 61 ctcgtccgcc cgcccgcccg cccgcccgcg ccatgaacgc caaggtcgtg gtcgtgctgg 121 tcctcgtgct gaccgcgctc tgcctcagcg acgggaagcc cgtcagcctg agctacagat 181 gcccatgccg attcttcgaa agccatgttg ccagagccaa cgtcaagcat ctcaaaattc 241 tcaacactcc aaactgtgcc cttcagattg tagcccggct gaagaacaac aacagacaag 301 tgtgcattga cccgaagcta aagtggattc aggagtacct ggagaaagct ttaaacaacc 361 tgatcagcgc cgcaccagcc gggaagaggg tgattgctgg ggctcgtgcc ctgcatccct 421 ctcctcccag ggcctgcccc acagctcggg ccctctgtga gatccgtctt tggcctcctc 481 cagaatggag ctggccctct cctggggatg tgtaatggtc cccctgctta cccgcaaaag 541 acaagtcttt acagaatcaa atgcaatttt aaatctgaga gctcgctttg agtgactggg 601 ttttgtgatt gcctctgaag cctatgtatg ccatggaggc actaacaaac tctgaggttt 661 ccgaaatcag aagcgaaaaa atcagtgaat aaaccatcat cttgccacta ccccctcctg 721 aagccacagc agggtttcag gttccaatca gaactgttgg caaggtgaca tttccatgca 781 taaatgcgat ccacagaagg tcctggtggt atttgtaact ttttgcaagg cattttttta 841 tatatatttt tgtgcacatt tttttttacg tttctttaga aaacaaatgt atttcaaaat 901 atatttatag tcgaacaatt catatatttg aagtggagcc atatgaatgt cagtagttta 961 tacttctcta ttatctcaaa ctactggcaa tttgtaaaga aatatatatg atatataaat 1021 gtgattgcag cttttcaatg ttagccacag tgtatttttt cacttgtact aaaattgtat 1081 caaatgtgac attatatgca ctagcaataa aatgctaatt gtttcatggt ataaacgtcc 1141 tactgtatgt gggaatttat ttacctgaaa taaaattcat tagttgttag tgatggagct 1201 taaaaaaaa (SEQ ID NO: 41) .

[0227] An exemplary amino acid sequence encoding CXCL12 (NP_001171605.1 , isoform delta) comprises or consists of:

MNAKWWLVLVLTALCLSDGKPVSLSYRCPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNRQVCIDPK LKWIQEYLEKALNNLISAAPAGKRVIAGARALHPSPPRACPTARALCEIRLWPPPEWSWPSPGDV (SEQ ID

NO: 42)

[0228] An exemplary nucleic acid sequence encoding CXCL12 (NM_001277990.1 transcript variant 5) comprises or consists of:

1 gccgcacttt cactctccgt cagccgcatt gcccgctcgg cgtccggccc ccgacccgcg 61 ctcgtccgcc cgcccgcccg cccgcccgcg ccatgaacgc caaggtcgtg gtcgtgctgg 121 tcctcgtgct gaccgcgctc tgcctcagcg acgggaagcc cgtcagcctg agctacagat 181 gcccatgccg attcttcgaa agccattatt gtacttgcct tattagagtg tctttccacg 241 gagccactcc tctgactcag ggctcctggg ttttgtattc tctgagctgt gcaggtgggg 301 agactgggct gagggagcct ggccccatgg tcagccctag ggtggagagc caccaagagg 361 gacgcctggg ggtgccagga ccagtcaacc tgggcaaagc ctagtgaagg cttctctctg 421 tgggatggga tggtggaggg ccacatggga ggctcacccc cttctccatc cacatgggag 481 ccgggtctgc ctcttctggg agggcagcag ggctaccctg agctgaggca gcagtgtgag 541 gccagggcag agtgagaccc agccctcatc ccgagcacct ccacatcctc cacgttctgc 601 tcatcattct ctgtctcatc catcatcatg tgtgtccacg actgtctcca tggccccgca 661 aaaggactct caggaccaaa gctttcatgt aaactgtgca ccaagcagga aatgaaaatg 721 tcttgtgtta cctgaaaaca ctgtgcacat ctgtgtcttg tttggaatat tgtccattgt 781 ccaatcctat gtttttgttc aaagccagcg tcctcctctg tgaccaatgt cttgatgcat 841 gcactgttcc ccctgtgcag ccgctgagcg aggagatgct ccttgggccc tttgagtgca 901 gtcctgatca gagccgtggt cctttggggt gaactacctt ggttccccca ctgatcacaa 961 aaacatggtg ggtccatggg cagagcccaa gggaattcgg tgtgcaccag ggttgacccc 1021 agaggattgc tgccccatca gtgctccctc acatgtcagt accttcaaac tagggccaag 1081 cccagcactg cttgaggaaa acaagcattc acaacttgtt tttggttttt aaaacccagt 1141 ccacaaaata accaatcctg gacatgaaga ttctttccca attcacatct aacctcatct 1201 tcttcaccat ttggcaatgc catcatctcc tgccttcctc ctgggccctc tctgctctgc 1261 gtgtcacctg tgcttcgggc ccttcccaca ggacatttct ctaagagaac aatgtgctat 1321 gtgaagagta agtcaacctg cctgacattt ggagtgttcc ccttccactg agggcagtcg 1381 atagagctgt attaagccac ttaaaatgtt cacttttgac aaaggcaagc acttgtgggt 1441 ttttgttttg tttttcattc agtcttacga atacttttgc cctttgatta aagactccag 1501 ttaaaaaaaa ttttaatgaa gaaagtggaa aacaaggaag tcaaagcaag gaaactatgt 1561 aacatgtagg aagtaggaag taaattatag tgatgtaatc ttgaattgta actgttcttg 1621 aatttaataa tctgtagggt aattagtaac atgtgttaag tattttcata agtatttcaa 1681 attggagctt catggcagaa ggcaaaccca tcaacaaaaa ttgtccctta aacaaaaatt 1741 aaaatcctca atccagctat gttatattga aaaaatagag cctgagggat ctttactagt 1801 tataaagata cagaactctt tcaaaacctt ttgaaattaa cctctcacta taccagtata 1861 attgagtttt cagtggggca gtcattatcc aggtaatcca agatatttta aaatctgtca 1921 cgtagaactt ggatgtacct gcccccaatc catgaaccaa gaccattgaa ttcttggttg 1981 aggaaacaaa catgacccta aatcttgact acagtcagga aaggaatcat ttctatttct 2041 cctccatggg agaaaataga taagagtaga aactgcaggg aaaattattt gcataacaat 2101 tcctctacta acaatcagct ccttcctgga gactgcccag ctaaagcaat atgcatttaa 2161 atacagtctt ccatttgcaa gggaaaagtc tcttgtaatc cgaatctctt tttgctttcg 2221 aactgctagt caagtgcgtc cacgagctgt ttactaggga tccctcatct gtccctccgg 2281 gacctggtgc tgcctctacc tgacactccc ttgggctccc tgtaacctct tcagaggccc 2341 tcgctgccag ctctgtatca ggacccagag gaaggggcca gaggctcgtt gactggctgt 2401 gtgttgggat tgagtctgtg ccacgtgttt gtgctgtggt gtgtccccct ctgtccaggc 2461 actgagatac cagcgaggag gctccagagg gcactctgct tgttattaga gattacctcc

2521 tgagaaaaaa ggttccgctt ggagcagagg ggctgaatag cagaaggttg cacctccccc

2581 aaccttagat gttctaagtc tttccattgg atctcattgg acccttccat ggtgtgatcg

2641 tctgactggt gttatcaccg tgggctccct gactgggagt tgatcgcctt tcccaggtgc

2701 tacacccttt tccagctgga tgagaatttg agtgctctga tccctctaca gagcttccct

2761 gactcattct gaaggagccc cattcctggg aaatattccc tagaaacttc caaatcccct

2821 aagcagacca ctgataaaac catgtagaaa atttgttatt ttgcaacctc gctggactct

2881 cagtctctga gcagtgaatg attcagtgtt aaatgtgatg aatactgtat tttgtattgt

2941 ttcaattgca tctcccagat aatgtgaaaa tggtccagga gaaggccaat tcctatacgc

3001 agcgtgcttt aaaaaataaa taagaaacaa ctctttgaga aacaacaatt tctactttga

3061 agtcatacca atgaaaaaat gtatatgcac ttataatttt cctaataaag ttctgtactc

3121 aaatgtagcc accaacagt (SEQ ID NO: 43).

[0229] An exemplary amino acid sequence encoding CXCL12 (NP_001264919.1 isoform 5) comprises or consists of:

MNAKWWLVLVLTALCLSDGKPVSLSYRCPCRFFESHYCTCLIRVSFHGATPLTQGS VLYSLSCAGGETGLRE

PGPMVSPRVESHQEGRLGVPGPVNLGKA (SEQ ID NO: 44)

[0230] An exemplary nucleic acid sequence encoding CXCR4 (NM_001008540.2 transcript variant 1) comprises or consists of:

1 cttccctcta gtgggcgggg cagaggagtt agccaagatg tgactttgaa accctcagcg 61 tctcagtgcc cttttgttct aaacaaagaa ttttgtaatt ggttctacca aagaaggata 121 taatgaagtc actatgggaa aagatgggga ggagagttgt aggattctac attaattctc 181 ttgtgccctt agcccactac ttcagaattt cctgaagaaa gcaagcctga attggttttt 241 taaattgctt taaaaatttt ttttaactgg gttaatgctt gctgaattgg aagtgaatgt 301 ccattccttt gcctcttttg cagatataca cttcagataa ctacaccgag gaaatgggct 361 caggggacta tgactccatg aaggaaccct gtttccgtga agaaaatgct aatttcaata 421 aaatcttcct gcccaccatc tactccatca tcttcttaac tggcattgtg ggcaatggat 481 tggtcatcct ggtcatgggt taccagaaga aactgagaag catgacggac aagtacaggc 541 tgcacctgtc agtggccgac ctcctctttg tcatcacgct tcccttctgg gcagttgatg 601 ccgtggcaaa ctggtacttt gggaacttcc tatgcaaggc agtccatgtc atctacacag 661 tcaacctcta cagcagtgtc ctcatcctgg ccttcatcag tctggaccgc tacctggcca 721 tcgtccacgc caccaacagt cagaggccaa ggaagctgtt ggctgaaaag gtggtctatg 781 ttggcgtctg gatccctgcc ctcctgctga ctattcccga cttcatcttt gccaacgtca 841 gtgaggcaga tgacagatat atctgtgacc gcttctaccc caatgacttg tgggtggttg 901 tgttccagtt tcagcacatc atggttggcc ttatcctgcc tggtattgtc atcctgtcct 961 gctattgcat tatcatctcc aagctgtcac actccaaggg ccaccagaag cgcaaggccc 1021 tcaagaccac agtcatcctc atcctggctt tcttcgcctg ttggctgcct tactacattg 1081 ggatcagcat cgactccttc atcctcctgg aaatcatcaa gcaagggtgt gagtttgaga 1141 acactgtgca caagtggatt tccatcaccg aggccctagc tttcttccac tgttgtctga 1201 accccatcct ctatgctttc cttggagcca aatttaaaac ctctgcccag cacgcactca 1261 cctctgtgag cagagggtcc agcctcaaga tcctctccaa aggaaagcga ggtggacatt 1321 catctgtttc cactgagtct gagtcttcaa gttttcactc cagctaacac agatgtaaaa 1381 gacttttttt tatacgataa ataacttttt tttaagttac acatttttca gatataaaag 1441 actgaccaat attgtacagt ttttattgct tgttggattt ttgtcttgtg tttctttagt 1501 ttttgtgaag tttaattgac ttatttatat aaattttttt tgtttcatat tgatgtgtgt 1561 ctaggcagga cctgtggcca agttcttagt tgctgtatgt ctcgtggtag gactgtagaa 1621 aagggaactg aacattccag agcgtgtagt gaatcacgta aagctagaaa tgatccccag 1681 ctgtttatgc atagataatc tctccattcc cgtggaacgt ttttcctgtt cttaagacgt 1741 gattttgctg tagaagatgg cacttataac caaagcccaa agtggtatag aaatgctggt 1801 ttttcagttt tcaggagtgg gttgatttca gcacctacag tgtacagtct tgtattaagt 1861 tgttaataaa agtacatgtt aaacttaaaa aaaaaaaaaa aaaa (SEQ ID NO: 45) .

[0231] An exemplary amino acid sequence encoding CXCR4 (NP_001008540.1 isoform a) comprises or consists of: MSIPLPLLQIYTSDNYTEEMGSGDYDSMKEPCFREENANFNKIFLPTIYSIIFLTGIVGNGL VILVMGYQKKLRSMTDKYRLHLSVADLLFVITLPFWAVDAVANWYFGNFLCKAVHVIYTVNL YSSVLILAFISLDRYLAIVHATNSQRPRKLLAEKWYVGVWIPALLLTIPDFIFANVSEADD RYICDRFYPNDLWVWFQFQHIMVGLILPGIVILSCYCIIISKLSHSKGHQKRKALKTTVIL ILAFFACWLPYYIGISIDSFILLEIIKQGCEFENTVHKWISITEALAFFHCCLNPILYAFLG AKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS (SEQ ID NO: 46) .

[0232] An exemplary nucleic acid sequence encoding CXCR4 (NM_003467.2 transcript 2) comprises or consists of:

1 aacttcagtt tgttggctgc ggcagcaggt agcaaagtga cgccgagggc ctgagtgctc 61 cagtagccac cgcatctgga gaaccagcgg ttaccatgga ggggatcagt atatacactt 121 cagataacta caccgaggaa atgggctcag gggactatga ctccatgaag gaaccctgtt 181 tccgtgaaga aaatgctaat ttcaataaaa tcttcctgcc caccatctac tccatcatct 241 tcttaactgg cattgtgggc aatggattgg tcatcctggt catgggttac cagaagaaac 301 tgagaagcat gacggacaag tacaggctgc acctgtcagt ggccgacctc ctctttgtca 361 tcacgcttcc cttctgggca gttgatgccg tggcaaactg gtactttggg aacttcctat 421 gcaaggcagt ccatgtcatc tacacagtca acctctacag cagtgtcctc atcctggcct 481 tcatcagtct ggaccgctac ctggccatcg tccacgccac caacagtcag aggccaagga 541 agctgttggc tgaaaaggtg gtctatgttg gcgtctggat ccctgccctc ctgctgacta 601 ttcccgactt catctttgcc aacgtcagtg aggcagatga cagatatatc tgtgaccgct 661 tctaccccaa tgacttgtgg gtggttgtgt tccagtttca gcacatcatg gttggcctta 721 tcctgcctgg tattgtcatc ctgtcctgct attgcattat catctccaag ctgtcacact 781 ccaagggcca ccagaagcgc aaggccctca agaccacagt catcctcatc ctggctttct 841 tcgcctgttg gctgccttac tacattggga tcagcatcga ctccttcatc ctcctggaaa 901 tcatcaagca agggtgtgag tttgagaaca ctgtgcacaa gtggatttcc atcaccgagg 961 ccctagcttt cttccactgt tgtctgaacc ccatcctcta tgctttcctt ggagccaaat 1021 ttaaaacctc tgcccagcac gcactcacct ctgtgagcag agggtccagc ctcaagatcc 1081 tctccaaagg aaagcgaggt ggacattcat ctgtttccac tgagtctgag tcttcaagtt 1141 ttcactccag ctaacacaga tgtaaaagac ttttttttat acgataaata actttttttt 1201 aagttacaca tttttcagat ataaaagact gaccaatatt gtacagtttt tattgcttgt 1261 tggatttttg tcttgtgttt ctttagtttt tgtgaagttt aattgactta tttatataaa 1321 ttttttttgt ttcatattga tgtgtgtcta ggcaggacct gtggccaagt tcttagttgc 1381 tgtatgtctc gtggtaggac tgtagaaaag ggaactgaac attccagagc gtgtagtgaa 1441 tcacgtaaag ctagaaatga tccccagctg tttatgcata gataatctct ccattcccgt 1501 ggaacgtttt tcctgttctt aagacgtgat tttgctgtag aagatggcac ttataaccaa 1561 agcccaaagt ggtatagaaa tgctggtttt tcagttttca ggagtgggtt gatttcagca 1621 cctacagtgt acagtcttgt attaagttgt taataaaagt acatgttaaa cttaaaaaaa 1681 aaaaaaaaaa a (SEQ ID NO: 47)

[0233] An exemplary amino acid sequence encoding CXCR4 (NP 003458.1 isoform b) comprises or consists of:

MEGISIYTSDNYTEEMGSGDYDSMKEPCFREENANFNKIFLPTIYSI IFLTGIVGNGLVILVMGYQKKLRSMTDK YRLHLSVADLLFVITLPFWAVDAVANWYFGNFLCKAVHVIYTVNLYSSVLILAFISLDRYLAIVHATNSQRPRKL LAEKWYVGVWIPALLLTIPDFIFANVSEADDRYICDRFYPNDLWVWFQFQHIMVGLILPGIVILSCYCIIISK LSHSKGHQKRKALKTTVILILAFFACWLPYYIGISIDSFILLEIIKQGCEFENTVHKWISITEALAFFHCCLNPI LYAFLGAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS (SEQ ID NO: 48) .

[0234] An exemplary nucleic acid sequence encoding CXCR4 (NM_001348056.1) comprises or consists of:

1 aacttcagtt tgttggctgc ggcagcaggt agcaaagtga cgccgagggc ctgagtgctc 61 cagtagccac cgcatctgga gaaccagcgg ttaccatgga ggggatcagt gaaaatgccc 121 cgctccctaa cgtcccaaac gcgccaagtg ataaacacga ggatggcaag agacccacac 181 accggaggag cgcccgcttg ggggaggagg tgccgtttgt tcattttctg acactcccgc 241 ccaatatacc ccaagcaccg aagggccttc gttttaagac cgcattctct ttacccacta 301 caagttgctt gaagcccaga atgatataca cttcagataa ctacaccgag gaaatgggct 361 caggggacta tgactccatg aaggaaccct gtttccgtga agaaaatgct aatttcaata 421 aaatcttcct gcccaccatc tactccatca tcttcttaac tggcattgtg ggcaatggat 481 tggtcatcct ggtcatgggt taccagaaga aactgagaag catgacggac aagtacaggc 541 tgcacctgtc agtggccgac ctcctctttg tcatcacgct tcccttctgg gcagttgatg 601 ccgtggcaaa ctggtacttt gggaacttcc tatgcaaggc agtccatgtc atctacacag 661 tcaacctcta cagcagtgtc ctcatcctgg ccttcatcag tctggaccgc tacctggcca 721 tcgtccacgc caccaacagt cagaggccaa ggaagctgtt ggctgaaaag gtggtctatg 781 ttggcgtctg gatccctgcc ctcctgctga ctattcccga cttcatcttt gccaacgtca 841 gtgaggcaga tgacagatat atctgtgacc gcttctaccc caatgacttg tgggtggttg 901 tgttccagtt tcagcacatc atggttggcc ttatcctgcc tggtattgtc atcctgtcct 961 gctattgcat tatcatctcc aagctgtcac actccaaggg ccaccagaag cgcaaggccc 1021 tcaagaccac agtcatcctc atcctggctt tcttcgcctg ttggctgcct tactacattg 1081 ggatcagcat cgactccttc atcctcctgg aaatcatcaa gcaagggtgt gagtttgaga 1141 acactgtgca caagtggatt tccatcaccg aggccctagc tttcttccac tgttgtctga 1201 accccatcct ctatgctttc cttggagcca aatttaaaac ctctgcccag cacgcactca 1261 cctctgtgag cagagggtcc agcctcaaga tcctctccaa aggaaagcga ggtggacatt 1321 catctgtttc cactgagtct gagtcttcaa gttttcactc cagctaacac agatgtaaaa 1381 gacttttttt tatacgataa ataacttttt tttaagttac acatttttca gatataaaag 1441 actgaccaat attgtacagt ttttattgct tgttggattt ttgtcttgtg tttctttagt 1501 ttttgtgaag tttaattgac ttatttatat aaattttttt tgtttcatat tgatgtgtgt 1561 ctaggcagga cctgtggcca agttcttagt tgctgtatgt ctcgtggtag gactgtagaa 1621 aagggaactg aacattccag agcgtgtagt gaatcacgta aagctagaaa tgatccccag 1681 ctgtttatgc atagataatc tctccattcc cgtggaacgt ttttcctgtt cttaagacgt 1741 gattttgctg tagaagatgg cacttataac caaagcccaa agtggtatag aaatgctggt 1801 ttttcagttt tcaggagtgg gttgatttca gcacctacag tgtacagtct tgtattaagt 1861 tgttaataaa agtacatgtt aaacttaaaa aaaaaaaaaa aaaa (SEQ ID NO: 49) .

[0235] An exemplary amino acid sequence encoding CXCR4 (NP_001334985.1 isoform c) comprises or consists of:

MEGISENAPLPNVPNAPSDKHEDGKRPTHRRSARLGEEVPFVHFLTLPPNIPQAPKGLRFKTAFSLPTTSCLKPR MIYTSDNYTEEMGSGDYDSMKEPCFREENANFNKIFLPTIYSI IFLTGIVGNGLVILVMGYQKKLRSMTDKYRLH LSVADLLFVITLPFWAVDAVANWYFGNFLCKAVHVIYTVNLYSSVLILAFISLDRYLAIVHATNSQRPRKLLAEK WYVGVWIPALLLTIPDFIFANVSEADDRYICDRFYPNDLWVWFQFQHIMVGLILPGIVILSCYCIIISKLSHS KGHQKRKALKTTVILILAFFACWLPYYIGISIDSFILLEIIKQGCEFENTVHKWISITEALAFFHCCLNPILYAF LGAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS (SEQ ID NO: 50) .

[0236] An exemplary nucleic acid sequence encoding CXCR4 (NM_001348059.1 variant 4) comprises or consists of:

1 aacttcagtt tgttggctgc ggcagcaggt agcaaagtga cgccgagggc ctgagtgctc 61 cagtagccac cgcatctgga gaaccagcgg ttaccatgga ggggatcagt gaaaatgccc 121 cgctccctaa cgtcccaaac gcgccaagtg ataaacacga ggatggcaag agacccacac 181 accggaggag cgcccgcttg ggggaggaga tatacacttc agataactac accgaggaaa 241 tgggctcagg ggactatgac tccatgaagg aaccctgttt ccgtgaagaa aatgctaatt 301 tcaataaaat cttcctgccc accatctact ccatcatctt cttaactggc attgtgggca 361 atggattggt catcctggtc atgggttacc agaagaaact gagaagcatg acggacaagt 421 acaggctgca cctgtcagtg gccgacctcc tctttgtcat cacgcttccc ttctgggcag 481 ttgatgccgt ggcaaactgg tactttggga acttcctatg caaggcagtc catgtcatct 541 acacagtcaa cctctacagc agtgtcctca tcctggcctt catcagtctg gaccgctacc 601 tggccatcgt ccacgccacc aacagtcaga ggccaaggaa gctgttggct gaaaaggtgg 661 tctatgttgg cgtctggatc cctgccctcc tgctgactat tcccgacttc atctttgcca 721 acgtcagtga ggcagatgac agatatatct gtgaccgctt ctaccccaat gacttgtggg 781 tggttgtgtt ccagtttcag cacatcatgg ttggccttat cctgcctggt attgtcatcc 841 tgtcctgcta ttgcattatc atctccaagc tgtcacactc caagggccac cagaagcgca 901 aggccctcaa gaccacagtc atcctcatcc tggctttctt cgcctgttgg ctgccttact 961 acattgggat cagcatcgac tccttcatcc tcctggaaat catcaagcaa gggtgtgagt 1021 ttgagaacac tgtgcacaag tggatttcca tcaccgaggc cctagctttc ttccactgtt 1081 gtctgaaccc catcctctat gctttccttg gagccaaatt taaaacctct gcccagcacg 1141 cactcacctc tgtgagcaga gggtccagcc tcaagatcct ctccaaagga aagcgaggtg 1201 gacattcatc tgtttccact gagtctgagt cttcaagttt tcactccagc taacacagat 1261 gtaaaagact tttttttata cgataaataa ctttttttta agttacacat ttttcagata 1321 taaaagactg accaatattg tacagttttt attgcttgtt ggatttttgt cttgtgtttc 1381 tttagttttt gtgaagttta attgacttat ttatataaat tttttttgtt tcatattgat 1441 gtgtgtctag gcaggacctg tggccaagtt cttagttgct gtatgtctcg tggtaggact 1501 gtagaaaagg gaactgaaca ttccagagcg tgtagtgaat cacgtaaagc tagaaatgat 1561 ccccagctgt ttatgcatag ataatctctc cattcccgtg gaacgttttt cctgttctta 1621 agacgtgatt ttgctgtaga agatggcact tataaccaaa gcccaaagtg gtatagaaat 1681 gctggttttt cagttttcag gagtgggttg atttcagcac ctacagtgta cagtcttgta 1741 ttaagttgtt aataaaagta catgttaaac ttaaaaaaaa aaaaaaaaaa (SEQ ID

NO:

[0237] An exemplary amino acid sequence encoding CXCR4 (NP_001334988.1, isoform d) comprises or consists of:

MEGISENAPLPNVPNAPSDKHEDGKRPTHRRSARLGEEIYTSDNYTEEMGSGDYDSMKEPCFREENANFNKIFLP TIYSIIFLTGIVGNGLVILVMGYQKKLRSMTDKYRLHLSVADLLFVITLPFWAVDAVANWYFGNFLCKAVHVIYT VNLYSSVLILAFISLDRYLAIVHATNSQRPRKLLAEKWYVGVWIPALLLTIPDFIFANVSEADDRYICDRFYPN DLWVVVFQFQHIMVGLILPGIVILSCYCII ISKLSHSKGHQKRKALKTTVILILAFFACWLPYYIGISIDSFILL EIIKQGCEFENTVHKWISITEALAFFHCCLNPILYAFLGAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVST ESESSSFHSS (SEQ ID NO: 52) .

[0238] An exemplary nucleic acid sequence encoding CXCR4 (NM_001348060.1 variant 5) comprises or consists of:

1 gagttacatt gtctgaattt agaggcggag ggcggcgtgc ctgggctgag ttcccaggag 61 gagattgcgc ccgctttaac ttcggggtta agcgcctggt gactgttctt gacactggat 121 atacacttca gataactaca ccgaggaaat gggctcaggg gactatgact ccatgaagga 181 accctgtttc cgtgaagaaa atgctaattt caataaaatc ttcctgccca ccatctactc 241 catcatcttc ttaactggca ttgtgggcaa tggattggtc atcctggtca tgggttacca 301 gaagaaactg agaagcatga cggacaagta caggctgcac ctgtcagtgg ccgacctcct 361 ctttgtcatc acgcttccct tctgggcagt tgatgccgtg gcaaactggt actttgggaa 421 cttcctatgc aaggcagtcc atgtcatcta cacagtcaac ctctacagca gtgtcctcat 481 cctggccttc atcagtctgg accgctacct ggccatcgtc cacgccacca acagtcagag 541 gccaaggaag ctgttggctg aaaaggtggt ctatgttggc gtctggatcc ctgccctcct 601 gctgactatt cccgacttca tctttgccaa cgtcagtgag gcagatgaca gatatatctg 661 tgaccgcttc taccccaatg acttgtgggt ggttgtgttc cagtttcagc acatcatggt 721 tggccttatc ctgcctggta ttgtcatcct gtcctgctat tgcattatca tctccaagct 781 gtcacactcc aagggccacc agaagcgcaa ggccctcaag accacagtca tcctcatcct 841 ggctttcttc gcctgttggc tgccttacta cattgggatc agcatcgact ccttcatcct 901 cctggaaatc atcaagcaag ggtgtgagtt tgagaacact gtgcacaagt ggatttccat 961 caccgaggcc ctagctttct tccactgttg tctgaacccc atcctctatg ctttccttgg 1021 agccaaattt aaaacctctg cccagcacgc actcacctct gtgagcagag ggtccagcct 1081 caagatcctc tccaaaggaa agcgaggtgg acattcatct gtttccactg agtctgagtc 1141 ttcaagtttt cactccagct aacacagatg taaaagactt ttttttatac gataaataac 1201 ttttttttaa gttacacatt tttcagatat aaaagactga ccaatattgt acagttttta 1261 ttgcttgttg gatttttgtc ttgtgtttct ttagtttttg tgaagtttaa ttgacttatt 1321 tatataaatt ttttttgttt catattgatg tgtgtctagg caggacctgt ggccaagttc 1381 ttagttgctg tatgtctcgt ggtaggactg tagaaaaggg aactgaacat tccagagcgt 1441 gtagtgaatc acgtaaagct agaaatgatc cccagctgtt tatgcataga taatctctcc 1501 attcccgtgg aacgtttttc ctgttcttaa gacgtgattt tgctgtagaa gatggcactt 1561 ataaccaaag cccaaagtgg tatagaaatg ctggtttttc agttttcagg agtgggttga 1621 tttcagcacc tacagtgtac agtcttgtat taagttgtta ataaaagtac atgttaaact 1681 taaaaaaaaa aaaaaaaaa (SEQ ID NO: 53).

[0239] An exemplary amino acid sequence encoding CXCR4 (NP_001334989.1 , isoform e) comprises or consists of:

MGSGDYDSMKEPCFREENANFNKIFLPTIYSIIFLTGIVGNGLVILVMGYQKKLRSMTDKYRLHLSVADLLFVIT LPFWAVDAVANWYFGNFLCKAVHVIYTVNLYSSVLILAFISLDRYLAIVHATNSQRPRKLLAEKWYVGVWIPAL LLTIPDFIFANVSEADDRYICDRFYPNDLWVVVFQFQHIMVGLILPGIVILSCYCI IISKLSHSKGHQKRKALKT TVILILAFFACWLPYYIGISIDSFILLEIIKQGCEFENTVHKWISITEALAFFHCCLNPILYAFLGAKFKTSAQH ALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS (SEQ ID NO: 54) .

[0240] An exemplary nucleic acid sequence encoding DDR2 (NM 001014796.1 variant 1) comprises or consists of:

1 gaatcctcag aatgtgaggt ttctctcaaa ggcatcttgc atcagcctgt ggatgtatgc 61 ctaccaccgg gctccttcac cagcaaagtg gaaaaagaag cgtttcacaa caaattcttc 121 tttttgggtt ggggaaacgc agtggattat agctctgttt tcttctttcc aaaactgtgc 181 acccctggat gaaacctcca tcaagggaga cctacaagtt gcctggggtt cagtgctcta 241 gaaagttcca aggtttgtgg cttgaattat tctaaagaag ctgaaataat tgaagagaag 301 cagaggccag ctgtttttga ggatcctgct ccacagagaa tgctctgcac ccgttgatat 361 gcctcccagg acccagaggg agactgtagc ctcatttctg tggagacctt tggctggact 421 ctcctggctc tcccagagac tccagttcca acaccatctt ctgagatgat cctgattccc 481 agaatgctct tggtgctgtt cctgctgctg cctatcttga gttctgcaaa agctcaggtt 541 aatccagcta tatgccgcta tcctctgggc atgtcaggag gccagattcc agatgaggac 601 atcacagctt ccagtcagtg gtcagagtcc acagctgcca aatatggaag gctggactca 661 gaagaagggg atggagcctg gtgccctgag attccagtgg aacctgatga cctgaaggag 721 tttctgcaga ttgacttgca caccctccat tttatcactc tggtggggac ccaggggcgc 781 catgcaggag gtcatggcat cgagtttgcc cccatgtaca agatcaatta cagtcgggat 841 ggcactcgct ggatctcttg gcggaaccgt catgggaaac aggtgctgga tggaaatagt 901 aacccctatg acattttcct aaaggacttg gagccgccca ttgtagccag atttgtccgg 961 ttcattccag tcaccgacca ctccatgaat gtgtgtatga gagtggagct ttacggctgt 1021 gtctggctag atggcttggt gtcttacaat gctccagctg ggcagcagtt tgtactccct 1081 ggaggttcca tcatttatct gaatgattct gtctatgatg gagctgttgg atacagcatg 1141 acagaagggc taggccaatt gaccgatggt gtgtctggcc tggacgattt cacccagacc 1201 catgaatacc acgtgtggcc cggctatgac tatgtgggct ggcggaacga gagtgccacc 1261 aatggctaca ttgagatcat gtttgaattt gaccgcatca ggaatttcac taccatgaag 1321 gtccactgca acaacatgtt tgctaaaggt gtgaagatct ttaaggaggt acagtgctac 1381 ttccgctctg aagccagtga gtgggaacct aatgccattt ccttccccct tgtcctggat 1441 gacgtcaacc ccagtgctcg gtttgtcacg gtgcctctcc accaccgaat ggccagtgcc 1501 atcaagtgtc aataccattt tgcagatacc tggatgatgt tcagtgagat caccttccaa 1561 tcagatgctg caatgtacaa caactctgaa gccctgccca cctctcctat ggcacccaca 1621 acctatgatc caatgcttaa agttgatgac agcaacactc ggatcctgat tggctgcttg 1681 gtggccatca tctttatcct cctggccatc attgtcatca tcctctggag gcagttctgg 1741 cagaaaatgc tggagaaggc ttctcggagg atgctggatg atgaaatgac agtcagcctt 1801 tccctgccaa gtgattctag catgttcaac aataaccgct cctcatcacc tagtgaacaa 1861 gggtccaact cgacttacga tcgcatcttt ccccttcgcc ctgactacca ggagccatcc 1921 aggctgatac gaaaactccc agaatttgct ccaggggagg aggagtcagg ctgcagcggt 1981 gttgtgaagc cagtccagcc cagtggccct gagggggtgc cccactatgc agaggctgac 2041 atagtgaacc tccaaggagt gacaggaggc aacacatact cagtgcctgc cgtcaccatg 2101 gacctgctct caggaaaaga tgtggctgtg gaggagttcc ccaggaaact cctaactttc 2161 aaagagaagc tgggagaagg acagtttggg gaggttcatc tctgtgaagt ggagggaatg 2221 gaaaaattca aagacaaaga ttttgcccta gatgtcagtg ccaaccagcc tgtcctggtg 2281 gctgtgaaaa tgctccgagc agatgccaac aagaatgcca ggaatgattt tcttaaggag 2341 ataaagatca tgtctcggct caaggaccca aacatcatcc atctattagc tgtgtgtatc 2401 actgatgacc ctctctgtat gatcactgaa tacatggaga atggagatct caatcagttt 2461 ctttcccgcc acgagccccc taattcttcc tccagcgatg tacgcactgt cagttacacc 2521 aatctgaagt ttatggctac ccaaattgcc tctggcatga agtacctttc ctctcttaat 2581 tttgttcacc gagatctggc cacacgaaac tgtttagtgg gtaagaacta cacaatcaag 2641 atagctgact ttggaatgag caggaacctg tacagtggtg actattaccg gatccagggc 2701 cgggcagtgc tccctatccg ctggatgtct tgggagagta tcttgctggg caagttcact 2761 acagcaagtg atgtgtgggc ctttggggtt actttgtggg agactttcac cttttgtcaa 2821 gaacagccct attcccagct gtcagatgaa caggttattg agaatactgg agagttcttc 2881 cgagaccaag ggaggcagac ttacctccct caaccagcca tttgtcctga ctctgtgtat 2941 aagctgatgc tcagctgctg gagaagagat acgaagaacc gtccctcatt ccaagaaatc 3001 caccttctgc tccttcaaca aggcgacgag tgatgctgtc agtgcctggc catgttccta 3061 cggctcaggt cctccctaca agacctacca ctcacccatg cctatgccac tccatctgga 3121 catttaatga aactgagaga cagaggcttg tttgctttgc cctcttttcc tggtcacccc 3181 cactccctac ccctgactca tatatacttt tttttttttt tacattaaag aactaaaaaa 3241 ggaaaaaaaa aa (SEQ ID NO: 55) .

[0241] An exemplary nucleic acid sequence encoding DDR2 (NM_006182.2 variant 2) comprises or consists of:

1 gaatcctcag aatgtgaggt ttctctcaaa ggcatcttgc atcagcctgt ggatgtatgc 61 ctaccaccgg gctccttcac cagcaaagtg gaaaaagaag cgtttcacaa caaattcttc 121 tttttgggtt ggggaaacgc agtggattat agctctgttt tcttctttcc aaaactgtgc 181 acccctggat gaaacctcca tcaagggaga cctacaagtt gcctggggtt cagtgctcta 241 gaaagttcca aggtttgtgg cttgaattat tctaaagaag ctgaaataat tgaagagaag 301 cagaggccag ctgtttttga ggatcctgct ccacagagaa tgctctgcac ccgttgatac 361 tccagttcca acaccatctt ctgagatgat cctgattccc agaatgctct tggtgctgtt 421 cctgctgctg cctatcttga gttctgcaaa agctcaggtt aatccagcta tatgccgcta 481 tcctctgggc atgtcaggag gccagattcc agatgaggac atcacagctt ccagtcagtg 541 gtcagagtcc acagctgcca aatatggaag gctggactca gaagaagggg atggagcctg 601 gtgccctgag attccagtgg aacctgatga cctgaaggag tttctgcaga ttgacttgca 661 caccctccat tttatcactc tggtggggac ccaggggcgc catgcaggag gtcatggcat 721 cgagtttgcc cccatgtaca agatcaatta cagtcgggat ggcactcgct ggatctcttg 781 gcggaaccgt catgggaaac aggtgctgga tggaaatagt aacccctatg acattttcct 841 aaaggacttg gagccgccca ttgtagccag atttgtccgg ttcattccag tcaccgacca 901 ctccatgaat gtgtgtatga gagtggagct ttacggctgt gtctggctag atggcttggt 961 gtcttacaat gctccagctg ggcagcagtt tgtactccct ggaggttcca tcatttatct 1021 gaatgattct gtctatgatg gagctgttgg atacagcatg acagaagggc taggccaatt 1081 gaccgatggt gtgtctggcc tggacgattt cacccagacc catgaatacc acgtgtggcc 1141 cggctatgac tatgtgggct ggcggaacga gagtgccacc aatggctaca ttgagatcat 1201 gtttgaattt gaccgcatca ggaatttcac taccatgaag gtccactgca acaacatgtt 1261 tgctaaaggt gtgaagatct ttaaggaggt acagtgctac ttccgctctg aagccagtga 1321 gtgggaacct aatgccattt ccttccccct tgtcctggat gacgtcaacc ccagtgctcg 1381 gtttgtcacg gtgcctctcc accaccgaat ggccagtgcc atcaagtgtc aataccattt 1441 tgcagatacc tggatgatgt tcagtgagat caccttccaa tcagatgctg caatgtacaa 1501 caactctgaa gccctgccca cctctcctat ggcacccaca acctatgatc caatgcttaa 1561 agttgatgac agcaacactc ggatcctgat tggctgcttg gtggccatca tctttatcct 1621 cctggccatc attgtcatca tcctctggag gcagttctgg cagaaaatgc tggagaaggc 1681 ttctcggagg atgctggatg atgaaatgac agtcagcctt tccctgccaa gtgattctag 1741 catgttcaac aataaccgct cctcatcacc tagtgaacaa gggtccaact cgacttacga 1801 tcgcatcttt ccccttcgcc ctgactacca ggagccatcc aggctgatac gaaaactccc 1861 agaatttgct ccaggggagg aggagtcagg ctgcagcggt gttgtgaagc cagtccagcc 1921 cagtggccct gagggggtgc cccactatgc agaggctgac atagtgaacc tccaaggagt 1981 gacaggaggc aacacatact cagtgcctgc cgtcaccatg gacctgctct caggaaaaga 2041 tgtggctgtg gaggagttcc ccaggaaact cctaactttc aaagagaagc tgggagaagg 2101 acagtttggg gaggttcatc tctgtgaagt ggagggaatg gaaaaattca aagacaaaga 2161 ttttgcccta gatgtcagtg ccaaccagcc tgtcctggtg gctgtgaaaa tgctccgagc 2221 agatgccaac aagaatgcca ggaatgattt tcttaaggag ataaagatca tgtctcggct 2281 caaggaccca aacatcatcc atctattagc tgtgtgtatc actgatgacc ctctctgtat 2341 gatcactgaa tacatggaga atggagatct caatcagttt ctttcccgcc acgagccccc 2401 taattcttcc tccagcgatg tacgcactgt cagttacacc aatctgaagt ttatggctac

2461 ccaaattgcc tctggcatga agtacctttc ctctcttaat tttgttcacc gagatctggc

2521 cacacgaaac tgtttagtgg gtaagaacta cacaatcaag atagctgact ttggaatgag

2581 caggaacctg tacagtggtg actattaccg gatccagggc cgggcagtgc tccctatccg

2641 ctggatgtct tgggagagta tcttgctggg caagttcact acagcaagtg atgtgtgggc

2701 ctttggggtt actttgtggg agactttcac cttttgtcaa gaacagccct attcccagct

2761 gtcagatgaa caggttattg agaatactgg agagttcttc cgagaccaag ggaggcagac

2821 ttacctccct caaccagcca tttgtcctga ctctgtgtat aagctgatgc tcagctgctg

2881 gagaagagat acgaagaacc gtccctcatt ccaagaaatc caccttctgc tccttcaaca

2941 aggcgacgag tgatgctgtc agtgcctggc catgttccta cggctcaggt cctccctaca

3001 agacctacca ctcacccatg cctatgccac tccatctgga catttaatga aactgagaga

3061 cagaggcttg tttgctttgc cctcttttcc tggtcacccc cactccctac ccctgactca

3121 tatatacttt tttttttttt tacattaaag aactaaaaaa ggaaaaaaaa aa (SEQ ID

NO : 56)

[0242] An exemplary amino acid sequence encoding DDR2 (NP 001014796.1) comprises or consists of:

MILIPRMLLVLFLLLPILSSAKAQVNPAICRYPLGMSGGQIPDEDITASSQWSESTAAKYGRLDSEEGDGAWCPE IPVEPDDLKEFLQIDLHTLHFITLVGTQGRHAGGHGIEFAPMYKINYSRDGTRWISWRNRHGKQVLDGNSNPYDI FLKDLEPPIVARFVRFIPVTDHSMNVCMRVELYGCVWLDGLVSYNAPAGQQFVLPGGSIIYLNDSVYDGAVGYSM TEGLGQLTDGVSGLDDFTQTHEYHVWPGYDYVGWRNESATNGYIEIMFEFDRIRNFTTMKVHCNNMFAKGVKIFK EVQCYFRSEASEWEPNAISFPLVLDD PSARFVTVPLHHRMASAIKCQYHFADTW MFSEITFQSDAAMYNNSE ALPTSPMAPTTYDPMLKVDDSNTRILIGCLVAI IFILLAIIVI ILWRQFWQKMLEKASRRMLDDEMTVSLSLPSD SSMFNNNRSSSPSEQGSNSTYDRIFPLRPDYQEPSRLIRKLPEFAPGEEESGCSGWKPVQPSGPEGVPHYAEAD IVNLQGVTGGNTYSVPAVTMDLLSGKDVAVEEFPRKLLTFKEKLGEGQFGEVHLCEVEGMEKFKDKDFALDVSAN QPVLVAVKMLRADANKNARNDFLKEIKIMSRLKDPNI IHLLAVCITDDPLCMITEYMENGDLNQFLSRHEPPNSS SSDVRTVSYTNLKFMATQIASGMKYLSSLNFVHRDLATRNCLVGKNYTIKIADFGMSRNLYSGDYYRIQGRAVLP IRWMSWESILLGKFTTASDVWAFGVTLWETFTFCQEQPYSQLSDEQVIENTGEFFRDQGRQTYLPQPAICPDSVY KLMLSCWRRDTKNRPSFQEIHLLLLQQGDE (SEQ ID NO: 57) .

[0243] An exemplary nucleic acid sequence encoding DPP4 (NM_001935.3 mRNA) comprises or consists of:

1 ctttcactgg caagagacgg agtcctgggt ttcagttcca gttgcctgcg gtgggctgtg 61 tgagtttgcc aaagtcccct gccctctctg ggtctcggtt ccctcgcctg tccacgtgag 121 gttggaggag ctgaacgccg acgtcatttt tagctaagag ggagcagggt ccccgagtcg 181 ccggcccagg gtctgcgcat ccgaggccgc gcgccctttc ccctccccca cggctcctcc 241 gggccccgca ctctgcgccc cggctgccgc ccagcgccct acaccgccct cagggggccc 301 tcgcgggctc cccccggccg ggatgccagt gccccgcgcc acgcgcgcct gctcccgcgc 361 cgcctgccct gcagcctgcc cgcggcgcct ttatacccag cgggctcggc gctcactaat 421 gtttaactcg gggccgaaac ttgccagcgg cgagtgactc caccgcccgg agcagcggtg 481 caggacgcgc gtctccgccg cccgcggtga cttctgcctg cgctccttct ctgaacgctc 541 acttccgagg agacgccgac gatgaagaca ccgtggaagg ttcttctggg actgctgggt 601 gctgctgcgc ttgtcaccat catcaccgtg cccgtggttc tgctgaacaa aggcacagat 661 gatgctacag ctgacagtcg caaaacttac actctaactg attacttaaa aaatacttat 721 agactgaagt tatactcctt aagatggatt tcagatcatg aatatctcta caaacaagaa 781 aataatatct tggtattcaa tgctgaatat ggaaacagct cagttttctt ggagaacagt 841 acatttgatg agtttggaca ttctatcaat gattattcaa tatctcctga tgggcagttt 901 attctcttag aatacaacta cgtgaagcaa tggaggcatt cctacacagc ttcatatgac 961 atttatgatt taaataaaag gcagctgatt acagaagaga ggattccaaa caacacacag 1021 tgggtcacat ggtcaccagt gggtcataaa ttggcatatg tttggaacaa tgacatttat 1081 gttaaaattg aaccaaattt accaagttac agaatcacat ggacggggaa agaagatata 1141 atatataatg gaataactga ctgggtttat gaagaggaag tcttcagtgc ctactctgct 1201 ctgtggtggt ctccaaacgg cactttttta gcatatgccc aatttaacga cacagaagtc 1261 ccacttattg aatactcctt ctactctgat gagtcactgc agtacccaaa gactgtacgg 1321 gttccatatc caaaggcagg agctgtgaat ccaactgtaa agttctttgt tgtaaataca 1381 gactctctca gctcagtcac caatgcaact tccatacaaa tcactgctcc tgcttctatg 1441 ttgatagggg atcactactt gtgtgatgtg acatgggcaa cacaagaaag aatttctttg 1501 cagtggctca ggaggattca gaactattcg gtcatggata tttgtgacta tgatgaatcc 1561 agtggaagat ggaactgctt agtggcacgg caacacattg aaatgagtac tactggctgg 1621 gttggaagat ttaggccttc agaacctcat tttacccttg atggtaatag cttctacaag 1681 atcatcagca atgaagaagg ttacagacac atttgctatt tccaaataga taaaaaagac 1741 tgcacattta ttacaaaagg cacctgggaa gtcatcggga tagaagctct aaccagtgat 1801 tatctatact acattagtaa tgaatataaa ggaatgccag gaggaaggaa tctttataaa 1861 atccaactta gtgactatac aaaagtgaca tgcctcagtt gtgagctgaa tccggaaagg 1921 tgtcagtact attctgtgtc attcagtaaa gaggcgaagt attatcagct gagatgttcc 1981 ggtcctggtc tgcccctcta tactctacac agcagcgtga atgataaagg gctgagagtc 2041 ctggaagaca attcagcttt ggataaaatg ctgcagaatg tccagatgcc ctccaaaaaa 2101 ctggacttca ttattttgaa tgaaacaaaa ttttggtatc agatgatctt gcctcctcat 2161 tttgataaat ccaagaaata tcctctacta ttagatgtgt atgcaggccc atgtagtcaa 2221 aaagcagaca ctgtcttcag actgaactgg gccacttacc ttgcaagcac agaaaacatt 2281 atagtagcta gctttgatgg cagaggaagt ggttaccaag gagataagat catgcatgca 2341 atcaacagaa gactgggaac atttgaagtt gaagatcaaa ttgaagcagc cagacaattt 2401 tcaaaaatgg gatttgtgga caacaaacga attgcaattt ggggctggtc atatggaggg 2461 tacgtaacct caatggtcct gggatcggga agtggcgtgt tcaagtgtgg aatagccgtg 2521 gcgcctgtat cccggtggga gtactatgac tcagtgtaca cagaacgtta catgggtctc 2581 ccaactccag aagacaacct tgaccattac agaaattcaa cagtcatgag cagagctgaa 2641 aattttaaac aagttgagta cctccttatt catggaacag cagatgataa cgttcacttt 2701 cagcagtcag ctcagatctc caaagccctg gtcgatgttg gagtggattt ccaggcaatg 2761 tggtatactg atgaagacca tggaatagct agcagcacag cacaccaaca tatatatacc 2821 cacatgagcc acttcataaa acaatgtttc tctttacctt agcacctcaa aataccatgc 2881 catttaaagc ttattaaaac tcatttttgt tttcattatc tcaaaactgc actgtcaaga 2941 tgatgatgat ctttaaaata cacactcaaa tcaagaaact taaggttacc tttgttccca 3001 aatttcatac ctatcatctt aagtagggac ttctgtcttc acaacagatt attaccttac 3061 agaagtttga attatccggt cgggttttat tgtttaaaat catttctgca tcagctgctg 3121 aaacaacaaa taggaattgt ttttatggag gctttgcata gattccctga gcaggatttt 3181 aatctttttc taactggact ggttcaaatg ttgttctctt ctttaaaggg atggcaagat 3241 gtgggcagtg atgtcactag ggcagggaca ggataagagg gattagggag agaagatagc 3301 agggcatggc tgggaaccca agtccaagca taccaacacg agcaggctac tgtcagctcc 3361 cctcggagaa gagctgttca cagccagact ggcacagttt tctgagaaag actattcaaa 3421 cagtctcagg aaatcaaata tgcaaagcac tgacttctaa gtaaaaccac agcagttgaa 3481 aagactccaa agaaatgtaa gggaaactgc cagcaacgca ggcccccagg tgccagttat 3541 ggctataggt gctacaaaaa cacagcaagg gtgatgggaa agcattgtaa atgtgctttt 3601 aaaaaaaaat actgatgttc ctagtgaaag aggcagcttg aaactgagat gtgaacacat 3661 cagcttgccc tgttaaaaga tgaaaatatt tgtatcacaa atcttaactt gaaggagtcc 3721 ttgcatcaat ttttcttatt tcatttcttt gagtgtctta attaaaagaa tattttaact 3781 tccttggact cattttaaaa aatggaacat aaaatacaat gttatgtatt attattccca 3841 ttctacatac tatggaattt ctcccagtca tttaataaat gtgccttcat tttttcagaa 3901 aaaaaaaaaa aaa (SEQ ID NO: 58) .

[0244] An exemplary amino acid sequence encoding DPP4 (NP 001926.2) comprises or consists of:

MKTPWKVLLGLLGAAALVTIITVPWLLNKGTDDATADSRKTYTLTDYLKNTYRLKLYSLRWISDHEYLYKQENN ILVFNAEYGNSSVFLENSTFDEFGHSINDYSISPDGQFILLEYNYVKQWRHSYTASYDIYDLNKRQLITEERIPN NTQ VTWSPVGHKLAYVWNNDIYVKIEPNLPSYRITWTGKEDI IYNGITDWVYEEEVFSAYSALWWSPNGTFLAY AQFNDTEVPLIEYSFYSDESLQYPKTVRVPYPKAGAVNPTVKFFWNTDSLSSVTNATSIQITAPASMLIGDHYL CDVTWATQERISLQWLRRIQNYSVMDICDYDESSGRWNCLVARQHIEMSTTG VGRFRPSEPHFTLDGNSFYKII SNEEGYRHICYFQIDKKDCTFITKGTWEVIGIEALTSDYLYYISNEYKGMPGGRNLYKIQLSDYTKVTCLSCELN PERCQYYSVSFSKEAKYYQLRCSGPGLPLYTLHSSV DKGLRVLEDNSALDKMLQNVQMPSKKLDFIILNETKFW YQMILPPHFDKSKKYPLLLDVYAGPCSQKADTVFRLNWATYLASTENIIVASFDGRGSGYQGDKIMHAINRRLGT FEVEDQIEAARQFSKMGFVDNKRIAIWGWSYGGYVTSMVLGSGSGVFKCGIAVAPVSRWEYYDSVYTERYMGLPT PEDNLDHYRNSTVMSRAENFKQVEYLLIHGTADDNVHFQQSAQISKALVDVGVDFQAMWYTDEDHGIASSTAHQH IYTHMSHFIKQCFSLP (SEQ ID NO: 59) .

[0245] An exemplary nucleic acid sequence encoding E2F 1 (NM_005225.2 mRNA) comprises or consists of:

1 ttggcgcgta aaagtggccg ggactttgca ggcagcggcg gccgggggcg gagcgggatc 61 gagccctcgc cgaggcctgc cgccatgggc ccgcgccgcc gccgccgcct gtcacccggg 121 ccgcgcgggc cgtgagcgtc atggccttgg ccggggcccc tgcgggcggc ccatgcgcgc 181 cggcgctgga ggccctgctc ggggccggcg cgctgcggct gctcgactcc tcgcagatcg 241 tcatcatctc cgccgcgcag gacgccagcg ccccgccggc tcccaccggc cccgcggcgc 301 ccgccgccgg cccctgcgac cctgacctgc tgctcttcgc cacaccgcag gcgccccggc 361 ccacacccag tgcgccgcgg cccgcgctcg gccgcccgcc ggtgaagcgg aggctggacc 421 tggaaactga ccatcagtac ctggccgaga gcagtgggcc agctcggggc agaggccgcc 481 atccaggaaa aggtgtgaaa tccccggggg agaagtcacg ctatgagacc tcactgaatc 541 tgaccaccaa gcgcttcctg gagctgctga gccactcggc tgacggtgtc gtcgacctga 601 actgggctgc cgaggtgctg aaggtgcaga agcggcgcat ctatgacatc accaacgtcc 661 ttgagggcat ccagctcatt gccaagaagt ccaagaacca catccagtgg ctgggcagcc 721 acaccacagt gggcgtcggc ggacggcttg aggggttgac ccaggacctc cgacagctgc 781 aggagagcga gcagcagctg gaccacctga tgaatatctg tactacgcag ctgcgcctgc 841 tctccgagga cactgacagc cagcgcctgg cctacgtgac gtgtcaggac cttcgtagca 901 ttgcagaccc tgcagagcag atggttatgg tgatcaaagc ccctcctgag acccagctcc 961 aagccgtgga ctcttcggag aactttcaga tctcccttaa gagcaaacaa ggcccgatcg 1021 atgttttcct gtgccctgag gagaccgtag gtgggatcag ccctgggaag accccatccc 1081 aggaggtcac ttctgaggag gagaacaggg ccactgactc tgccaccata gtgtcaccac 1141 caccatcatc tcccccctca tccctcacca cagatcccag ccagtctcta ctcagcctgg 1201 agcaagaacc gctgttgtcc cggatgggca gcctgcgggc tcccgtggac gaggaccgcc 1261 tgtccccgct ggtggcggcc gactcgctcc tggagcatgt gcgggaggac ttctccggcc 1321 tcctccctga ggagttcatc agcctttccc caccccacga ggccctcgac taccacttcg 1381 gcctcgagga gggcgagggc atcagagacc tcttcgactg tgactttggg gacctcaccc 1441 ccctggattt ctgacagggc ttggagggac cagggtttcc agagatgctc accttgtctc 1501 tgcagccctg gagccccctg tccctggccg tcctcccagc ctgtttggaa acatttaatt 1561 tatacccctc tcctctgtct ccagaagctt ctagctctgg ggtctggcta ccgctaggag 1621 gctgagcaag ccaggaaggg aaggagtctg tgtggtgtgt atgtgcatgc agcctacacc 1681 cacacgtgtg taccgggggt gaatgtgtgt gagcatgtgt gtgtgcatgt accggggaat 1741 gaaggtgaac atacacctct gtgtgtgcac tgcagacacg ccccagtgtg tccacatgtg 1801 tgtgcatgag tccatgtgtg cgcgtggggg ggctctaact gcactttcgg cccttttgct 1861 ctgggggtcc cacaaggccc agggcagtgc ctgctcccag aatctggtgc tctgaccagg 1921 ccaggtgggg aggctttggc tggctgggcg tgtaggacgg tgagagcact tctgtcttaa 1981 aggttttttc tgattgaagc tttaatggag cgttatttat ttatcgaggc ctctttggtg 2041 agcctgggga atcagcaaag gggaggaggg gtgtggggtt gataccccaa ctccctctac 2101 ccttgagcaa gggcaggggt ccctgagctg ttcttctgcc ccatactgaa ggaactgagg 2161 cctgggtgat ttatttattg ggaaagtgag ggagggagac agactgactg acagccatgg 2221 gtggtcagat ggtggggtgg gccctctcca gggggccagt tcagggcccc agctgccccc 2281 caggatggat atgagatggg agaggtgagt gggggacctt cactgatgtg ggcaggaggg 2341 gtggtgaagg cctcccccag cccagaccct gtggtccctc ctgcagtgtc tgaagcgcct 2401 gcctccccac tgctctgccc caccctccaa tctgcacttt gatttgcttc ctaacagctc 2461 tgttccctcc tgctttggtt ttaataaata ttttgatgac gtttgggccg ggttttggga 2521 ctctgttggg aacatttcgg ggcgggagag gccaaggttg ctggggaaat gcccattctc 2581 cacttccctt ctccctgtcc gtgcccgatt tgatttgagc ctcataactc gaagaaaggt 2641 cagcttcctc gctgttttgg tcctaactca aaagcagatc cagtaaaggt ttttgttgta 2701 aaaaaaaaaa aaaaaaaaaa aa (SEQ ID NO: 60) .

[0246] An exemplary amino acid sequence encoding E2F 1 (NP_005216.1) comprises or consists of:

MALAGAPAGGPCAPALEALLGAGALRLLDSSQIVIISAAQDASAPPAPTGPAAPAAGPCDPDLLLFATPQAPRPT

PSAPRPALGRPPVKRRLDLETDHQYLAESSGPARGRGRHPGKGVKSPGEKSRYETSLNLTTKRFLELLSHSADGV

VDLNWAAEVLKVQKRRIYDITNVLEGIQLIAKKSKNHIQWLGSHTTVGVGGRLEGLTQDLRQLQESEQQLDHLMN

ICTTQLRLLSEDTDSQRLAYVTCQDLRSIADPAEQMVMVIKAPPETQLQAVDSSENFQISLKSKQGPIDVFLCPE

ETVGGISPGKTPSQEVTSEEENRATDSATIVSPPPSSPPSSLTTDPSQSLLSLEQEPLLSRMGSLRAPVDEDRLS

PLVAADSLLEHVREDFSGLLPEEFISLSPPHEALDYHFGLEEGEGIRDLFDCDFGDLTPLDF (SEQ ID NO:

61) .

[0247] An exemplary nucleic acid sequence encoding E2F 1 (KT584073.1, 3' UTR) comprises or consists of:

1 acccccctgg atttctgaca gggcttggag ggaccagggt ttccagagat gctcaccttg

61 tctctgcagc cctggagccc cctgtccctg gccgtcctcc cagcctgttn ggaaacattt

121 aatttatacc cctctcctct gtctccagaa gcttctagct ctggggtctg gctaccgcta

181 ggaggctgag caagccagga agggaaggag tctgtgtggt gtgtatgtgc atgcagccta

241 cacccacacg tgtgtaccgg gggtgaatgt gtgtgagcat gtgtgtgtgc atgtaccggg

301 gaatgaaggt gaacatacac ctctgtgtgt gcactgcaga cacgccccag tgtgtccaca

361 tgtgtgtgca tgagtccatg tgtgcgcgtg ggggggctct aactgcactt tcggcccttt

421 tgctctgggg gtcccacaag gcccagggca gtgcctgctc ccagaatc (SEQ ID NO:

62)

[0248] An exemplary nucleic acid sequence encoding ERBB2 (NM 004448.3 variant 1) comprises or consists of:

1 gcttgctccc aatcacagga gaaggaggag gtggaggagg agggctgctt gaggaagtat 61 aagaatgaag ttgtgaagct gagattcccc tccattggga ccggagaaac caggggagcc 121 ccccgggcag ccgcgcgccc cttcccacgg ggccctttac tgcgccgcgc gcccggcccc 181 cacccctcgc agcaccccgc gccccgcgcc ctcccagccg ggtccagccg gagccatggg 241 gccggagccg cagtgagcac catggagctg gcggccttgt gccgctgggg gctcctcctc 301 gccctcttgc cccccggagc cgcgagcacc caagtgtgca ccggcacaga catgaagctg 361 cggctccctg ccagtcccga gacccacctg gacatgctcc gccacctcta ccagggctgc 421 caggtggtgc agggaaacct ggaactcacc tacctgccca ccaatgccag cctgtccttc 481 ctgcaggata tccaggaggt gcagggctac gtgctcatcg ctcacaacca agtgaggcag 541 gtcccactgc agaggctgcg gattgtgcga ggcacccagc tctttgagga caactatgcc 601 ctggccgtgc tagacaatgg agacccgctg aacaatacca cccctgtcac aggggcctcc 661 ccaggaggcc tgcgggagct gcagcttcga agcctcacag agatcttgaa aggaggggtc 721 ttgatccagc ggaaccccca gctctgctac caggacacga ttttgtggaa ggacatcttc 781 cacaagaaca accagctggc tctcacactg atagacacca accgctctcg ggcctgccac 841 ccctgttctc cgatgtgtaa gggctcccgc tgctggggag agagttctga ggattgtcag 901 agcctgacgc gcactgtctg tgccggtggc tgtgcccgct gcaaggggcc actgcccact 961 gactgctgcc atgagcagtg tgctgccggc tgcacgggcc ccaagcactc tgactgcctg 1021 gcctgcctcc acttcaacca cagtggcatc tgtgagctgc actgcccagc cctggtcacc 1081 tacaacacag acacgtttga gtccatgccc aatcccgagg gccggtatac attcggcgcc 1141 agctgtgtga ctgcctgtcc ctacaactac ctttctacgg acgtgggatc ctgcaccctc 1201 gtctgccccc tgcacaacca agaggtgaca gcagaggatg gaacacagcg gtgtgagaag 1261 tgcagcaagc cctgtgcccg agtgtgctat ggtctgggca tggagcactt gcgagaggtg 1321 agggcagtta ccagtgccaa tatccaggag tttgctggct gcaagaagat ctttgggagc 1381 ctggcatttc tgccggagag ctttgatggg gacccagcct ccaacactgc cccgctccag 1441 ccagagcagc tccaagtgtt tgagactctg gaagagatca caggttacct atacatctca 1501 gcatggccgg acagcctgcc tgacctcagc gtcttccaga acctgcaagt aatccgggga 1561 cgaattctgc acaatggcgc ctactcgctg accctgcaag ggctgggcat cagctggctg 1621 gggctgcgct cactgaggga actgggcagt ggactggccc tcatccacca taacacccac 1681 ctctgcttcg tgcacacggt gccctgggac cagctctttc ggaacccgca ccaagctctg 1741 ctccacactg ccaaccggcc agaggacgag tgtgtgggcg agggcctggc ctgccaccag 1801 ctgtgcgccc gagggcactg ctggggtcca gggcccaccc agtgtgtcaa ctgcagccag 1861 ttccttcggg gccaggagtg cgtggaggaa tgccgagtac tgcaggggct ccccagggag 1921 tatgtgaatg ccaggcactg tttgccgtgc caccctgagt gtcagcccca gaatggctca 1981 gtgacctgtt ttggaccgga ggctgaccag tgtgtggcct gtgcccacta taaggaccct 2041 cccttctgcg tggcccgctg ccccagcggt gtgaaacctg acctctccta catgcccatc 2101 tggaagtttc cagatgagga gggcgcatgc cagccttgcc ccatcaactg cacccactcc 2161 tgtgtggacc tggatgacaa gggctgcccc gccgagcaga gagccagccc tctgacgtcc 2221 atcatctctg cggtggttgg cattctgctg gtcgtggtct tgggggtggt ctttgggatc 2281 ctcatcaagc gacggcagca gaagatccgg aagtacacga tgcggagact gctgcaggaa 2341 acggagctgg tggagccgct gacacctagc ggagcgatgc ccaaccaggc gcagatgcgg 2401 atcctgaaag agacggagct gaggaaggtg aaggtgcttg gatctggcgc ttttggcaca 2461 gtctacaagg gcatctggat ccctgatggg gagaatgtga aaattccagt ggccatcaaa 2521 gtgttgaggg aaaacacatc ccccaaagcc aacaaagaaa tcttagacga agcatacgtg 2581 atggctggtg tgggctcccc atatgtctcc cgccttctgg gcatctgcct gacatccacg 2641 gtgcagctgg tgacacagct tatgccctat ggctgcctct tagaccatgt ccgggaaaac 2701 cgcggacgcc tgggctccca ggacctgctg aactggtgta tgcagattgc caaggggatg 2761 agctacctgg aggatgtgcg gctcgtacac agggacttgg ccgctcggaa cgtgctggtc 2821 aagagtccca accatgtcaa aattacagac ttcgggctgg ctcggctgct ggacattgac 2881 gagacagagt accatgcaga tgggggcaag gtgcccatca agtggatggc gctggagtcc 2941 attctccgcc ggcggttcac ccaccagagt gatgtgtgga gttatggtgt gactgtgtgg 3001 gagctgatga cttttggggc caaaccttac gatgggatcc cagcccggga gatccctgac 3061 ctgctggaaa agggggagcg gctgccccag ccccccatct gcaccattga tgtctacatg 3121 atcatggtca aatgttggat gattgactct gaatgtcggc caagattccg ggagttggtg 3181 tctgaattct cccgcatggc cagggacccc cagcgctttg tggtcatcca gaatgaggac 3241 ttgggcccag ccagtccctt ggacagcacc ttctaccgct cactgctgga ggacgatgac 3301 atgggggacc tggtggatgc tgaggagtat ctggtacccc agcagggctt cttctgtcca 3361 gaccctgccc cgggcgctgg gggcatggtc caccacaggc accgcagctc atctaccagg 3421 agtggcggtg gggacctgac actagggctg gagccctctg aagaggaggc ccccaggtct 3481 ccactggcac cctccgaagg ggctggctcc gatgtatttg atggtgacct gggaatgggg 3541 gcagccaagg ggctgcaaag cctccccaca catgacccca gccctctaca gcggtacagt 3601 gaggacccca cagtacccct gccctctgag actgatggct acgttgcccc cctgacctgc 3661 agcccccagc ctgaatatgt gaaccagcca gatgttcggc cccagccccc ttcgccccga 3721 gagggccctc tgcctgctgc ccgacctgct ggtgccactc tggaaaggcc caagactctc 3781 tccccaggga agaatggggt cgtcaaagac gtttttgcct ttgggggtgc cgtggagaac 3841 cccgagtact tgacacccca gggaggagct gcccctcagc cccaccctcc tcctgccttc 3901 agcccagcct tcgacaacct ctattactgg gaccaggacc caccagagcg gggggctcca 3961 cccagcacct tcaaagggac acctacggca gagaacccag agtacctggg tctggacgtg 4021 ccagtgtgaa ccagaaggcc aagtccgcag aagccctgat gtgtcctcag ggagcaggga 4081 aggcctgact tctgctggca tcaagaggtg ggagggccct ccgaccactt ccaggggaac 4141 ctgccatgcc aggaacctgt cctaaggaac cttccttcct gcttgagttc ccagatggct 4201 ggaaggggtc cagcctcgtt ggaagaggaa cagcactggg gagtctttgt ggattctgag 4261 gccctgccca atgagactct agggtccagt ggatgccaca gcccagcttg gccctttcct 4321 tccagatcct gggtactgaa agccttaggg aagctggcct gagaggggaa gcggccctaa 4381 gggagtgtct aagaacaaaa gcgacccatt cagagactgt ccctgaaacc tagtactgcc 4441 ccccatgagg aaggaacagc aatggtgtca gtatccaggc tttgtacaga gtgcttttct 4501 gtttagtttt tacttttttt gttttgtttt tttaaagatg aaataaagac ccagggggag 4561 aatgggtgtt gtatggggag gcaagtgtgg ggggtccttc tccacaccca ctttgtccat 4621 ttgcaaatat attttggaaa acagctaaaa aaaaaaaaaa aaaa (SEQ ID NO: 63) .

[0249] An exemplary amino acid sequence encoding ERBB2 (NP 004439.2, isoform a) comprises or consists of:

MELAALCRWGLLLALLPPGAASTQVCTGTDMKLRLPASPETHLDMLRHLYQGCQWQGNLELTYLPTNASLSFLQ DIQEVQGYVLIAHNQVRQVPLQRLRIVRGTQLFEDNYALAVLDNGDPLNNTTPVTGASPGGLRELQLRSLTEILK GGVLIQRNPQLCYQDTILWKDIFHKNNQLALTLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGCA RCKGPLPTDCCHEQCAAGCTGPKHSDCLACLHFNHSGICELHCPALVTYNTDTFESMPNPEGRYTFGASCVTACP YNYLSTDVGSCTLVCPLHNQEVTAEDGTQRCEKCSKPCARVCYGLGMEHLREVRAVTSANIQEFAGCKKIFGSLA FLPESFDGDPASNTAPLQPEQLQVFETLEEITGYLYISAWPDSLPDLSVFQNLQVIRGRILHNGAYSLTLQGLGI SWLGLRSLRELGSGLALIHHNTHLCFVHTVPWDQLFRNPHQALLHTANRPEDECVGEGLACHQLCARGHCWGPGP TQCV CSQFLRGQECVEECRVLQGLPREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFCVARC PSGVKPDLSYMPIWKFPDEEGACQPCPINCTHSCVDLDDKGCPAEQRASPLTSIISAWGILLVWLGWFGILI KRRQQKIRKYTMRRLLQETELVEPLTPSGAMPNQAQMRILKETELRKVKVLGSGAFGTVYKGIWIPDGENVKIPV AIKVLRENTSPKANKEILDEAYVMAGVGSPYVSRLLGICLTSTVQLVTQLMPYGCLLDHVRENRGRLGSQDLLNW CMQIAKGMSYLEDVRLVHRDLAARNVLVKSPNHVKITDFGLARLLDIDETEYHADGGKVPIKWMALESILRRRFT HQSDVWSYGVTVWELMTFGAKPYDGIPAREIPDLLEKGERLPQPPICTIDVYMIMVKCWMIDSECRPRFRELVSE FSRMARDPQRFWIQNEDLGPASPLDSTFYRSLLEDDDMGDLVDAEEYLVPQQGFFCPDPAPGAGGMVHHRHRSS STRSGGGDLTLGLEPSEEEAPRSPLAPSEGAGSDVFDGDLGMGAAKGLQSLPTHDPSPLQRYSEDPTVPLPSETD GYVAPLTCSPQPEYV QPDVRPQPPSPREGPLPAARPAGATLERPKTLSPGKNGWKDVFAFGGAVENPEYLTPQ GGAAPQPHPPPAFSPAFDNLYYWDQDPPERGAPPSTFKGTPTAENPEYLGLDVPV (SEQ ID NO: 64) .

[0250] An exemplary nucleic acid sequence encoding ERBB2 (NM_001005862.2, variant 2) comprises or consists of:

1 aagttcctgt gttctttatt ctactctccg ctgaagtcca cacagtttaa attaaagttc 61 ccggattttt gtgggcgcct gccccgcccc tcgtccccct gctgtgtcca tatatcgagg 121 cgatagggtt aagggaaggc ggacgcctga tgggttaatg agcaaactga agtgttttcc 181 atgatctttt ttgagtcgca attgaagtac cacctcccga gggtgattgc ttccccatgc 241 ggggtagaac ctttgctgtc ctgttcacca ctctacctcc agcacagaat ttggcttatg 301 cctactcaat gtgaagatga tgaggatgaa aacctttgtg atgatccact tccacttaat 361 gaatggtggc aaagcaaagc tatattcaag accacatgca aagctactcc ctgagcaaag 421 agtcacagat aaaacggggg caccagtaga atggccagga caaacgcagt gcagcacaga 481 gactcagacc ctggcagcca tgcctgcgca ggcagtgatg agagtgacat gtactgttgt 541 ggacatgcac aaaagtgagt gtgcaccggc acagacatga agctgcggct ccctgccagt 601 cccgagaccc acctggacat gctccgccac ctctaccagg gctgccaggt ggtgcaggga 661 aacctggaac tcacctacct gcccaccaat gccagcctgt ccttcctgca ggatatccag 721 gaggtgcagg gctacgtgct catcgctcac aaccaagtga ggcaggtccc actgcagagg 781 ctgcggattg tgcgaggcac ccagctcttt gaggacaact atgccctggc cgtgctagac 841 aatggagacc cgctgaacaa taccacccct gtcacagggg cctccccagg aggcctgcgg 901 gagctgcagc ttcgaagcct cacagagatc ttgaaaggag gggtcttgat ccagcggaac 961 ccccagctct gctaccagga cacgattttg tggaaggaca tcttccacaa gaacaaccag 1021 ctggctctca cactgataga caccaaccgc tctcgggcct gccacccctg ttctccgatg 1081 tgtaagggct cccgctgctg gggagagagt tctgaggatt gtcagagcct gacgcgcact 1141 gtctgtgccg gtggctgtgc ccgctgcaag gggccactgc ccactgactg ctgccatgag 1201 cagtgtgctg ccggctgcac gggccccaag cactctgact gcctggcctg cctccacttc 1261 aaccacagtg gcatctgtga gctgcactgc ccagccctgg tcacctacaa cacagacacg 1321 tttgagtcca tgcccaatcc cgagggccgg tatacattcg gcgccagctg tgtgactgcc 1381 tgtccctaca actacctttc tacggacgtg ggatcctgca ccctcgtctg ccccctgcac 1441 aaccaagagg tgacagcaga ggatggaaca cagcggtgtg agaagtgcag caagccctgt 1501 gcccgagtgt gctatggtct gggcatggag cacttgcgag aggtgagggc agttaccagt 1561 gccaatatcc aggagtttgc tggctgcaag aagatctttg ggagcctggc atttctgccg 1621 gagagctttg atggggaccc agcctccaac actgccccgc tccagccaga gcagctccaa 1681 gtgtttgaga ctctggaaga gatcacaggt tacctataca tctcagcatg gccggacagc 1741 ctgcctgacc tcagcgtctt ccagaacctg caagtaatcc ggggacgaat tctgcacaat 1801 ggcgcctact cgctgaccct gcaagggctg ggcatcagct ggctggggct gcgctcactg 1861 agggaactgg gcagtggact ggccctcatc caccataaca cccacctctg cttcgtgcac 1921 acggtgccct gggaccagct ctttcggaac ccgcaccaag ctctgctcca cactgccaac 1981 cggccagagg acgagtgtgt gggcgagggc ctggcctgcc accagctgtg cgcccgaggg 2041 cactgctggg gtccagggcc cacccagtgt gtcaactgca gccagttcct tcggggccag 2101 gagtgcgtgg aggaatgccg agtactgcag gggctcccca gggagtatgt gaatgccagg 2161 cactgtttgc cgtgccaccc tgagtgtcag ccccagaatg gctcagtgac ctgttttgga 2221 ccggaggctg accagtgtgt ggcctgtgcc cactataagg accctccctt ctgcgtggcc 2281 cgctgcccca gcggtgtgaa acctgacctc tcctacatgc ccatctggaa gtttccagat 2341 gaggagggcg catgccagcc ttgccccatc aactgcaccc actcctgtgt ggacctggat 2401 gacaagggct gccccgccga gcagagagcc agccctctga cgtccatcat ctctgcggtg 2461 gttggcattc tgctggtcgt ggtcttgggg gtggtctttg ggatcctcat caagcgacgg 2521 cagcagaaga tccggaagta cacgatgcgg agactgctgc aggaaacgga gctggtggag 2581 ccgctgacac ctagcggagc gatgcccaac caggcgcaga tgcggatcct gaaagagacg 2641 gagctgagga aggtgaaggt gcttggatct ggcgcttttg gcacagtcta caagggcatc 2701 tggatccctg atggggagaa tgtgaaaatt ccagtggcca tcaaagtgtt gagggaaaac 2761 acatccccca aagccaacaa agaaatctta gacgaagcat acgtgatggc tggtgtgggc 2821 tccccatatg tctcccgcct tctgggcatc tgcctgacat ccacggtgca gctggtgaca 2881 cagcttatgc cctatggctg cctcttagac catgtccggg aaaaccgcgg acgcctgggc 2941 tcccaggacc tgctgaactg gtgtatgcag attgccaagg ggatgagcta cctggaggat 3001 gtgcggctcg tacacaggga cttggccgct cggaacgtgc tggtcaagag tcccaaccat 3061 gtcaaaatta cagacttcgg gctggctcgg ctgctggaca ttgacgagac agagtaccat 3121 gcagatgggg gcaaggtgcc catcaagtgg atggcgctgg agtccattct ccgccggcgg 3181 ttcacccacc agagtgatgt gtggagttat ggtgtgactg tgtgggagct gatgactttt 3241 ggggccaaac cttacgatgg gatcccagcc cgggagatcc ctgacctgct ggaaaagggg 3301 gagcggctgc cccagccccc catctgcacc attgatgtct acatgatcat ggtcaaatgt 3361 tggatgattg actctgaatg tcggccaaga ttccgggagt tggtgtctga attctcccgc 3421 atggccaggg acccccagcg ctttgtggtc atccagaatg aggacttggg cccagccagt 3481 cccttggaca gcaccttcta ccgctcactg ctggaggacg atgacatggg ggacctggtg 3541 gatgctgagg agtatctggt accccagcag ggcttcttct gtccagaccc tgccccgggc 3601 gctgggggca tggtccacca caggcaccgc agctcatcta ccaggagtgg cggtggggac 3661 ctgacactag ggctggagcc ctctgaagag gaggccccca ggtctccact ggcaccctcc 3721 gaaggggctg gctccgatgt atttgatggt gacctgggaa tgggggcagc caaggggctg 3781 caaagcctcc ccacacatga ccccagccct ctacagcggt acagtgagga ccccacagta 3841 cccctgccct ctgagactga tggctacgtt gcccccctga cctgcagccc ccagcctgaa 3901 tatgtgaacc agccagatgt tcggccccag cccccttcgc cccgagaggg ccctctgcct 3961 gctgcccgac ctgctggtgc cactctggaa aggcccaaga ctctctcccc agggaagaat 4021 ggggtcgtca aagacgtttt tgcctttggg ggtgccgtgg agaaccccga gtacttgaca 4081 ccccagggag gagctgcccc tcagccccac cctcctcctg ccttcagccc agccttcgac 4141 aacctctatt actgggacca ggacccacca gagcgggggg ctccacccag caccttcaaa 4201 gggacaccta cggcagagaa cccagagtac ctgggtctgg acgtgccagt gtgaaccaga 4261 aggccaagtc cgcagaagcc ctgatgtgtc ctcagggagc agggaaggcc tgacttctgc 4321 tggcatcaag aggtgggagg gccctccgac cacttccagg ggaacctgcc atgccaggaa 4381 cctgtcctaa ggaaccttcc ttcctgcttg agttcccaga tggctggaag gggtccagcc 4441 tcgttggaag aggaacagca ctggggagtc tttgtggatt ctgaggccct gcccaatgag 4501 actctagggt ccagtggatg ccacagccca gcttggccct ttccttccag atcctgggta 4561 ctgaaagcct tagggaagct ggcctgagag gggaagcggc cctaagggag tgtctaagaa 4621 caaaagcgac ccattcagag actgtccctg aaacctagta ctgcccccca tgaggaagga 4681 acagcaatgg tgtcagtatc caggctttgt acagagtgct tttctgttta gtttttactt 4741 tttttgtttt gtttttttaa agatgaaata aagacccagg gggagaatgg gtgttgtatg 4801 gggaggcaag tgtggggggt ccttctccac acccactttg tccatttgca aatatatttt 4861 ggaaaacagc taaaaaaaaa aaaaaaaaa (SEQ ID NO: 65) .

[0251] An exemplary amino acid sequence encoding ERBB2 (NP 001005862.1, isoform b) comprises or consists of:

MKLRLPASPETHLDMLRHLYQGCQWQGNLELTYLPTNASLSFLQDIQEVQGYVLIAHNQVRQVPLQRLRIVRGT QLFEDNYALAVLDNGDPLNNTTPVTGASPGGLRELQLRSLTEILKGGVLIQRNPQLCYQDTILWKDIFHKNNQLA LTLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGCARCKGPLPTDCCHEQCAAGCTGPKHSDCLAC LHFNHSGICELHCPALVTYNTDTFESMPNPEGRYTFGASCVTACPYNYLSTDVGSCTLVCPLHNQEVTAEDGTQR CEKCSKPCARVCYGLGMEHLREVRAVTSANIQEFAGCKKIFGSLAFLPESFDGDPASNTAPLQPEQLQVFETLEE ITGYLYISAWPDSLPDLSVFQNLQVIRGRILHNGAYSLTLQGLGISWLGLRSLRELGSGLALIHHNTHLCFVHTV PWDQLFRNPHQALLHTANRPEDECVGEGLACHQLCARGHCWGPGPTQCVNCSQFLRGQECVEECRVLQGLPREYV NARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFCVARCPSGVKPDLSYMPIWKFPDEEGACQPCPINC THSCVDLDDKGCPAEQRASPLTSIISAWGILLVWLGWFGILIKRRQQKIRKYTMRRLLQETELVEPLTPSGA MPNQAQMRILKETELRKVKVLGSGAFGTVYKGIWIPDGENVKIPVAIKVLRENTSPKANKEILDEAYVMAGVGSP YVSRLLGICLTSTVQLVTQLMPYGCLLDHVRENRGRLGSQDLLNWCMQIAKGMSYLEDVRLVHRDLAARNVLVKS PNHVKITDFGLARLLDIDETEYHADGGKVPIKWMALESILRRRFTHQSDVWSYGVTVWELMTFGAKPYDGIPARE IPDLLEKGERLPQPPICTIDVYMIMVKCWMIDSECRPRFRELVSEFSRMARDPQRFWIQNEDLGPASPLDSTFY RSLLEDDDMGDLVDAEEYLVPQQGFFCPDPAPGAGGMVHHRHRSSSTRSGGGDLTLGLEPSEEEAPRSPLAPSEG AGSDVFDGDLGMGAAKGLQSLPTHDPSPLQRYSEDPTVPLPSETDGYVAPLTCSPQPEYVNQPDVRPQPPSPREG PLPAARPAGATLERPKTLSPGKNGWKDVFAFGGAVENPEYLTPQGGAAPQPHPPPAFSPAFDNLYYWDQDPPER GAPPSTFKGTPTAENPEYLGLDVPV (SEQ ID NO: 66) .

[0252] An exemplary nucleic acid sequence encoding ERBB2 (NM 001289936.1 variant 3) comprises or consists of:

1 aagttcctgt gttctttatt ctactctccg ctgaagtcca cacagtttaa attaaagttc 61 ccggattttt gtgggcgcct gccccgcccc tcgtccccct gctgtgtcca tatatcgagg 121 cgatagggtt aagggaaggc ggacgcctga tgggttaatg agcaaactga agtgttttcc 181 atgatctttt ttgagtcgca attgaagtac cacctcccga gggtgattgc ttccccatgc 241 ggggtagaac ctttgctgtc ctgttcacca ctctacctcc agcacagaat ttggcttatg 301 cctactcaat gtgaagatga tgaggatgaa aacctttgtg atgatccact tccacttaat 361 gaatggtggc aaagcaaagc tatattcaag accacatgca aagctactcc ctgagcaaag 421 agtcacagat aaaacggggg caccagtaga atggccagga caaacgcagt gcagcacaga 481 gactcagacc ctggcagcca tgcctgcgca ggcagtgatg agagtgacat gtactgttgt 541 ggacatgcac aaaagtgaga tacttcaaag attccagaag atatgccccg ggggtcctgg 601 aagccacaag tgtgcaccgg cacagacatg aagctgcggc tccctgccag tcccgagacc 661 cacctggaca tgctccgcca cctctaccag ggctgccagg tggtgcaggg aaacctggaa 721 ctcacctacc tgcccaccaa tgccagcctg tccttcctgc aggatatcca ggaggtgcag 781 ggctacgtgc tcatcgctca caaccaagtg aggcaggtcc cactgcagag gctgcggatt 841 gtgcgaggca cccagctctt tgaggacaac tatgccctgg ccgtgctaga caatggagac 901 ccgctgaaca ataccacccc tgtcacaggg gcctccccag gaggcctgcg ggagctgcag 961 cttcgaagcc tcacagagat cttgaaagga ggggtcttga tccagcggaa cccccagctc 1021 tgctaccagg acacgatttt gtggaaggac atcttccaca agaacaacca gctggctctc 1081 acactgatag acaccaaccg ctctcgggcc tgccacccct gttctccgat gtgtaagggc 1141 tcccgctgct ggggagagag ttctgaggat tgtcagagcc tgacgcgcac tgtctgtgcc 1201 ggtggctgtg cccgctgcaa ggggccactg cccactgact gctgccatga gcagtgtgct 1261 gccggctgca cgggccccaa gcactctgac tgcctggcct gcctccactt caaccacagt 1321 ggcatctgtg agctgcactg cccagccctg gtcacctaca acacagacac gtttgagtcc 1381 atgcccaatc ccgagggccg gtatacattc ggcgccagct gtgtgactgc ctgtccctac 1441 aactaccttt ctacggacgt gggatcctgc accctcgtct gccccctgca caaccaagag 1501 gtgacagcag aggatggaac acagcggtgt gagaagtgca gcaagccctg tgcccgagtg 1561 tgctatggtc tgggcatgga gcacttgcga gaggtgaggg cagttaccag tgccaatatc 1621 caggagtttg ctggctgcaa gaagatcttt gggagcctgg catttctgcc ggagagcttt 1681 gatggggacc cagcctccaa cactgccccg ctccagccag agcagctcca agtgtttgag 1741 actctggaag agatcacagg ttacctatac atctcagcat ggccggacag cctgcctgac 1801 ctcagcgtct tccagaacct gcaagtaatc cggggacgaa ttctgcacaa tggcgcctac 1861 tcgctgaccc tgcaagggct gggcatcagc tggctggggc tgcgctcact gagggaactg 1921 ggcagtggac tggccctcat ccaccataac acccacctct gcttcgtgca cacggtgccc 1981 tgggaccagc tctttcggaa cccgcaccaa gctctgctcc acactgccaa ccggccagag 2041 gacgagtgtg tgggcgaggg cctggcctgc caccagctgt gcgcccgagg gcactgctgg 2101 ggtccagggc ccacccagtg tgtcaactgc agccagttcc ttcggggcca ggagtgcgtg 2161 gaggaatgcc gagtactgca ggggctcccc agggagtatg tgaatgccag gcactgtttg 2221 ccgtgccacc ctgagtgtca gccccagaat ggctcagtga cctgttttgg accggaggct 2281 gaccagtgtg tggcctgtgc ccactataag gaccctccct tctgcgtggc ccgctgcccc 2341 agcggtgtga aacctgacct ctcctacatg cccatctgga agtttccaga tgaggagggc 2401 gcatgccagc cttgccccat caactgcacc cactcctgtg tggacctgga tgacaagggc 2461 tgccccgccg agcagagagc cagccctctg acgtccatca tctctgcggt ggttggcatt 2521 ctgctggtcg tggtcttggg ggtggtcttt gggatcctca tcaagcgacg gcagcagaag 2581 atccggaagt acacgatgcg gagactgctg caggaaacgg agctggtgga gccgctgaca 2641 cctagcggag cgatgcccaa ccaggcgcag atgcggatcc tgaaagagac ggagctgagg 2701 aaggtgaagg tgcttggatc tggcgctttt ggcacagtct acaagggcat ctggatccct 2761 gatggggaga atgtgaaaat tccagtggcc atcaaagtgt tgagggaaaa cacatccccc 2821 aaagccaaca aagaaatctt agacgaagca tacgtgatgg ctggtgtggg ctccccatat 2881 gtctcccgcc ttctgggcat ctgcctgaca tccacggtgc agctggtgac acagcttatg 2941 ccctatggct gcctcttaga ccatgtccgg gaaaaccgcg gacgcctggg ctcccaggac 3001 ctgctgaact ggtgtatgca gattgccaag gggatgagct acctggagga tgtgcggctc 3061 gtacacaggg acttggccgc tcggaacgtg ctggtcaaga gtcccaacca tgtcaaaatt 3121 acagacttcg ggctggctcg gctgctggac attgacgaga cagagtacca tgcagatggg 3181 ggcaaggtgc ccatcaagtg gatggcgctg gagtccattc tccgccggcg gttcacccac 3241 cagagtgatg tgtggagtta tggtgtgact gtgtgggagc tgatgacttt tggggccaaa 3301 ccttacgatg ggatcccagc ccgggagatc cctgacctgc tggaaaaggg ggagcggctg 3361 ccccagcccc ccatctgcac cattgatgtc tacatgatca tggtcaaatg ttggatgatt 3421 gactctgaat gtcggccaag attccgggag ttggtgtctg aattctcccg catggccagg 3481 gacccccagc gctttgtggt catccagaat gaggacttgg gcccagccag tcccttggac 3541 agcaccttct accgctcact gctggaggac gatgacatgg gggacctggt ggatgctgag 3601 gagtatctgg taccccagca gggcttcttc tgtccagacc ctgccccggg cgctgggggc 3661 atggtccacc acaggcaccg cagctcatct accaggagtg gcggtgggga cctgacacta 3721 gggctggagc cctctgaaga ggaggccccc aggtctccac tggcaccctc cgaaggggct 3781 ggctccgatg tatttgatgg tgacctggga atgggggcag ccaaggggct gcaaagcctc 3841 cccacacatg accccagccc tctacagcgg tacagtgagg accccacagt acccctgccc 3901 tctgagactg atggctacgt tgcccccctg acctgcagcc cccagcctga atatgtgaac 3961 cagccagatg ttcggcccca gcccccttcg ccccgagagg gccctctgcc tgctgcccga 4021 cctgctggtg ccactctgga aaggcccaag actctctccc cagggaagaa tggggtcgtc 4081 aaagacgttt ttgcctttgg gggtgccgtg gagaaccccg agtacttgac accccaggga 4141 ggagctgccc ctcagcccca ccctcctcct gccttcagcc cagccttcga caacctctat 4201 tactgggacc aggacccacc agagcggggg gctccaccca gcaccttcaa agggacacct 4261 acggcagaga acccagagta cctgggtctg gacgtgccag tgtgaaccag aaggccaagt 4321 ccgcagaagc cctgatgtgt cctcagggag cagggaaggc ctgacttctg ctggcatcaa 4381 gaggtgggag ggccctccga ccacttccag gggaacctgc catgccagga acctgtccta 4441 aggaaccttc cttcctgctt gagttcccag atggctggaa ggggtccagc ctcgttggaa 4501 gaggaacagc actggggagt ctttgtggat tctgaggccc tgcccaatga gactctaggg 4561 tccagtggat gccacagccc agcttggccc tttccttcca gatcctgggt actgaaagcc 4621 ttagggaagc tggcctgaga ggggaagcgg ccctaaggga gtgtctaaga acaaaagcga 4681 cccattcaga gactgtccct gaaacctagt actgcccccc atgaggaagg aacagcaatg 4741 gtgtcagtat ccaggctttg tacagagtgc ttttctgttt agtttttact ttttttgttt 4801 tgttttttta aagatgaaat aaagacccag ggggagaatg ggtgttgtat ggggaggcaa 4861 gtgtgggggg tccttctcca cacccacttt gtccatttgc aaatatattt tggaaaacag 4921 ctaaaaaaaa aaaaaaaaaa (SEQ ID NO 67) .

[0253] An exemplary amino acid sequence encoding ERBB2 (NP 001276865.1, isoform c) comprises or consists of:

MPRGSWKPQVCTGTDMKLRLPASPETHLDMLRHLYQGCQWQGNLELTYLPTNASLSFLQDIQEVQGYVLIAHNQ VRQVPLQRLRIVRGTQLFEDNYALAVLDNGDPLNNTTPVTGASPGGLRELQLRSLTEILKGGVLIQRNPQLCYQD TILWKDIFHKNNQLALTLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGCARCKGPLPTDCCHEQC AAGCTGPKHSDCLACLHFNHSGICELHCPALVTYNTDTFESMPNPEGRYTFGASCVTACPYNYLSTDVGSCTLVC PLHNQEVTAEDGTQRCEKCSKPCARVCYGLGMEHLREVRAVTSANIQEFAGCKKIFGSLAFLPESFDGDPASNTA PLQPEQLQVFETLEEITGYLYISAWPDSLPDLSVFQNLQVIRGRILHNGAYSLTLQGLGISWLGLRSLRELGSGL ALIHHNTHLCFVHTVPWDQLFRNPHQALLHTANRPEDECVGEGLACHQLCARGHCWGPGPTQCVNCSQFLRGQEC VEECRVLQGLPREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFCVARCPSGVKPDLSYMPIWK FPDEEGACQPCPINCTHSCVDLDDKGCPAEQRASPLTSIISAWGILLVWLGWFGILIKRRQQKIRKYTMRRL LQETELVEPLTPSGAMPNQAQMRILKETELRKVKVLGSGAFGTVYKGIWIPDGENVKIPVAIKVLRENTSPKANK EILDEAYVMAGVGSPYVSRLLGICLTSTVQLVTQLMPYGCLLDHVRENRGRLGSQDLLNWCMQIAKGMSYLEDVR LVHRDLAARNVLVKSPNHVKITDFGLARLLDIDETEYHADGGKVPIKWMALESILRRRFTHQSDVWSYGVTVWEL MTFGAKPYDGIPAREIPDLLEKGERLPQPPICTIDVYMIMVKCWMIDSECRPRFRELVSEFSRMARDPQRFWIQ NEDLGPASPLDSTFYRSLLEDDDMGDLVDAEEYLVPQQGFFCPDPAPGAGGMVHHRHRSSSTRSGGGDLTLGLEP SEEEAPRSPLAPSEGAGSDVFDGDLGMGAAKGLQSLPTHDPSPLQRYSEDPTVPLPSETDGYVAPLTCSPQPEYV NQPDVRPQPPSPREGPLPAARPAGATLERPKTLSPGKNGWKDVFAFGGAVENPEYLTPQGGAAPQPHPPPAFSP AFDNLYYWDQDPPERGAPPSTFKGTPTAENPEYLGLDVPV (SEQ ID NO: 68) .

[0254] An exemplary nucleic acid sequence encoding ERBB2 (NM 001289937.1 variant 4) comprises or consists of:

1 gcttgctccc aatcacagga gaaggaggag gtggaggagg agggctgctt gaggaagtat 61 aagaatgaag ttgtgaagct gagattcccc tccattggga ccggagaaac caggggagcc 121 ccccgggcag ccgcgcgccc cttcccacgg ggccctttac tgcgccgcgc gcccggcccc 181 cacccctcgc agcaccccgc gccccgcgcc ctcccagccg ggtccagccg gagccatggg 241 gccggagccg cagtgagcac catggagctg gcggccttgt gccgctgggg gctcctcctc 301 gccctcttgc cccccggagc cgcgagcacc caagtgtgca ccggcacaga catgaagctg 361 cggctccctg ccagtcccga gacccacctg gacatgctcc gccacctcta ccagggctgc 421 caggtggtgc agggaaacct ggaactcacc tacctgccca ccaatgccag cctgtccttc 481 ctgcaggata tccaggaggt gcagggctac gtgctcatcg ctcacaacca agtgaggcag 541 gtcccactgc agaggctgcg gattgtgcga ggcacccagc tctttgagga caactatgcc 601 ctggccgtgc tagacaatgg agacccgctg aacaatacca cccctgtcac aggggcctcc 661 ccaggaggcc tgcgggagct gcagcttcga agcctcacag agatcttgaa aggaggggtc 721 ttgatccagc ggaaccccca gctctgctac caggacacga ttttgtggaa ggacatcttc 781 cacaagaaca accagctggc tctcacactg atagacacca accgctctcg ggcctgccac 841 ccctgttctc cgatgtgtaa gggctcccgc tgctggggag agagttctga ggattgtcag 901 agcctgacgc gcactgtctg tgccggtggc tgtgcccgct gcaaggggcc actgcccact 961 gactgctgcc atgagcagtg tgctgccggc tgcacgggcc ccaagcactc tgactgcctg 1021 gcctgcctcc acttcaacca cagtggcatc tgtgagctgc actgcccagc cctggtcacc 1081 tacaacacag acacgtttga gtccatgccc aatcccgagg gccggtatac attcggcgcc 1141 agctgtgtga ctgcctgtcc ctacaactac ctttctacgg acgtgggatc ctgcaccctc 1201 gtctgccccc tgcacaacca agaggtgaca gcagaggatg gaacacagcg gtgtgagaag 1261 tgcagcaagc cctgtgcccg agtgtgctat ggtctgggca tggagcactt gcgagaggtg 1321 agggcagtta ccagtgccaa tatccaggag tttgctggct gcaagaagat ctttgggagc 1381 ctggcatttc tgccggagag ctttgatggg gacccagcct ccaacactgc cccgctccag 1441 ccagagcagc tccaagtgtt tgagactctg gaagagatca caggttacct atacatctca 1501 gcatggccgg acagcctgcc tgacctcagc gtcttccaga acctgcaagt aatccgggga 1561 cgaattctgc acaatggcgc ctactcgctg accctgcaag ggctgggcat cagctggctg 1621 gggctgcgct cactgaggga actgggcagt ggactggccc tcatccacca taacacccac 1681 ctctgcttcg tgcacacggt gccctgggac cagctctttc ggaacccgca ccaagctctg 1741 ctccacactg ccaaccggcc agaggacgag tgtgtgggcg agggcctggc ctgccaccag 1801 ctgtgcgccc gagggcactg ctggggtcca gggcccaccc agtgtgtcaa ctgcagccag 1861 ttccttcggg gccaggagtg cgtggaggaa tgccgagtac tgcaggggct ccccagggag 1921 tatgtgaatg ccaggcactg tttgccgtgc caccctgagt gtcagcccca gaatggctca 1981 gtgacctgtt ttggaccgga ggctgaccag tgtgtggcct gtgcccacta taaggaccct 2041 cccttctgcg tggcccgctg ccccagcggt gtgaaacctg acctctccta catgcccatc 2101 tggaagtttc cagatgagga gggcgcatgc cagccttgcc ccatcaactg cacccactcc 2161 tgtgtggacc tggatgacaa gggctgcccc gccgagcaga gagccagccc tctgacgtcc 2221 atcatctctg cggtggttgg cattctgctg gtcgtggtct tgggggtggt ctttgggatc 2281 ctcatcaagc gacggcagca gaagatccgg aagtacacga tgcggagact gctgcaggaa 2341 acggagctgg tggagccgct gacacctagc ggagcgatgc ccaaccaggc gcagatgcgg 2401 atcctgaaag agacggagct gaggaaggtg aaggtgcttg gatctggcgc ttttggcaca 2461 gtctacaagg gcatctggat ccctgatggg gagaatgtga aaattccagt ggccatcaaa 2521 gtgttgaggg aaaacacatc ccccaaagcc aacaaagaaa tcttagacga agcatacgtg 2581 atggctggtg tgggctcccc atatgtctcc cgccttctgg gcatctgcct gacatccacg 2641 gtgcagctgg tgacacagct tatgccctat ggctgcctct tagaccatgt ccgggaaaac 2701 cgcggacgcc tgggctccca ggacctgctg aactggtgta tgcagattgc caaggggatg 2761 agctacctgg aggatgtgcg gctcgtacac agggacttgg ccgctcggaa cgtgctggtc 2821 aagagtccca accatgtcaa aattacagac ttcgggctgg ctcggctgct ggacattgac 2881 gagacagagt accatgcaga tgggggcaag gtgcccatca agtggatggc gctggagtcc 2941 attctccgcc ggcggttcac ccaccagagt gatgtgtgga gttatggtgt gactgtgtgg 3001 gagctgatga cttttggggc caaaccttac gatgggatcc cagcccggga gatccctgac 3061 ctgctggaaa agggggagcg gctgccccag ccccccatct gcaccattga tgtctacatg 3121 atcatggtca aatgttggat gattgactct gaatgtcggc caagattccg ggagttggtg 3181 tctgaattct cccgcatggc cagggacccc cagcgctttg tggtcatcca gaatgaggac 3241 ttgggcccag ccagtccctt ggacagcacc ttctaccgct cactgctgga ggacgatgac 3301 atgggggacc tggtggatgc tgaggagtat ctggtacccc agcagggctt cttctgtcca 3361 gaccctgccc cgggcgctgg gggcatggtc caccacaggc accgcagctc atctaccagg 3421 aatatgtgaa ccagccagat gttcggcccc agcccccttc gccccgagag ggccctctgc 3481 ctgctgcccg acctgctggt gccactctgg aaaggcccaa gactctctcc ccagggaaga 3541 atggggtcgt caaagacgtt tttgcctttg ggggtgccgt ggagaacccc gagtacttga 3601 caccccaggg aggagctgcc cctcagcccc accctcctcc tgccttcagc ccagccttcg 3661 acaacctcta ttactgggac caggacccac cagagcgggg ggctccaccc agcaccttca 3721 aagggacacc tacggcagag aacccagagt acctgggtct ggacgtgcca gtgtgaacca 3781 gaaggccaag tccgcagaag ccctgatgtg tcctcaggga gcagggaagg cctgacttct 3841 gctggcatca agaggtggga gggccctccg accacttcca ggggaacctg ccatgccagg 3901 aacctgtcct aaggaacctt ccttcctgct tgagttccca gatggctgga aggggtccag 3961 cctcgttgga agaggaacag cactggggag tctttgtgga ttctgaggcc ctgcccaatg 4021 agactctagg gtccagtgga tgccacagcc cagcttggcc ctttccttcc agatcctggg 4081 tactgaaagc cttagggaag ctggcctgag aggggaagcg gccctaaggg agtgtctaag 4141 aacaaaagcg acccattcag agactgtccc tgaaacctag tactgccccc catgaggaag 4201 gaacagcaat ggtgtcagta tccaggcttt gtacagagtg cttttctgtt tagtttttac 4261 tttttttgtt ttgttttttt aaagatgaaa taaagaccca gggggagaat gggtgttgta 4321 tggggaggca agtgtggggg gtccttctcc acacccactt tgtccatttg caaatatatt 4381 ttggaaaaca gctaaaaaaa aaaaaaaaaa a (SEQ ID NO: 69)

[0255] An exemplary amino acid sequence encoding ERBB2 (NP 001276866.1, isoform d ) comprises or consists of:

MELAALCRWGLLLALLPPGAASTQVCTGTDMKLRLPASPETHLDMLRHLYQGCQWQGNLELTYLPTNASLSFLQ DIQEVQGYVLIAHNQVRQVPLQRLRIVRGTQLFEDNYALAVLDNGDPLNNTTPVTGASPGGLRELQLRSLTEILK GGVLIQRNPQLCYQDTILWKDIFHKNNQLALTLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGCA RCKGPLPTDCCHEQCAAGCTGPKHSDCLACLHFNHSGICELHCPALVTYNTDTFESMPNPEGRYTFGASCVTACP YNYLSTDVGSCTLVCPLHNQEVTAEDGTQRCEKCSKPCARVCYGLGMEHLREVRAVTSANIQEFAGCKKIFGSLA FLPESFDGDPASNTAPLQPEQLQVFETLEEITGYLYISAWPDSLPDLSVFQNLQVIRGRILHNGAYSLTLQGLGI SWLGLRSLRELGSGLALIHHNTHLCFVHTVPWDQLFRNPHQALLHTANRPEDECVGEGLACHQLCARGHCWGPGP TQCVNCSQFLRGQECVEECRVLQGLPREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFCVARC PSGVKPDLSYMPIWKFPDEEGACQPCPINCTHSCVDLDDKGCPAEQRASPLTSIISAWGILLVWLGWFGILI KRRQQKIRKYTMRRLLQETELVEPLTPSGAMPNQAQMRILKETELRKVKVLGSGAFGTVYKGIWIPDGENVKIPV AIKVLRENTSPKANKEILDEAYVMAGVGSPYVSRLLGICLTSTVQLVTQLMPYGCLLDHVRENRGRLGSQDLLNW CMQIAKGMSYLEDVRLVHRDLAARNVLVKSPNHVKITDFGLARLLDIDETEYHADGGKVPIKWMALESILRRRFT HQSDVWSYGVTVWELMTFGAKPYDGIPAREIPDLLEKGERLPQPPICTIDVYMIMVKCWMIDSECRPRFRELVSE FSRMARDPQRFWIQNEDLGPASPLDSTFYRSLLEDDDMGDLVDAEEYLVPQQGFFCPDPAPGAGGMVHHRHRSS STRNM (SEQ ID NO: 70) .

[0256] An exemplary nucleic acid sequence encoding ERBB2 (NM 001289938 variant 5) comprises or consists of:

1 aagttcctgt gttctttatt ctactctccg ctgaagtcca cacagtttaa attaaagttc 61 ccggattttt gtgggcgcct gccccgcccc tcgtccccct gctgtgtcca tatatcgagg 121 cgatagggtt aagggaaggc ggacgcctga tgggttaatg agcaaactga agtgttttcc 181 atgatctttt ttgagtcgca attgaagtac cacctcccga gggtgattgc ttccccatgc 241 ggggtagaac ctttgctgtc ctgttcacca ctctacctcc agcacagaat ttggcttatg 301 cctactcaat gtgaagatga tgaggatgaa aacctttgtg atgatccact tccacttaat 361 gaatggtggc aaagcaaagc tatattcaag accacatgca aagctactcc ctgagcaaag 421 agtcacagat aaaacggggg caccagtaga atggccagga caaacgcagt gcagcacaga 481 gactcagacc ctggcagcca tgcctgcgca ggcagtgatg agagtgacat gtactgttgt 541 ggacatgcac aaaagtgagt gtgcaccggc acagacatga agctgcggct ccctgccagt 601 cccgagaccc acctggacat gctccgccac ctctaccagg gctgccaggt ggtgcaggga 661 aacctggaac tcacctacct gcccaccaat gccagcctgt ccttcctgca ggatatccag 721 gaggtgcagg gctacgtgct catcgctcac aaccaagtga ggcaggtccc actgcagagg 781 ctgcggattg tgcgaggcac ccagctcttt gaggacaact atgccctggc cgtgctagac 841 aatggagacc cgctgaacaa taccacccct gtcacagggg cctccccagg aggcctgcgg 901 gagctgcagc ttcgaagcct cacagagatc ttgaaaggag gggtcttgat ccagcggaac 961 ccccagctct gctaccagga cacgattttg tggaaggaca tcttccacaa gaacaaccag 1021 ctggctctca cactgataga caccaaccgc tctcgggcct gccacccctg ttctccgatg 1081 tgtaagggct cccgctgctg gggagagagt tctgaggatt gtcagagcct gacgcgcact 1141 gtctgtgccg gtggctgtgc ccgctgcaag gggccactgc ccactgactg ctgccatgag 1201 cagtgtgctg ccggctgcac gggccccaag cactctgact gcctggcctg cctccacttc 1261 aaccacagtg gcatctgtga gctgcactgc ccagccctgg tcacctacaa cacagacacg 1321 tttgagtcca tgcccaatcc cgagggccgg tatacattcg gcgccagctg tgtgactgcc 1381 tgtccctaca actacctttc tacggacgtg ggatcctgca ccctcgtctg ccccctgcac 1441 aaccaagagg tgacagcaga ggatggaaca cagcggtgtg agaagtgcag caagccctgt 1501 gcccgagtgt gctatggtct gggcatggag cacttgcgag aggtgagggc agttaccagt 1561 gccaatatcc aggagtttgc tggctgcaag aagatctttg ggagcctggc atttctgccg 1621 gagagctttg atggggaccc agcctccaac actgccccgc tccagccaga gcagctccaa 1681 gtgtttgaga ctctggaaga gatcacaggt tacctataca tctcagcatg gccggacagc 1741 ctgcctgacc tcagcgtctt ccagaacctg caagtaatcc ggggacgaat tctgcacaat 1801 ggcgcctact cgctgaccct gcaagggctg ggcatcagct ggctggggct gcgctcactg 1861 agggaactgg gcagtggact ggccctcatc caccataaca cccacctctg cttcgtgcac 1921 acggtgccct gggaccagct ctttcggaac ccgcaccaag ctctgctcca cactgccaac 1981 cggccagagg acgagtgtgt gggcgagggc ctggcctgcc accagctgtg cgcccgaggg 2041 cactgctggg gtccagggcc cacccagtgt gtcaactgca gccagttcct tcggggccag 2101 gagtgcgtgg aggaatgccg agtactgcag gggctcccca gggagtatgt gaatgccagg 2161 cactgtttgc cgtgccaccc tgagtgtcag ccccagaatg gctcagtgac ctgttttgga 2221 ccggaggctg accagtgtgt ggcctgtgcc cactataagg accctccctt ctgcgtggcc 2281 cgctgcccca gcggtgtgaa acctgacctc tcctacatgc ccatctggaa gtttccagat 2341 gaggagggcg catgccagcc ttgccccatc aactgcaccc actcgtgagt ccaacggtct 2401 tttctgcaga aaggaggact ttcctttcag gggtctttct ggggctctta ctataaaagg 2461 ggaccaactc tccctttgtc atatcttgtt tctgatgaca aaaataacac attgttaaaa 2521 ttgtaaaatt aaaacatgaa atataaatta atgccctagc aaaaaaaaaa aaaaaaaaaa 2581 aaaaaaaaaa (SEQ ID NO 71) .

[0257] An exemplary amino acid sequence encoding ERBB2 (NP 001276867.1, isoform e) comprises or consists of:

MKLRLPASPETHLDMLRHLYQGCQWQGNLELTYLPTNASLSFLQDIQEVQGYVLIAHNQVRQVPLQRLRIVRGT QLFEDNYALAVLDNGDPLNNTTPVTGASPGGLRELQLRSLTEILKGGVLIQRNPQLCYQDTILWKDIFHKNNQLA LTLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGCARCKGPLPTDCCHEQCAAGCTGPKHSDCLAC LHFNHSGICELHCPALVTYNTDTFESMPNPEGRYTFGASCVTACPYNYLSTDVGSCTLVCPLHNQEVTAEDGTQR CEKCSKPCARVCYGLGMEHLREVRAVTSANIQEFAGCKKIFGSLAFLPESFDGDPASNTAPLQPEQLQVFETLEE ITGYLYISAWPDSLPDLSVFQNLQVIRGRILHNGAYSLTLQGLGISWLGLRSLRELGSGLALIHHNTHLCFVHTV PWDQLFRNPHQALLHTANRPEDECVGEGLACHQLCARGHCWGPGPTQCVNCSQFLRGQECVEECRVLQGLPREYV NARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFCVARCPSGVKPDLSYMPIWKFPDEEGACQPCPINC THS (SEQ ID NO: 72) . [0258] An exemplary nucleic acid sequence encoding ERBB2 (NR_110535.1, variant 6 ) comprises or consists of:

1 gcttgctccc aatcacagga gaaggaggag gtggaggagg agggctgctt gaggaagtat 61 aagaatgaag ttgtgaagct gagattcccc tccattggga ccggagaaac caggggagcc 121 ccccgggcag ccgcgcgccc cttcccacgg ggccctttac tgcgccgcgc gcccggcccc 181 cacccctcgc agcaccccgc gccccgcgcc ctcccagccg ggtccagccg gagccatggg 241 gccggagccg cagtgagcac catggagctg gcggccttgt gccgctgggg gctcctcctc 301 gccctcttgc cccccggagc cgcgagcacc caagtgtgca ccggcacaga catgaagctg 361 cggctccctg ccagtcccga gacccacctg gacatgctcc gccacctcta ccagggctgc 421 caggtggtgc agggaaacct ggaactcacc tacctgccca ccaatgccag cctgtccttc 481 ctgcaggtga ggcccgtggg caacccagcc aggccctgcc tccagctggg ctgagccctc 541 tgtttacagg atatccagga ggtgcagggc tacgtgctca tcgctcacaa ccaagtgagg 601 caggtcccac tgcagaggct gcggattgtg cgaggcaccc agctctttga ggacaactat 661 gccctggccg tgctagacaa tggagacccg ctgaacaata ccacccctgt cacaggggcc 721 tccccaggag gcctgcggga gctgcagctt cgaagcctca cagagatctt gaaaggaggg 781 gtcttgatcc agcggaaccc ccagctctgc taccaggaca cgattttgtg gaaggacatc 841 ttccacaaga acaaccagct ggctctcaca ctgatagaca ccaaccgctc tcgggcctgc 901 cacccctgtt ctccgatgtg taagggctcc cgctgctggg gagagagttc tgaggattgt 961 cagagcctga cgcgcactgt ctgtgccggt ggctgtgccc gctgcaaggg gccactgccc 1021 actgactgct gccatgagca gtgtgctgcc ggctgcacgg gccccaagca ctctgactgc 1081 ctggcctgcc tccacttcaa ccacagtggc atctgtgagc tgcactgccc agccctggtc 1141 acctacaaca cagacacgtt tgagtccatg cccaatcccg agggccggta tacattcggc 1201 gccagctgtg tgactgcctg tccctacaac tacctttcta cggacgtggg atcctgcacc 1261 ctcgtctgcc ccctgcacaa ccaagaggtg acagcagagg atggaacaca gcggtgtgag 1321 aagtgcagca agccctgtgc ccgagtgtgc tatggtctgg gcatggagca cttgcgagag 1381 gtgagggcag ttaccagtgc caatatccag gagtttgctg gctgcaagaa gatctttggg 1441 agcctggcat ttctgccgga gagctttgat ggggacccag cctccaacac tgccccgctc 1501 cagccagagc agctccaagt gtttgagact ctggaagaga tcacaggtta cctatacatc 1561 tcagcatggc cggacagcct gcctgacctc agcgtcttcc agaacctgca agtaatccgg 1621 ggacgaattc tgcacaatgg cgcctactcg ctgaccctgc aagggctggg catcagctgg 1681 ctggggctgc gctcactgag ggaactgggc agtggactgg ccctcatcca ccataacacc 1741 cacctctgct tcgtgcacac ggtgccctgg gaccagctct ttcggaaccc gcaccaagct 1801 ctgctccaca ctgccaaccg gccagaggac gagtgtgtgg gcgagggcct ggcctgccac 1861 cagctgtgcg cccgagggca ctgctggggt ccagggccca cccagtgtgt caactgcagc 1921 cagttccttc ggggccagga gtgcgtggag gaatgccgag tactgcaggg gctccccagg 1981 gagtatgtga atgccaggca ctgtttgccg tgccaccctg agtgtcagcc ccagaatggc 2041 tcagtgacct gttttggacc ggaggctgac cagtgtgtgg cctgtgccca ctataaggac 2101 cctcccttct gcgtggcccg ctgccccagc ggtgtgaaac ctgacctctc ctacatgccc 2161 atctggaagt ttccagatga ggagggcgca tgccagcctt gccccatcaa ctgcacccac 2221 tcctgtgtgg acctggatga caagggctgc cccgccgagc agagagccag ccctctgacg 2281 tccatcatct ctgcggtggt tggcattctg ctggtcgtgg tcttgggggt ggtctttggg 2341 atcctcatca agcgacggca gcagaagatc cggaagtaca cgatgcggag actgctgcag 2401 gaaacggagc tggtggagcc gctgacacct agcggagcga tgcccaacca ggcgcagatg 2461 cggatcctga aagagacgga gctgaggaag gtgaaggtgc ttggatctgg cgcttttggc 2521 acagtctaca agggcatctg gatccctgat ggggagaatg tgaaaattcc agtggccatc 2581 aaagtgttga gggaaaacac atcccccaaa gccaacaaag aaatcttaga cgaagcatac 2641 gtgatggctg gtgtgggctc cccatatgtc tcccgccttc tgggcatctg cctgacatcc 2701 acggtgcagc tggtgacaca gcttatgccc tatggctgcc tcttagacca tgtccgggaa 2761 aaccgcggac gcctgggctc ccaggacctg ctgaactggt gtatgcagat tgccaagggg 2821 atgagctacc tggaggatgt gcggctcgta cacagggact tggccgctcg gaacgtgctg 2881 gtcaagagtc ccaaccatgt caaaattaca gacttcgggc tggctcggct gctggacatt 2941 gacgagacag agtaccatgc agatgggggc aaggtgccca tcaagtggat ggcgctggag 3001 tccattctcc gccggcggtt cacccaccag agtgatgtgt ggagttatgg tgtgactgtg 3061 tgggagctga tgacttttgg ggccaaacct tacgatggga tcccagcccg ggagatccct 3121 gacctgctgg aaaaggggga gcggctgccc cagcccccca tctgcaccat tgatgtctac 3181 atgatcatgg tcaaatgttg gatgattgac tctgaatgtc ggccaagatt ccgggagttg 3241 gtgtctgaat tctcccgcat ggccagggac ccccagcgct ttgtggtcat ccagaatgag 3301 gacttgggcc cagccagtcc cttggacagc accttctacc gctcactgct ggaggacgat 3361 gacatggggg acctggtgga tgctgaggag tatctggtac cccagcaggg cttcttctgt 3421 ccagaccctg ccccgggcgc tgggggcatg gtccaccaca ggcaccgcag ctcatctacc 3481 aggagtggcg gtggggacct gacactaggg ctggagccct ctgaagagga ggcccccagg 3541 tctccactgg caccctccga aggggctggc tccgatgtat ttgatggtga cctgggaatg 3601 ggggcagcca aggggctgca aagcctcccc acacatgacc ccagccctct acagcggtac 3661 agtgaggacc ccacagtacc cctgccctct gagactgatg gctacgttgc ccccctgacc 3721 tgcagccccc agcctgaata tgtgaaccag ccagatgttc ggccccagcc cccttcgccc 3781 cgagagggcc ctctgcctgc tgcccgacct gctggtgcca ctctggaaag gcccaagact 3841 ctctccccag ggaagaatgg ggtcgtcaaa gacgtttttg cctttggggg tgccgtggag 3901 aaccccgagt acttgacacc ccagggagga gctgcccctc agccccaccc tcctcctgcc 3961 ttcagcccag ccttcgacaa cctctattac tgggaccagg acccaccaga gcggggggct 4021 ccacccagca ccttcaaagg gacacctacg gcagagaacc cagagtacct gggtctggac 4081 gtgccagtgt gaaccagaag gccaagtccg cagaagccct gatgtgtcct cagggagcag 4141 ggaaggcctg acttctgctg gcatcaagag gtgggagggc cctccgacca cttccagggg 4201 aacctgccat gccaggaacc tgtcctaagg aaccttcctt cctgcttgag ttcccagatg 4261 gctggaaggg gtccagcctc gttggaagag gaacagcact ggggagtctt tgtggattct 4321 gaggccctgc ccaatgagac tctagggtcc agtggatgcc acagcccagc ttggcccttt 4381 ccttccagat cctgggtact gaaagcctta gggaagctgg cctgagaggg gaagcggccc 4441 taagggagtg tctaagaaca aaagcgaccc attcagagac tgtccctgaa acctagtact 4501 gccccccatg aggaaggaac agcaatggtg tcagtatcca ggctttgtac agagtgcttt 4561 tctgtttagt ttttactttt tttgttttgt ttttttaaag atgaaataaa gacccagggg 4621 gagaatgggt gttgtatggg gaggcaagtg tggggggtcc ttctccacac ccactttgtc 4681 catttgcaaa tatattttgg aaaacagcta aaaaaaaaaa aaaaaaa (SEQ ID NO:

73)

[0259] An exemplary nucleic acid sequence encoding ERBB2 (KT583887.1 , 3 ' UTR) comprises or consists of:

1 ggacgtgcca gtgtgaacca gaaggccaag tccgcagaag ccctgatgtg tcctcaggga

61 gcagggaagg cctgacttct gctggcatca agaggtggga gggccctccg accacttcca

121 ggggaacctg ccatgccagg aacctgtcct aaggaacctt ccttcctgct tgagttccca

181 gatggctgga aggggtccag cctcgttgga agaggaacag cactggggag tctttgtgga

241 ttctgaggcc ctgcccaatg agactctagg gtccagtgga tgccacagcc cagcttggcc

301 ctttccttcc agatcctggg tactgaaagc cttagggaag ctggcctgag aggggaagcg

361 gccctaaggg agtgtctaag aacaaaagcg acccattcag agactgtccc tgaaacctag

421 tactgccccc catgaggaag gaacagcaat ggtgtcagta tccaggct (SEQ ID NO:

74)

[0260] An exemplary nucleic acid sequence encoding F3 (NM 001993.4 variant 1) comprises or consists of:

1 ggagtcggga ggagcggcgg gggcgggcgc cgggggcggg cagaggcgcg ggagagcgcg 61 ccgccggccc tttatagcgc gcggggcacc ggctccccaa gactgcgagc tccccgcacc 121 ccctcgcact ccctctggcc ggcccagggc gccttcagcc caacctcccc agccccacgg 181 gcgccacgga acccgctcga tctcgccgcc aactggtaga catggagacc cctgcctggc 241 cccgggtccc gcgccccgag accgccgtcg ctcggacgct cctgctcggc tgggtcttcg 301 cccaggtggc cggcgcttca ggcactacaa atactgtggc agcatataat ttaacttgga 361 aatcaactaa tttcaagaca attttggagt gggaacccaa acccgtcaat caagtctaca 421 ctgttcaaat aagcactaag tcaggagatt ggaaaagcaa atgcttttac acaacagaca 481 cagagtgtga cctcaccgac gagattgtga aggatgtgaa gcagacgtac ttggcacggg 541 tcttctccta cccggcaggg aatgtggaga gcaccggttc tgctggggag cctctgtatg 601 agaactcccc agagttcaca ccttacctgg agacaaacct cggacagcca acaattcaga 661 gttttgaaca ggtgggaaca aaagtgaatg tgaccgtaga agatgaacgg actttagtca 721 gaaggaacaa cactttccta agcctccggg atgtttttgg caaggactta atttatacac 781 tttattattg gaaatcttca agttcaggaa agaaaacagc caaaacaaac actaatgagt 841 ttttgattga tgtggataaa ggagaaaact actgtttcag tgttcaagca gtgattccct 901 cccgaacagt taaccggaag agtacagaca gcccggtaga gtgtatgggc caggagaaag 961 gggaattcag agaaatattc tacatcattg gagctgtggt atttgtggtc atcatccttg 1021 tcatcatcct ggctatatct ctacacaagt gtagaaaggc aggagtgggg cagagctgga 1081 aggagaactc cccactgaat gtttcataaa ggaagcactg ttggagctac tgcaaatgct 1141 atattgcact gtgaccgaga acttttaaga ggatagaata catggaaacg caaatgagta 1201 tttcggagca tgaagaccct ggagttcaaa aaactcttga tatgacctgt tattaccatt 1261 agcattctgg ttttgacatc agcattagtc actttgaaat gtaacgaatg gtactacaac 1321 caattccaag ttttaatttt taacaccatg gcaccttttg cacataacat gctttagatt 1381 atatattccg cactcaagga gtaaccaggt cgtccaagca aaaacaaatg ggaaaatgtc 1441 ttaaaaaatc ctgggtggac ttttgaaaag cttttttttt tttttttttt tttttgagac 1501 ggagtcttgc tctgttgccc aggctggagt gcagtagcac gatctcggct cactgcaccc 1561 tccgtctctc gggttcaagc aattgtctgc ctcagcctcc cgagtagctg ggattacagg 1621 tgcgcactac cacgccaagc taatttttgt attttttagt agagatgggg tttcaccatc 1681 ttggccaggc tggtcttgaa ttcctgacct caggtgatcc acccaccttg gcctcccaaa 1741 gtgctagtat tatgggcgtg aaccaccatg cccagccgaa aagcttttga ggggctgact 1801 tcaatccatg taggaaagta aaatggaagg aaattgggtg catttctagg acttttctaa 1861 catatgtcta taatatagtg tttaggttct tttttttttc aggaatacat ttggaaattc 1921 aaaacaattg gcaaactttg tattaatgtg ttaagtgcag gagacattgg tattctgggc 1981 accttcctaa tatgctttac aatctgcact ttaactgact taagtggcat taaacatttg 2041 agagctaact atatttttat aagactacta tacaaactac agagtttatg atttaaggta 2101 cttaaagctt ctatggttga cattgtatat ataatttttt aaaaaggttt tctatatggg 2161 gattttctat ttatgtaggt aatattgttc tatttgtata tattgagata atttatttaa 2221 tatactttaa ataaaggtga ctgggaattg ttactgttgt acttattcta tcttccattt 2281 attatttatg tacaatttgg tgtttgtatt agctctacta cagtaaatga ctgtaaaatt 2341 gtcagtggct tacaacaacg tatctttttc gcttataata cattttggtg act (SEQ NO : 75)

[0261] An exemplary amino acid sequence encoding F3 (NP 001984.1) comprises or consists of:

METPAWPRVPRPETAVARTLLLGWVFAQVAGASGTTNTVAAYNLTWKSTNFKTILEWEPKPVNQVYTVQISTKSG DWKSKCFYTTDTECDLTDEIVKDVKQTYLARVFSYPAGNVESTGSAGEPLYENSPEFTPYLETNLGQPTIQSFEQ VGTKVNVTVEDERTLVRRNNTFLSLRDVFGKDLIYTLYYWKSSSSGKKTAKTNTNEFLIDVDKGENYCFSVQAVI PSRTVNRKSTDSPVECMGQEKGEFREIFYI IGAWFWI ILVI ILAISLHKCRKAGVGQSWKENSPLNVS ( SEQ ID NO: 76) .

[0262] An exemplary nucleic acid sequence encoding F3 (NM_001178096.1 variant 2) comprises or consists of:

1 ggagtcggga ggagcggcgg gggcgggcgc cgggggcggg cagaggcgcg ggagagcgcg 61 ccgccggccc tttatagcgc gcggggcacc ggctccccaa gactgcgagc tccccgcacc 121 ccctcgcact ccctctggcc ggcccagggc gccttcagcc caacctcccc agccccacgg 181 gcgccacgga acccgctcga tctcgccgcc aactggtaga catggagacc cctgcctggc 241 cccgggtccc gcgccccgag accgccgtcg ctcggacgct cctgctcggc tgggtcttcg 301 cccaggtggc cggcgcttca ggcactacaa atactgtggc agcatataat ttaacttgga 361 aatcaactaa tttcaagaca attttggagt gggaacccaa acccgtcaat caagtctaca 421 ctgttcaaat aagcactaag tcaggagatt ggaaaagcaa atgcttttac acaacagaca 481 cagagtgtga cctcaccgac gagattgtga aggatgtgaa gcagacgtac ttggcacggg 541 tcttctccta cccggcaggg aatgtggaga gcaccggttc tgctggggag cctctgtatg 601 agaactcccc agagttcaca ccttacctgg agacaaacct cggacagcca acaattcaga 661 gttttgaaca ggtgggaaca aaagtgaatg tgaccgtaga agatgaacgg actttagtca 721 gaaggaacaa cactttccta agcctccggg atgtttttgg caaggactta atttatacac 781 tttattattg gaaatcttca agttcaggaa agaaatattc tacatcattg gagctgtggt 841 atttgtggtc atcatccttg tcatcatcct ggctatatct ctacacaagt gtagaaaggc 901 aggagtgggg cagagctgga aggagaactc cccactgaat gtttcataaa ggaagcactg 961 ttggagctac tgcaaatgct atattgcact gtgaccgaga acttttaaga ggatagaata 1021 catggaaacg caaatgagta tttcggagca tgaagaccct ggagttcaaa aaactcttga 1081 tatgacctgt tattaccatt agcattctgg ttttgacatc agcattagtc actttgaaat 1141 gtaacgaatg gtactacaac caattccaag ttttaatttt taacaccatg gcaccttttg 1201 cacataacat gctttagatt atatattccg cactcaagga gtaaccaggt cgtccaagca 1261 aaaacaaatg ggaaaatgtc ttaaaaaatc ctgggtggac ttttgaaaag cttttttttt 1321 tttttttttt tttttgagac ggagtcttgc tctgttgccc aggctggagt gcagtagcac 1381 gatctcggct cactgcaccc tccgtctctc gggttcaagc aattgtctgc ctcagcctcc

1441 cgagtagctg ggattacagg tgcgcactac cacgccaagc taatttttgt attttttagt

1501 agagatgggg tttcaccatc ttggccaggc tggtcttgaa ttcctgacct caggtgatcc

1561 acccaccttg gcctcccaaa gtgctagtat tatgggcgtg aaccaccatg cccagccgaa

1621 aagcttttga ggggctgact tcaatccatg taggaaagta aaatggaagg aaattgggtg

1681 catttctagg acttttctaa catatgtcta taatatagtg tttaggttct tttttttttc

1741 aggaatacat ttggaaattc aaaacaattg gcaaactttg tattaatgtg ttaagtgcag

1801 gagacattgg tattctgggc accttcctaa tatgctttac aatctgcact ttaactgact

1861 taagtggcat taaacatttg agagctaact atatttttat aagactacta tacaaactac

1921 agagtttatg atttaaggta cttaaagctt ctatggttga cattgtatat ataatttttt

1981 aaaaaggttt tctatatggg gattttctat ttatgtaggt aatattgttc tatttgtata

2041 tattgagata atttatttaa tatactttaa ataaaggtga ctgggaattg ttactgttgt

2101 acttattcta tcttccattt attatttatg tacaatttgg tgtttgtatt agctctacta

2161 cagtaaatga ctgtaaaatt gtcagtggct tacaacaacg tatctttttc gcttataata

2221 cattttggtg act (SEQ ID NO: 77) .

[0263] An exemplary amino acid sequence encoding F3 (NP 001 171567.1 , isoform 2 precursor) comprises or consists of:

METPAWPRVPRPETAVARTLLLGWVFAQVAGASGTTNTVAAYNLTWKSTNFKTILEWEPKPVNQVYTVQISTKSG DWKSKCFYTTDTECDLTDEIVKDVKQTYLARVFSYPAGNVESTGSAGEPLYENSPEFTPYLETNLGQPTIQSFEQ VGTKVNVTVEDERTLVRRNNTFLSLRDVFGKDLIYTLYYWKSSSSGKKYSTSLELWYLWSSSLSSSWLYLYTSVE

RQEWGRAGRRTPH (SEQ ID NO: 78)

[0264] An exemplary nucleic acid sequence encoding FAAH (NM_001441.2 mRNA comprises or consists of:

1 tccgggtttt gcggcggagc gggcgggctg cgcgtgcggc ggcttcaact gtcgcggtag 61 gcagcagcag gctgaaggga tcatggtgca gtacgagctg tgggccgcgc tgcctggcgc 121 ctccggggtc gccctggcct gctgcttcgt ggcggcggcc gtggccctgc gctggtccgg 181 gcgccggacg gcgcggggcg cggtggtccg ggcgcgacag aggcagcgag cgggcctgga 241 gaacatggac agggcggcgc agcgcttccg gctccagaac ccagacctgg actcagaggc 301 gctgctagcc ctgcccctgc ctcagctggt gcagaagtta cacagtagag agctggcccc 361 tgaggccgtg ctcttcacct atgtgggaaa ggcctgggaa gtgaacaaag ggaccaactg 421 tgtgacctcc tatctggctg actgtgagac tcagctgtct caggccccaa ggcagggcct 481 gctctatggc gtccctgtga gcctcaagga gtgcttcacc tacaagggcc aggactccac 541 gctgggcttg agcctgaatg aaggggtgcc ggcggagtgc gacagcgtag tggtgcatgt 601 gctgaagctg cagggtgccg tgcccttcgt gcacaccaat gttccacagt ccatgttcag 661 ctatgactgc agtaaccccc tctttggcca gaccgtgaac ccatggaagt cctccaaaag 721 cccagggggc tcctcagggg gtgaaggggc cctcatcggg tctggaggct cccccctggg 781 cttaggcact gatatcggag gcagcatccg cttcccctcc tccttctgcg gcatctgcgg 841 cctcaagccc acagggaacc gcctcagcaa gagtggcctg aagggctgtg tctatggaca 901 ggaggcagtg cgtctctccg tgggccccat ggcccgggac gtggagagcc tggcactgtg 961 cctgcgagcc ctgctgtgcg aggacatgtt ccgcttggac cccactgtgc ctcccttgcc 1021 cttcagagaa gaggtctaca ccagctctca gcccctgcgt gtggggtact atgagactga 1081 caactatacc atgccctccc cggccatgag gcgggccgtg ctggagacca aacagagcct 1141 tgaggctgcg gggcacacgc tggttccctt cttgccaagc aacatacccc atgctctgga 1201 gaccctgtca acaggtgggc tcttcagtga tggtggccac accttcctac agaacttcaa 1261 aggtgatttc gtggacccct gcctggggga cctggtctca attctgaagc ttccccaatg 1321 gcttaaagga ctgctggcct tcctggtgaa gcctctgctg ccaaggctgt cagctttcct 1381 cagcaacatg aagtctcgtt cggctggaaa actctgggaa ctgcagcacg agatcgaggt 1441 gtaccgcaaa accgtgattg cccagtggag ggcgctggac ctggatgtgg tgctgacccc 1501 catgctggcc cctgctctgg acttgaatgc cccaggcagg gccacagggg ccgtcagcta 1561 cactatgctg tacaactgcc tggacttccc tgcaggggtg gtgcctgtca ccacggtgac 1621 tgctgaggac gaggcccaga tggaacatta caggggctac tttggggata tctgggacaa 1681 gatgctgcag aagggcatga agaagagtgt ggggctgccg gtggccgtgc agtgtgtggc 1741 tctgccctgg caagaagagt tgtgtctgcg gttcatgcgg gaggtggagc gactgatgac 1801 ccctgaaaag cagtcatcct gatggctctg gctccagagg acctgagact cacactctct 1861 gcagcccagc ctagtcaggg cacagctgcc ctgctgccac agcaaggaaa tgtcctgcat 1921 ggggcagagg cttccgtgtc ctctccccca accccctgca agaagcgccg actccctgag 1981 tctggacctc catccctgct ctggtcccct ctcttcgtcc tgatccctcc acccccatgt 2041 ggcagcccat gggtatgaca taggccaagg cccaactaac agtcaagaaa cagctaaaaa 2101 aaaaa (SEQ ID NO: 79) .

[0265] An exemplary amino acid sequence encoding FAAH (NP_001432.2) comprises or consists of:

MVQYELWAALPGASGVALACCFVAAAVALRWSGRRTARGAWRARQRQRAGLENMDRAAQRFRLQNPDLDSEALL ALPLPQLVQKLHSRELAPEAVLFTYVGKAWEVNKGTNCVTSYLADCETQLSQAPRQGLLYGVPVSLKECFTYKGQ DSTLGLSLNEGVPAECDSVWHVLKLQGAVPFVHTNVPQSMFSYDCSNPLFGQTVNPWKSSKSPGGSSGGEGALI GSGGSPLGLGTDIGGSIRFPSSFCGICGLKPTGNRLSKSGLKGCVYGQEAVRLSVGPMARDVESLALCLRALLCE DMFRLDPTVPPLPFREEVYTSSQPLRVGYYETDNYTMPSPAMRRAVLETKQSLEAAGHTLVPFLPSNIPHALETL STGGLFSDGGHTFLQNFKGDFVDPCLGDLVSILKLPQWLKGLLAFLVKPLLPRLSAFLSNMKSRSAGKLWELQHE IEVYRKTVIAQWRALDLDWLTPMLAPALDLNAPGRATGAVSYTMLYNCLDFPAGWPVTTVTAEDEAQMEHYRG YFGDIWDKMLQKGMKKSVGLPVAVQCVALPWQEELCLRFMREVERLMTPEKQSS (SEQ ID NO: 80) .

[0266] An exemplary nucleic acid sequence encoding FAP (NM_004460.4 variant 1) comprises or consists of:

1 actcacagtt catttgaggg ccaagaacgc ccccaaaatc tgtttctaat tttacagaaa

61 tcttttgaaa cttggcacgg tattcaaaag tccgtggaaa gaaaaaaacc ttgtcctggc

121 ttcagcttcc aactacaaag acagacttgg tccttttcaa cggttttcac agatccagtg

181 acccacgctc tgaagacaga attagctaac tttcaaaaac atctggaaaa atgaagactt

241 gggtaaaaat cgtatttgga gttgccacct ctgctgtgct tgccttattg gtgatgtgca

301 ttgtcttacg cccttcaaga gttcataact ctgaagaaaa tacaatgaga gcactcacac

361 tgaaggatat tttaaatgga acattttctt ataaaacatt ttttccaaac tggatttcag

421 gacaagaata tcttcatcaa tctgcagata acaatatagt actttataat attgaaacag

481 gacaatcata taccattttg agtaatagaa ccatgaaaag tgtgaatgct tcaaattacg

541 gcttatcacc tgatcggcaa tttgtatatc tagaaagtga ttattcaaag ctttggagat

601 actcttacac agcaacatat tacatctatg accttagcaa tggagaattt gtaagaggaa

661 atgagcttcc tcgtccaatt cagtatttat gctggtcgcc tgttgggagt aaattagcat

721 atgtctatca aaacaatatc tatttgaaac aaagaccagg agatccacct tttcaaataa

781 catttaatgg aagagaaaat aaaatattta atggaatccc agactgggtt tatgaagagg

841 aaatgcttgc tacaaaatat gctctctggt ggtctcctaa tggaaaattt ttggcatatg

901 cggaatttaa tgatacggat ataccagtta ttgcctattc ctattatggc gatgaacaat

961 atcctagaac aataaatatt ccatacccaa aggctggagc taagaatccc gttgttcgga

1021 tatttattat cgataccact taccctgcgt atgtaggtcc ccaggaagtg cctgttccag

1081 caatgatagc ctcaagtgat tattatttca gttggctcac gtgggttact gatgaacgag

1141 tatgtttgca gtggctaaaa agagtccaga atgtttcggt cctgtctata tgtgacttca

1201 gggaagactg gcagacatgg gattgtccaa agacccagga gcatatagaa gaaagcagaa

1261 ctggatgggc tggtggattc tttgtttcaa caccagtttt cagctatgat gccatttcgt

1321 actacaaaat atttagtgac aaggatggct acaaacatat tcactatatc aaagacactg

1381 tggaaaatgc tattcaaatt acaagtggca agtgggaggc cataaatata ttcagagtaa

1441 cacaggattc actgttttat tctagcaatg aatttgaaga ataccctgga agaagaaaca

1501 tctacagaat tagcattgga agctatcctc caagcaagaa gtgtgttact tgccatctaa

1561 ggaaagaaag gtgccaatat tacacagcaa gtttcagcga ctacgccaag tactatgcac

1621 ttgtctgcta cggcccaggc atccccattt ccacccttca tgatggacgc actgatcaag

1681 aaattaaaat cctggaagaa aacaaggaat tggaaaatgc tttgaaaaat atccagctgc

1741 ctaaagagga aattaagaaa cttgaagtag atgaaattac tttatggtac aagatgattc

1801 ttcctcctca atttgacaga tcaaagaagt atcccttgct aattcaagtg tatggtggtc

1861 cctgcagtca gagtgtaagg tctgtatttg ctgttaattg gatatcttat cttgcaagta

1921 aggaagggat ggtcattgcc ttggtggatg gtcgaggaac agctttccaa ggtgacaaac 1981 tcctctatgc agtgtatcga aagctgggtg tttatgaagt tgaagaccag attacagctg

2041 tcagaaaatt catagaaatg ggtttcattg atgaaaaaag aatagccata tggggctggt

2101 cctatggagg atacgtttca tcactggccc ttgcatctgg aactggtctt ttcaaatgtg

2161 gtatagcagt ggctccagtc tccagctggg aatattacgc gtctgtctac acagagagat

2221 tcatgggtct cccaacaaag gatgataatc ttgagcacta taagaattca actgtgatgg

2281 caagagcaga atatttcaga aatgtagact atcttctcat ccacggaaca gcagatgata

2341 atgtgcactt tcaaaactca gcacagattg ctaaagctct ggttaatgca caagtggatt

2401 tccaggcaat gtggtactct gaccagaacc acggcttatc cggcctgtcc acgaaccact

2461 tatacaccca catgacccac ttcctaaagc agtgtttctc tttgtcagac taaaaacgat

2521 gcagatgcaa gcctgtatca gaatctgaaa accttatata aacccctcag acagtttgct

2581 tattttattt tttatgttgt aaaatgctag tataaacaaa caaattaatg ttgttctaaa

2641 ggctgttaaa aaaaagatga ggactcagaa gttcaagcta aatattgttt acattttctg

2701 gtactctgtg aaagaagaga aaagggagtc atgcattttg ctttggacac agtgttttat

2761 cacctgttca tttgaagaaa aataataaag tcagaagttc aagtgctaaa aaaaaaaaaa

2821 aaaaaaaaaa aaaaaaa (SEQ ID NO: 81) .

[0267] An exemplary amino acid sequence encoding FAP (NP 004451.2, isoform 1) comprises or consists of:

MKT VKIVFGVATSAVLALLVMCIVLRPSRVHNSEENTMRALTLKDILNGTFSYKTFFPNWISGQEYLHQSADNN IVLYNIETGQSYTILSNRTMKSVNASNYGLSPDRQFVYLESDYSKLWRYSYTATYYIYDLSNGEFVRGNELPRPI QYLCWSPVGSKLAYVYQNNIYLKQRPGDPPFQITFNGRENKIFNGIPDWVYEEEMLATKYALWWSPNGKFLAYAE FNDTDIPVIAYSYYGDEQYPRTINIPYPKAGAKNPVVRIFI IDTTYPAYVGPQEVPVPAMIASSDYYFSWLT VT DERVCLQWLKRVQNVSVLSICDFREDWQTWDCPKTQEHIEESRTGWAGGFFVSTPVFSYDAISYYKIFSDKDGYK HIHYIKDTVENAIQITSGKWEAINIFRVTQDSLFYSSNEFEEYPGRRNIYRISIGSYPPSKKCVTCHLRKERCQY YTASFSDYAKYYALVCYGPGIPISTLHDGRTDQEIKILEENKELENALKNIQLPKEEIKKLEVDEITLWYKMILP PQFDRSKKYPLLIQVYGGPCSQSVRSVFAVNWISYLASKEGMVIALVDGRGTAFQGDKLLYAVYRKLGVYEVEDQ ITAVRKFIEMGFIDEKRIAIWGWSYGGYVSSLALASGTGLFKCGIAVAPVSSWEYYASVYTERFMGLPTKDDNLE HYKNSTVMARAEYFRNVDYLLIHGTADDNVHFQNSAQIAKALVNAQVDFQAMWYSDQNHGLSGLSTNHLYTHMTH FLKQCFSLSD (SEQ ID NO: 82) .

[0268] An exemplary nucleic acid sequence encoding FAP (NM_001291807.2 variant 2) comprises or consists of:

1 actcacagtt catttgaggg ccaagaacgc ccccaaaatc tgtttctaat tttacagaaa 61 tcttttgaaa cttggcacgg tattcaaaag tccgtggaaa gaaaaaaacc ttgtcctggc 121 ttcagcttcc aactacaaag acagacttgg tccttttcaa cggttttcac agatccagtg 181 acccacgctc tgaagacaga attagctaac tttcaaaaac atctggaaaa atgaagactt 241 gggtaaaaat cgtatttgga gttgccacct ctgctgtgct tgccttattg gtgatgtgca 301 ttgtcttacg cccttcaaga gttcataact ctgaagaaaa tacaatgaga gcactcacac 361 tgaaggatat tttaaatgga acattttctt ataaaacatt ttttccaaac tggatttcag 421 gacaagaata tcttcatcaa tctgcagata acaatatagt actttataat attgaaacag 481 gacaatcata taccattttg agtaatagaa ccatgctttg gagatactct tacacagcaa 541 catattacat ctatgacctt agcaatggag aatttgtaag aggaaatgag cttcctcgtc 601 caattcagta tttatgctgg tcgcctgttg ggagtaaatt agcatatgtc tatcaaaaca 661 atatctattt gaaacaaaga ccaggagatc caccttttca aataacattt aatggaagag 721 aaaataaaat atttaatgga atcccagact gggtttatga agaggaaatg cttgctacaa 781 aatatgctct ctggtggtct cctaatggaa aatttttggc atatgcggaa tttaatgata 841 cggatatacc agttattgcc tattcctatt atggcgatga acaatatcct agaacaataa 901 atattccata cccaaaggct ggagctaaga atcccgttgt tcggatattt attatcgata 961 ccacttaccc tgcgtatgta ggtccccagg aagtgcctgt tccagcaatg atagcctcaa 1021 gtgattatta tttcagttgg ctcacgtggg ttactgatga acgagtatgt ttgcagtggc 1081 taaaaagagt ccagaatgtt tcggtcctgt ctatatgtga cttcagggaa gactggcaga 1141 catgggattg tccaaagacc caggagcata tagaagaaag cagaactgga tgggctggtg 1201 gattctttgt ttcaacacca gttttcagct atgatgccat ttcgtactac aaaatattta 1261 gtgacaagga tggctacaaa catattcact atatcaaaga cactgtggaa aatgctattc 1321 aaattacaag tggcaagtgg gaggccataa atatattcag agtaacacag gattcactgt 1381 tttattctag caatgaattt gaagaatacc ctggaagaag aaacatctac agaattagca 1441 ttggaagcta tcctccaagc aagaagtgtg ttacttgcca tctaaggaaa gaaaggtgcc 1501 aatattacac agcaagtttc agcgactacg ccaagtacta tgcacttgtc tgctacggcc 1561 caggcatccc catttccacc cttcatgatg gacgcactga tcaagaaatt aaaatcctgg 1621 aagaaaacaa ggaattggaa aatgctttga aaaatatcca gctgcctaaa gaggaaatta 1681 agaaacttga agtagatgaa attactttat ggtacaagat gattcttcct cctcaatttg 1741 acagatcaaa gaagtatccc ttgctaattc aagtgtatgg tggtccctgc agtcagagtg 1801 taaggtctgt atttgctgtt aattggatat cttatcttgc aagtaaggaa gggatggtca 1861 ttgccttggt ggatggtcga ggaacagctt tccaaggtga caaactcctc tatgcagtgt 1921 atcgaaagct gggtgtttat gaagttgaag accagattac agctgtcaga aaattcatag 1981 aaatgggttt cattgatgaa aaaagaatag ccatatgggg ctggtcctat ggaggatacg 2041 tttcatcact ggcccttgca tctggaactg gtcttttcaa atgtggtata gcagtggctc 2101 cagtctccag ctgggaatat tacgcgtctg tctacacaga gagattcatg ggtctcccaa 2161 caaaggatga taatcttgag cactataaga attcaactgt gatggcaaga gcagaatatt 2221 tcagaaatgt agactatctt ctcatccacg gaacagcaga tgataatgtg cactttcaaa 2281 actcagcaca gattgctaaa gctctggtta atgcacaagt ggatttccag gcaatgtggt 2341 actctgacca gaaccacggc ttatccggcc tgtccacgaa ccacttatac acccacatga 2401 cccacttcct aaagcagtgt ttctctttgt cagactaaaa acgatgcaga tgcaagcctg 2461 tatcagaatc tgaaaacctt atataaaccc ctcagacagt ttgcttattt tattttttat 2521 gttgtaaaat gctagtataa acaaacaaat taatgttgtt ctaaaggctg ttaaaaaaaa 2581 gatgaggact cagaagttca agctaaatat tgtttacatt ttctggtact ctgtgaaaga 2641 agagaaaagg gagtcatgca ttttgctttg gacacagtgt tttatcacct gttcatttga 2701 agaaaaataa taaagtcaga agttcaagtg ctaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2761 aa (SEQ ID NO: 83) .

[0269] An exemplary amino acid sequence encoding FAP (NP 001278736.1 isoform 2) comprises or consists of:

MKT VKIVFGVATSAVLALLVMCIVLRPSRVHNSEENTMRALTLKDILNGTFSYKTFFPNWISGQEYLHQSADNN

IVLYNIETGQSYTILSNRTMLWRYSYTATYYIYDLSNGEFVRGNELPRPIQYLCWSPVGSKLAYVYQNNIYLKQR

PGDPPFQITFNGRENKIFNGIPDWVYEEEMLATKYALWWSPNGKFLAYAEFNDTDIPVIAYSYYGDEQYPRTINI

PYPKAGAKNPWRIFIIDTTYPAYVGPQEVPVPAMIASSDYYFSWLT VTDERVCLQWLKRVQNVSVLSICDFRE

DWQTWDCPKTQEHIEESRTGWAGGFFVSTPVFSYDAISYYKIFSDKDGYKHIHYIKDTVENAIQITSGKWEAINI

FRVTQDSLFYSSNEFEEYPGRRNIYRISIGSYPPSKKCVTCHLRKERCQYYTASFSDYAKYYALVCYGPGIPIST

LHDGRTDQEIKILEENKELENALKNIQLPKEEIKKLEVDEITLWYKMILPPQFDRSKKYPLLIQVYGGPCSQSVR

SVFAVNWISYLASKEGMVIALVDGRGTAFQGDKLLYAVYRKLGVYEVEDQITAVRKFIEMGFIDEKRIAIWGWSY

GGYVSSLALASGTGLFKCGIAVAPVSSWEYYASVYTERFMGLPTKDDNLEHYKNSTVMARAEYFRNVDYLLIHGT

ADDNVHFQNSAQIAKALVNAQVDFQAMWYSDQNHGLSGLSTNHLYTHMTHFLKQCFSLSD (SEQ ID NO:

84) .

[0270] An exemplary nucleic acid sequence encoding FAP (KT584069.1 , 3 ' UTR) comprises or consists of:

1 ctaaagcagt gtttctcttt gtcagactaa aaacgatgca gatgcaagcc tgtatcagaa

61 tctgaaaacc ttatataaac ccctcagaca gtttgcttat tttatttttt atgttgtaaa

121 atgctagtat aaacaaacaa attaatgttg ttctaaaggc tgttaaaaaa agatgaggac

181 tcagaagttc aagctaaata ttgtttacat tttctggtac tctgtgaaag aagagaaaag

241 ggagtcatgc attttgcttt ggacacagtg ttttatcacc tgttcatttg aagaaaaata

301 ataaagtcag aagttcaagt gctattgtgt tgtctgtatt cattgatttc aggttccagg

361 ttttatcaca gaaagaggtg tttgtgcaaa gcaagtgcat gaataacatt agggtggtca

421 tggaggagaa gaatctagaa gtgattttgg atttctgtca tgagaactcc a (SEQ ID NO : 85)

[0271] An exemplary nucleic acid sequence encoding GSTP1 (NM_000852.3 mRNA) comprises or consists of:

1 tgggaaagag ggaaaggctt ccccggccag ctgcgcggcg actccgggga ctccagggcg 61 cccctctgcg gccgacgccc ggggtgcagc ggccgccggg gctggggccg gcgggagtcc 121 gcgggaccct ccagaagagc ggccggcgcc gtgactcagc actggggcgg agcggggcgg 181 gaccaccctt ataaggctcg gaggccgcga ggccttcgct ggagtttcgc cgccgcagtc 241 ttcgccacca tgccgcccta caccgtggtc tatttcccag ttcgaggccg ctgcgcggcc 301 ctgcgcatgc tgctggcaga tcagggccag agctggaagg aggaggtggt gaccgtggag 361 acgtggcagg agggctcact caaagcctcc tgcctatacg ggcagctccc caagttccag 421 gacggagacc tcaccctgta ccagtccaat accatcctgc gtcacctggg ccgcaccctt 481 gggctctatg ggaaggacca gcaggaggca gccctggtgg acatggtgaa tgacggcgtg 541 gaggacctcc gctgcaaata catctccctc atctacacca actatgaggc gggcaaggat 601 gactatgtga aggcactgcc cgggcaactg aagccttttg agaccctgct gtcccagaac 661 cagggaggca agaccttcat tgtgggagac cagatctcct tcgctgacta caacctgctg 721 gacttgctgc tgatccatga ggtcctagcc cctggctgcc tggatgcgtt ccccctgctc 781 tcagcatatg tggggcgcct cagtgcccgg cccaagctca aggccttcct ggcctcccct 841 gagtacgtga acctccccat caatggcaac gggaaacagt gagggttggg gggactctga 901 gcgggaggca gagtttgcct tcctttctcc aggaccaata aaatttctaa gagagctaaa 961 aaaaaaaaaa aaaaaaaaaa aaaaaa (SEQ ID NO: 86)

[0272] An exemplary amino acid sequence encoding GSTP1 (NP 000843.1) comprises or consists of:

MPPYTWYFPVRGRCAALRMLLADQGQSWKEEWTVETWQEGSLKASCLYGQLPKFQDGDLTLYQSNTILRHLGR TLGLYGKDQQEAALVDMVNDGVEDLRCKYISLIYTNYEAGKDDYVKALPGQLKPFETLLSQNQGGKTFIVGDQIS FADYNLLDLLLIHEVLAPGCLDAFPLLSAYVGRLSARPKLKAFLASPEYVNLPINGNGKQ (SEQ ID NO: 87) .

[0273] An exemplary nucleic acid sequence encoding IL7R (NR 120485.2, transcript variant

2 ) comprises or consists of:

1 gtggttagat aagtataaag ccctagatct aagcttctct gtcttcctcc ctccctccct 61 tcctcttact ctcattcatt tcatacacac tggctcacac atctactctc tctctctatc 121 tctctcagaa tgacaattct aggtacaact tttggcatgg ttttttcttt acttcaagtc 181 gtttctggag aaagtggcta tgctcaaaat ggagacttgg aagatgcaga actggatgac 241 tactcattct catgctatag ccagttggaa gtgaatggat cgcagcactc actgacctgt 301 gcttttgagg acccagatgt caacatcacc aatctggaat ttgaaatatg tggggccctc 361 gtggaggtaa agtgcctgaa tttcaggaaa ctacaagaga tatatttcat cgagacaaag 421 aaattcttac tgattggaaa gagcaatata tgtgtgaagg ttggagaaaa gagtctaacc 481 tgcaaaaaaa tagacctaac cactatagtt aaacctgagg ctccttttga cctgagtgtc 541 gtctatcggg aaggagccaa tgactttgtg gtgacattta atacatcaca cttgcaaaag 601 aagtatgtaa aagttttaat gcacgatgta gcttaccgcc aggaaaagga tgaaaacaaa 661 tggacggatt aagcctatcg tatggcccag tctccccgat cataagaaga ctctggaaca 721 tctttgtaag aaaccaagaa aaaatttaaa tgtgagtttc aatcctgaaa gtttcctgga 781 ctgccagatt catagggtgg atgacattca agctagagat gaagtggaag gttttctgca 841 agatacgttt cctcagcaac tagaagaatc tgagaagcag aggcttggag gggatgtgca 901 gagccccaac tgcccatctg aggatgtagt catcactcca gaaagctttg gaagagattc 961 atccctcaca tgcctggctg ggaatgtcag tgcatgtgac gcccctattc tctcctcttc 1021 caggtcccta gactgcaggg agagtggcaa gaatgggcct catgtgtacc aggacctcct 1081 gcttagcctt gggactacaa acagcacgct gccccctcca ttttctctcc aatctggaat 1141 cctgacattg aacccagttg ctcagggtca gcccattctt acttccctgg gatcaaatca 1201 agaagaagca tatgtcacca tgtccagctt ctaccaaaac cagtgaagtg taagaaaccc 1261 agactgaact taccgtgagc gacaaagatg atttaaaagg gaagtctaga gttcctagtc 1321 tccctcacag cacagagaag acaaaattag caaaacccca ctacacagtc tgcaagattc

1381 tgaaacattg ctttgaccac tcttcctgag ttcagtggca ctcaacatga gtcaagagca

1441 tcctgcttct accatgtgga tttggtcaca aggtttaagg tgacccaatg attcagctat

1501 ttaaaaaaaa aagaggaaag aatgaaagag taaaggaaat gattgaggag tgaggaaggc

1561 aggaagagag catgagagga aagaaagaaa ggaaaataaa aaatgatagt tgccattatt

1621 aggatttaat atatatccag tgctttgcaa gtgctctgcg caccttgtct cactccatcc

1681 tgacaataat cctgggaggt gtgtgcaatt actacgacta ctctcttttt tatagatcat

1741 taaattcaga actaaggagt taagtaactt gtccaagttg ttcacacagt gaagggaggg

1801 gccaagatat gatggctggg agtctaattg cagttccctg agccatgtgc ctttctcttc

1861 actgaggact gccccattct tgagtgccaa acgtcactag taacagggtg tgcctagata

1921 atttatgatc caaactgagt cagtttggaa agtgaaaggg aaacttacat ataatccctc

1981 cgggacaatg agcaaaaact aggactgtcc ccagacaaat gtgaacatac atatcatcac

2041 ttaaattaaa atggctatga gaaagaaaga gggggagaaa cagtcttgcg ggtgtgaagt

2101 cccatgacca gccatgtcaa aagaaggtaa agaagtcaag aaaaagccat gaagcccatt

2161 tggtttcatt tttctgaaaa taggctcaag agggaataaa ttagaaactc acaatttctc

2221 ttgtttgtta ccaagacagt gattctcttg ctgctaccac ccaactgcat ccgtccatga

2281 tctcagagga aactgtcgct gaccctggac atgggtacgt ttgacgagtg agaggaggca

2341 tgacccctcc catgtgtata gacactaccc caacctaaat tcatccctaa attgtcccaa

2401 gttctccagc aatagaggct gccacaaact tcagggagaa agagttacaa gtacatgcaa

2461 tgagtgaact gactgtggct acaatcttga agatatacgg aagagacgta ttattaatgc

2521 ttgacatata tcatcttgcc tttcttggtc tagactgact tctaatgact aactcaaagt

2581 caaggcaact gagtaatgtc agctcagcaa agtgcagcaa acccatctcc cacaggcctc

2641 caaaccctgg ctgttcacag aaccacaaag ggcagatgct gcacagaaaa ctagagaagg

2701 ggtcataggt tcatggtttt gtttgagatt tgttgctact gtttttctgt tttgaatttt

2761 cttctttgtt ctgtttttac tttatttagg gggactaggt gtttctgata ttttagtttt

2821 cttgtttgtt ttgttttgtg ttgtctgtga atggggtttt aactgtggat gaatggacct

2881 tatctgttgg cttaaaggac tggtaagatc agaccatctt attcttcagg tgaatgtttt

2941 actttccaaa gtgctctcct ctgcaccagc agtaataaat acaatgccat aatcccttag

3001 gtttgcctag tgcttttgca attttcaaag cacttccata agcattcctt ccacctcctt

3061 gataggcatt tatggaaagc ctgctacatg tcaatcatac tgttaggcac aggggaccta

3121 aagacacata aaaggatggc attctgcctc ataaattgca aaacctaatg aaagtgactg

3181 cttggtaaac aaattattat tatattataa aatgctataa aagagccata ttgaaagtgc

3241 cctgttggag acagggcaaa tgccacaaaa atgatgtaaa tttacatgga ggaaaagtag

3301 aatctgcctg gtttgtaggc agcagaagac atttttcatc agtgggcagg tgttctttac

3361 cttttgtaga aatgggagtc aagtctcaaa taggaggctc cacaaaatct catgccaggt

3421 ctctgatacc ttattcacag aagttctttg aagtatttat tgttattttc tttgacttat

3481 gggaaaactg ggacacagga agacaggtaa attacccaac ctcacacgtt aagtcagaac

3541 tgggagccat aattttgtat ccctggtata aatagacaat ctcttgaaga aatgaagaga

3601 tgaccataga aaaacatcga gatatctcca gctctaaaat cctttgtttc aatgttgttt

3661 ggcatatgtt atctttggaa tttagtgtct gagcctctgt ctgttactgt agtatttaaa

3721 atgcatgtat tataatcata taatcataac tgctgttaat tcttgattat atacctaggg

3781 acaatgtgta atgtaagatt actaattggt tctgcccaat ctcctttcag attttattag

3841 gaaaaaaaaa taaacctcct gatcggagac aatgtattaa tcagaagtgt aaactgccag

3901 ttctatatag catgaaatga aaagacagct aatttggtcc aacaaacatg actgggtcta

3961 gggcacccag gctgattcag ctgatttcct accagccttt gcctcttcct tcaatgtggt

4021 ttccatggga atttgcttca gaaaagccaa gtatgggctg ttcagaggtg cacacctgca

4081 ttttcttagc tcttctagag gggctaagag acttggtacg ggccaggaag aatatgtggc

4141 agagctcctg gaaatgatgc agattaggtg gcatttttgt cagctctgtg gtttattgtt

4201 gggactattc tttaaaatat ccattgttca ctacagtgaa gatctctgat ttaaccgtgt

4261 actatccaca tgcattacaa acatttcgca gagctgctta gtatataagc gtacaatgta

4321 tgtaataacc atctcatatt taattaaatg gtatagaaga acaaaaaaaa aaaaaaaaaa

(SEQ ID NO: 88) .

[0274] An exemplary nucleic acid sequence encoding IL7R (NM_002185.4) comprises or consists of:

1 gtggttagat aagtataaag ccctagatct aagcttctct gtcttcctcc ctccctccct

61 tcctcttact ctcattcatt tcatacacac tggctcacac atctactctc tctctctatc

121 tctctcagaa tgacaattct aggtacaact tttggcatgg ttttttcttt acttcaagtc

181 gtttctggag aaagtggcta tgctcaaaat ggagacttgg aagatgcaga actggatgac 241 tactcattct catgctatag ccagttggaa gtgaatggat cgcagcactc actgacctgt 301 gcttttgagg acccagatgt caacatcacc aatctggaat ttgaaatatg tggggccctc 361 gtggaggtaa agtgcctgaa tttcaggaaa ctacaagaga tatatttcat cgagacaaag 421 aaattcttac tgattggaaa gagcaatata tgtgtgaagg ttggagaaaa gagtctaacc 481 tgcaaaaaaa tagacctaac cactatagtt aaacctgagg ctccttttga cctgagtgtc 541 gtctatcggg aaggagccaa tgactttgtg gtgacattta atacatcaca cttgcaaaag 601 aagtatgtaa aagttttaat gcacgatgta gcttaccgcc aggaaaagga tgaaaacaaa 661 tggacgcatg tgaatttatc cagcacaaag ctgacactcc tgcagagaaa gctccaaccg 721 gcagcaatgt atgagattaa agttcgatcc atccctgatc actattttaa aggcttctgg 781 agtgaatgga gtccaagtta ttacttcaga actccagaga tcaataatag ctcaggggag 841 atggatccta tcttactaac catcagcatt ttgagttttt tctctgtcgc tctgttggtc 901 atcttggcct gtgtgttatg gaaaaaaagg attaagccta tcgtatggcc cagtctcccc 961 gatcataaga agactctgga acatctttgt aagaaaccaa gaaaaaattt aaatgtgagt 1021 ttcaatcctg aaagtttcct ggactgccag attcataggg tggatgacat tcaagctaga 1081 gatgaagtgg aaggttttct gcaagatacg tttcctcagc aactagaaga atctgagaag 1141 cagaggcttg gaggggatgt gcagagcccc aactgcccat ctgaggatgt agtcatcact 1201 ccagaaagct ttggaagaga ttcatccctc acatgcctgg ctgggaatgt cagtgcatgt 1261 gacgccccta ttctctcctc ttccaggtcc ctagactgca gggagagtgg caagaatggg 1321 cctcatgtgt accaggacct cctgcttagc cttgggacta caaacagcac gctgccccct 1381 ccattttctc tccaatctgg aatcctgaca ttgaacccag ttgctcaggg tcagcccatt 1441 cttacttccc tgggatcaaa tcaagaagaa gcatatgtca ccatgtccag cttctaccaa 1501 aaccagtgaa gtgtaagaaa cccagactga acttaccgtg agcgacaaag atgatttaaa 1561 agggaagtct agagttccta gtctccctca cagcacagag aagacaaaat tagcaaaacc 1621 ccactacaca gtctgcaaga ttctgaaaca ttgctttgac cactcttcct gagttcagtg 1681 gcactcaaca tgagtcaaga gcatcctgct tctaccatgt ggatttggtc acaaggttta 1741 aggtgaccca atgattcagc tatttaaaaa aaaaagagga aagaatgaaa gagtaaagga 1801 aatgattgag gagtgaggaa ggcaggaaga gagcatgaga ggaaagaaag aaaggaaaat 1861 aaaaaatgat agttgccatt attaggattt aatatatatc cagtgctttg caagtgctct 1921 gcgcaccttg tctcactcca tcctgacaat aatcctggga ggtgtgtgca attactacga 1981 ctactctctt ttttatagat cattaaattc agaactaagg agttaagtaa cttgtccaag 2041 ttgttcacac agtgaaggga ggggccaaga tatgatggct gggagtctaa ttgcagttcc 2101 ctgagccatg tgcctttctc ttcactgagg actgccccat tcttgagtgc caaacgtcac 2161 tagtaacagg gtgtgcctag ataatttatg atccaaactg agtcagtttg gaaagtgaaa 2221 gggaaactta catataatcc ctccgggaca atgagcaaaa actaggactg tccccagaca 2281 aatgtgaaca tacatatcat cacttaaatt aaaatggcta tgagaaagaa agagggggag 2341 aaacagtctt gcgggtgtga agtcccatga ccagccatgt caaaagaagg taaagaagtc 2401 aagaaaaagc catgaagccc atttggtttc atttttctga aaataggctc aagagggaat 2461 aaattagaaa ctcacaattt ctcttgtttg ttaccaagac agtgattctc ttgctgctac 2521 cacccaactg catccgtcca tgatctcaga ggaaactgtc gctgaccctg gacatgggta 2581 cgtttgacga gtgagaggag gcatgacccc tcccatgtgt atagacacta ccccaaccta 2641 aattcatccc taaattgtcc caagttctcc agcaatagag gctgccacaa acttcaggga 2701 gaaagagtta caagtacatg caatgagtga actgactgtg gctacaatct tgaagatata 2761 cggaagagac gtattattaa tgcttgacat atatcatctt gcctttcttg gtctagactg 2821 acttctaatg actaactcaa agtcaaggca actgagtaat gtcagctcag caaagtgcag 2881 caaacccatc tcccacaggc ctccaaaccc tggctgttca cagaaccaca aagggcagat 2941 gctgcacaga aaactagaga aggggtcata ggttcatggt tttgtttgag atttgttgct 3001 actgtttttc tgttttgaat tttcttcttt gttctgtttt tactttattt agggggacta 3061 ggtgtttctg atattttagt tttcttgttt gttttgtttt gtgttgtctg tgaatggggt 3121 tttaactgtg gatgaatgga ccttatctgt tggcttaaag gactggtaag atcagaccat 3181 cttattcttc aggtgaatgt tttactttcc aaagtgctct cctctgcacc agcagtaata 3241 aatacaatgc cataatccct taggtttgcc tagtgctttt gcaattttca aagcacttcc 3301 ataagcattc cttccacctc cttgataggc atttatggaa agcctgctac atgtcaatca 3361 tactgttagg cacaggggac ctaaagacac ataaaaggat ggcattctgc ctcataaatt 3421 gcaaaaccta atgaaagtga ctgcttggta aacaaattat tattatatta taaaatgcta 3481 taaaagagcc atattgaaag tgccctgttg gagacagggc aaatgccaca aaaatgatgt 3541 aaatttacat ggaggaaaag tagaatctgc ctggtttgta ggcagcagaa gacatttttc 3601 atcagtgggc aggtgttctt taccttttgt agaaatggga gtcaagtctc aaataggagg 3661 ctccacaaaa tctcatgcca ggtctctgat accttattca cagaagttct ttgaagtatt 3721 tattgttatt ttctttgact tatgggaaaa ctgggacaca ggaagacagg taaattaccc 3781 aacctcacac gttaagtcag aactgggagc cataattttg tatccctggt ataaatagac 3841 aatctcttga agaaatgaag agatgaccat agaaaaacat cgagatatct ccagctctaa 3901 aatcctttgt ttcaatgttg tttggcatat gttatctttg gaatttagtg tctgagcctc

3961 tgtctgttac tgtagtattt aaaatgcatg tattataatc atataatcat aactgctgtt

4021 aattcttgat tatataccta gggacaatgt gtaatgtaag attactaatt ggttctgccc

4081 aatctccttt cagattttat taggaaaaaa aaataaacct cctgatcgga gacaatgtat

4141 taatcagaag tgtaaactgc cagttctata tagcatgaaa tgaaaagaca gctaatttgg

4201 tccaacaaac atgactgggt ctagggcacc caggctgatt cagctgattt cctaccagcc

4261 tttgcctctt ccttcaatgt ggtttccatg ggaatttgct tcagaaaagc caagtatggg

4321 ctgttcagag gtgcacacct gcattttctt agctcttcta gaggggctaa gagacttggt

4381 acgggccagg aagaatatgt ggcagagctc ctggaaatga tgcagattag gtggcatttt

4441 tgtcagctct gtggtttatt gttgggacta ttctttaaaa tatccattgt tcactacagt

4501 gaagatctct gatttaaccg tgtactatcc acatgcatta caaacatttc gcagagctgc

4561 ttagtatata agcgtacaat gtatgtaata accatctcat atttaattaa atggtataga

4621 agaacaaaaa aaaaaaaaaa aaa (SEQ ID NO: 89) .

[0275] An exemplary amino acid sequence encoding IL7R (NP 002176.2) comprises or consists of:

MTILGTTFGMVFSLLQWSGESGYAQNGDLEDAELDDYSFSCYSQLEVNGSQHSLTCAFEDPDVNITNLEFEICG ALVEVKCLNFRKLQEIYFIETKKFLLIGKSNICVKVGEKSLTCKKIDLTTIVKPEAPFDLSWYREGANDFWTF NTSHLQKKYVKVLMHDVAYRQEKDENKWTHVNLSSTKLTLLQRKLQPAAMYEIKVRSIPDHYFKGFWSEWSPSYY FRTPEINNSSGEMDPILLTISILSFFSVALLVILACVLWKKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNP ESFLDCQIHRVDDIQARDEVEGFLQDTFPQQLEESEKQRLGGDVQSPNCPSEDWITPESFGRDSSLTCLAGNVS ACDAPILSSSRSLDCRESGKNGPHVYQDLLLSLGTTNSTLPPPFSLQSGILTLNPVAQGQPILTSLGSNQEEAYV TMSSFYQNQ (SEQ ID NO: 90) .

[0276] An exemplary nucleic acid sequence encoding IL7R (DQ821273.1, IL7R promoter region and exon 1) comprises or consists of:

1 atacctaggc actaatttag ttccatatgt actatgtgta cctgaaaagt tgtgtggcaa 61 tcaaattttc acaaatagaa tcctgtttta aatacactaa gaaagtacct actttatcct 121 ttaaacaaga ggtcagcaga ctttttctac aaagggtcag atagtaaaga ttttacacct 181 tttgtacaat acaatctcta tctcatctac ttagctctgc cattgttgca taaaagcagc 241 tgtagatgat acacaaatgg gtgaggctgt attccaatga aacgttattt gcaaaaacag 301 gtggtagatt aaatttggtc ccaaggctta cttgggaaaa aaaaagatct tttgaaaaag 361 aaaaaataaa tgaataattt tttaaaaaat tgttccctag gtcatagttt gccagcccct 421 gccctaaaca aataattctt gaatgcctac tgtggtgtgt aagatatgag taaataccag 481 ggatacacag agaacaaaag agaaaaactg ctattcttgt gaaacttgga agttggaggt 541 aagctattta aaataaaccc acaataaagt acttcacata gtgcagactg tttctttaaa 601 tcaaaactca ctccaaacaa ccaattgatt cactttgtaa gtttgaattt ttgtcttcag 661 attcttttaa agtgggccct tagtcaggag cggtggctca tgcctgtagt cctagcactt 721 tgggaggctg aggcaggcag atcacttgag gtcaggagtt cgagacaagc ctggccaaca 781 tggcgaaacc ccgtctccac tgaaaacaca aaaattaggc tggcatagtg gcatttgcct 841 gtagtcctag ctactcagga ggctgaggca ggagaattgc ttgaacctgg gaggtgaaaa 901 ttgcagtgag ccgagatcat gctattgtac tccagcctgg gcaacaaagc aagactctgt 961 ctcaaaaaaa taaaaattaa aaaaataaag tagcctctag cctaagatag cttgagccta 1021 ggtgtgaatc tactgcctta ctctgatgta agcacagtaa gtgtgggggc tgcagggaat 1081 atccaggagg aacaataatt tcagaggctc tgtctcttca tgtccttgac ctctgcttac 1141 agcagcaata cttttactca gacttcctgt ttctggaact tgccttcttt tttgctgtgt 1201 ttatacttcc cttgtctgtg gttagataag tataaagccc tagatctaag cttctctgtc 1261 ttcctccctc cctcccttcc tcttactctc attcatttca tacacactgg ctcacacatc 1321 tactctctct ctctatctct ctcaga (SEQ ID NO: 91)

[0277] An exemplary nucleic acid sequence encoding MMP1 (NM_002421.3, variant 1) comprises or consists of: 1 agcatgagtc agacagcctc tggctttctg gaagggcaag gactctatat atacagaggg 61 agcttcctag ctgggatatt ggagcagcaa gaggctggga agccatcact taccttgcac 121 tgagaaagaa gacaaaggcc agtatgcaca gctttcctcc actgctgctg ctgctgttct 181 ggggtgtggt gtctcacagc ttcccagcga ctctagaaac acaagagcaa gatgtggact 241 tagtccagaa atacctggaa aaatactaca acctgaagaa tgatgggagg caagttgaaa 301 agcggagaaa tagtggccca gtggttgaaa aattgaagca aatgcaggaa ttctttgggc 361 tgaaagtgac tgggaaacca gatgctgaaa ccctgaaggt gatgaagcag cccagatgtg 421 gagtgcctga tgtggctcag tttgtcctca ctgaggggaa ccctcgctgg gagcaaacac 481 atctgaccta caggattgaa aattacacgc cagatttgcc aagagcagat gtggaccatg 541 ccattgagaa agccttccaa ctctggagta atgtcacacc tctgacattc accaaggtct 601 ctgagggtca agcagacatc atgatatctt ttgtcagggg agatcatcgg gacaactctc 661 cttttgatgg acctggagga aatcttgctc atgcttttca accaggccca ggtattggag 721 gggatgctca ttttgatgaa gatgaaaggt ggaccaacaa tttcagagag tacaacttac 781 atcgtgttgc agctcatgaa ctcggccatt ctcttggact ctcccattct actgatatcg 841 gggctttgat gtaccctagc tacaccttca gtggtgatgt tcagctagct caggatgaca 901 ttgatggcat ccaagccata tatggacgtt cccaaaatcc tgtccagccc atcggcccac 961 aaaccccaaa agcgtgtgac agtaagctaa cctttgatgc tataactacg attcggggag 1021 aagtgatgtt ctttaaagac agattctaca tgcgcacaaa tcccttctac ccggaagttg 1081 agctcaattt catttctgtt ttctggccac aactgccaaa tgggcttgaa gctgcttacg 1141 aatttgccga cagagatgaa gtccggtttt tcaaagggaa taagtactgg gctgttcagg 1201 gacagaatgt gctacacgga taccccaagg acatctacag ctcctttggc ttccctagaa 1261 ctgtgaagca tatcgatgct gctctttctg aggaaaacac tggaaaaacc tacttctttg 1321 ttgctaacaa atactggagg tatgatgaat ataaacgatc tatggatcca ggttatccca 1381 aaatgatagc acatgacttt cctggaattg gccacaaagt tgatgcagtt ttcatgaaag 1441 atggattttt ctatttcttt catggaacaa gacaatacaa atttgatcct aaaacgaaga 1501 gaattttgac tctccagaaa gctaatagct ggttcaactg caggaaaaat tgaacattac 1561 taatttgaat ggaaaacaca tggtgtgagt ccaaagaagg tgttttcctg aagaactgtc 1621 tattttctca gtcattttta acctctagag tcactgatac acagaatata atcttattta 1681 tacctcagtt tgcatatttt tttactattt agaatgtagc cctttttgta ctgatataat 1741 ttagttccac aaatggtggg tacaaaaagt caagtttgtg gcttatggat tcatataggc 1801 cagagttgca aagatctttt ccagagtatg caactctgac gttgatccca gagagcagct 1861 tcagtgacaa acatatcctt tcaagacaga aagagacagg agacatgagt ctttgccgga 1921 ggaaaagcag ctcaagaaca catgtgcagt cactggtgtc accctggata ggcaagggat 1981 aactcttcta acacaaaata agtgttttat gtttggaata aagtcaacct tgtttctact 2041 gttttataca ctttcaaaaa aaaaaaaaaa aaaaaaaaaa a (SEQ ID NO: 92)

[0278] An exemplary amino acid sequence encoding MMP1 (NP_002412.1 , isoform 1) comprises or consists of:

MHSFPPLLLLLFWGWSHSFPATLETQEQDVDLVQKYLEKYYNLKNDGRQVEKRRNSGPWEKLKQMQEFFGLKV TGKPDAETLKVMKQPRCGVPDVAQFVLTEGNPRWEQTHLTYRIENYTPDLPRADVDHAIEKAFQLWSNVTPLTFT KVSEGQADIMISFVRGDHRDNSPFDGPGGNLAHAFQPGPGIGGDAHFDEDERWTNNFREYNLHRVAAHELGHSLG LSHSTDIGALMYPSYTFSGDVQLAQDDIDGIQAIYGRSQNPVQPIGPQTPKACDSKLTFDAITTIRGEVMFFKDR FYMRTNPFYPEVELNFISVFWPQLPNGLEAAYEFADRDEVRFFKGNKYWAVQGQNVLHGYPKDIYSSFGFPRTVK HIDAALSEENTGKTYFFVANKYWRYDEYKRSMDPGYPKMIAHDFPGIGHKVDAVFMKDGFFYFFHGTRQYKFDPK TKRILTLQKANSWFNCRKN (SEQ ID NO: 93) .

[0279] An exemplary nucleic acid sequence encoding MMP1 (NM_001 145938.1 variant 2) comprises or consists of:

1 agcatgagtc agacagcctc tggctttctg gaagggcaag gactctatat atacagaggg

61 agcttcctag ctgggatatt ggagcagcaa gaggctggga agccatcact taccttgcac

121 tgagaaagaa gacaaaggca agttgaaaag cggagaaata gtggcccagt ggttgaaaaa

181 ttgaagcaaa tgcaggaatt ctttgggctg aaagtgactg ggaaaccaga tgctgaaacc

241 ctgaaggtga tgaagcagcc cagatgtgga gtgcctgatg tggctcagtt tgtcctcact

301 gaggggaacc ctcgctggga gcaaacacat ctgacctaca ggattgaaaa ttacacgcca 361 gatttgccaa gagcagatgt ggaccatgcc attgagaaag ccttccaact ctggagtaat 421 gtcacacctc tgacattcac caaggtctct gagggtcaag cagacatcat gatatctttt 481 gtcaggggag atcatcggga caactctcct tttgatggac ctggaggaaa tcttgctcat 541 gcttttcaac caggcccagg tattggaggg gatgctcatt ttgatgaaga tgaaaggtgg 601 accaacaatt tcagagagta caacttacat cgtgttgcag ctcatgaact cggccattct 661 cttggactct cccattctac tgatatcggg gctttgatgt accctagcta caccttcagt 721 ggtgatgttc agctagctca ggatgacatt gatggcatcc aagccatata tggacgttcc 781 caaaatcctg tccagcccat cggcccacaa accccaaaag cgtgtgacag taagctaacc 841 tttgatgcta taactacgat tcggggagaa gtgatgttct ttaaagacag attctacatg 901 cgcacaaatc ccttctaccc ggaagttgag ctcaatttca tttctgtttt ctggccacaa 961 ctgccaaatg ggcttgaagc tgcttacgaa tttgccgaca gagatgaagt ccggtttttc 1021 aaagggaata agtactgggc tgttcaggga cagaatgtgc tacacggata ccccaaggac 1081 atctacagct cctttggctt ccctagaact gtgaagcata tcgatgctgc tctttctgag 1141 gaaaacactg gaaaaaccta cttctttgtt gctaacaaat actggaggta tgatgaatat 1201 aaacgatcta tggatccagg ttatcccaaa atgatagcac atgactttcc tggaattggc 1261 cacaaagttg atgcagtttt catgaaagat ggatttttct atttctttca tggaacaaga 1321 caatacaaat ttgatcctaa aacgaagaga attttgactc tccagaaagc taatagctgg 1381 ttcaactgca ggaaaaattg aacattacta atttgaatgg aaaacacatg gtgtgagtcc 1441 aaagaaggtg ttttcctgaa gaactgtcta ttttctcagt catttttaac ctctagagtc 1501 actgatacac agaatataat cttatttata cctcagtttg catatttttt tactatttag 1561 aatgtagccc tttttgtact gatataattt agttccacaa atggtgggta caaaaagtca 1621 agtttgtggc ttatggattc atataggcca gagttgcaaa gatcttttcc agagtatgca 1681 actctgacgt tgatcccaga gagcagcttc agtgacaaac atatcctttc aagacagaaa 1741 gagacaggag acatgagtct ttgccggagg aaaagcagct caagaacaca tgtgcagtca 1801 ctggtgtcac cctggatagg caagggataa ctcttctaac acaaaataag tgttttatgt 1861 ttggaataaa gtcaaccttg tttctactgt tttatacact ttc (SEQ ID NO: 94)

[0280] An exemplary amino acid sequence encoding MMP1 (NP 001 139410.1, isoform 2) comprises or consists of:

MQEFFGLKVTGKPDAETLKVMKQPRCGVPDVAQFVLTEGNPRWEQTHLTYRIENYTPDLPRADVDHAIEKAFQLW SNVTPLTFTKVSEGQADIMISFVRGDHRDNSPFDGPGGNLAHAFQPGPGIGGDAHFDEDERWTNNFREYNLHRVA AHELGHSLGLSHSTDIGALMYPSYTFSGDVQLAQDDIDGIQAIYGRSQNPVQPIGPQTPKACDSKLTFDAITTIR GEVMFFKDRFYMRTNPFYPEVELNFISVFWPQLPNGLEAAYEFADRDEVRFFKGNKYWAVQGQNVLHGYPKDIYS SFGFPRTVKHIDAALSEENTGKTYFFVANKYWRYDEYKRSMDPGYPKMIAHDFPGIGHKVDAVFMKDGFFYFFHG TRQYKFDPKTKRILTLQKANSWFNCRKN (SEQ ID NO: 95) .

[0281] An exemplary nucleic acid sequence encoding MMP14 (NM_004995.3, mRNA) comprises or consists of:

1 gagaggctgt gggagaaggg agggaccaga ggagagagcg agagagggaa ccagacccca 61 gttcgccgac taagcagaag aaagatcaaa aaccggaaaa gaggagaaga gcaaacaggc 121 actttgagga acaatcccct ttaactccaa gccgacagcg gtctaggaat tcaagttcag 181 tgcctaccga agacaaaggc gccccgaggg agtggcggtg cgaccccagg gcgtgggccc 241 ggccgcggag cccacactgc ccggctgacc cggtggtctc ggaccatgtc tcccgcccca 301 agaccccccc gttgtctcct gctccccctg ctcacgctcg gcaccgcgct cgcctccctc 361 ggctcggccc aaagcagcag cttcagcccc gaagcctggc tacagcaata tggctacctg 421 cctcccgggg acctacgtac ccacacacag cgctcacccc agtcactctc agcggccatc 481 gctgccatgc agaagtttta cggcttgcaa gtaacaggca aagctgatgc agacaccatg 541 aaggccatga ggcgcccccg atgtggtgtt ccagacaagt ttggggctga gatcaaggcc 601 aatgttcgaa ggaagcgcta cgccatccag ggtctcaaat ggcaacataa tgaaatcact 661 ttctgcatcc agaattacac ccccaaggtg ggcgagtatg ccacatacga ggccattcgc 721 aaggcgttcc gcgtgtggga gagtgccaca ccactgcgct tccgcgaggt gccctatgcc 781 tacatccgtg agggccatga gaagcaggcc gacatcatga tcttctttgc cgagggcttc 841 catggcgaca gcacgccctt cgatggtgag ggcggcttcc tggcccatgc ctacttccca 901 ggccccaaca ttggaggaga cacccacttt gactctgccg agccttggac tgtcaggaat 961 gaggatctga atggaaatga catcttcctg gtggctgtgc acgagctggg ccatgccctg 1021 gggctcgagc attccagtga cccctcggcc atcatggcac ccttttacca gtggatggac 1081 acggagaatt ttgtgctgcc cgatgatgac cgccggggca tccagcaact ttatgggggt 1141 gagtcagggt tccccaccaa gatgccccct caacccagga ctacctcccg gccttctgtt 1201 cctgataaac ccaaaaaccc cacctatggg cccaacatct gtgacgggaa ctttgacacc 1261 gtggccatgc tccgagggga gatgtttgtc ttcaaggagc gctggttctg gcgggtgagg 1321 aataaccaag tgatggatgg atacccaatg cccattggcc agttctggcg gggcctgcct 1381 gcgtccatca acactgccta cgagaggaag gatggcaaat tcgtcttctt caaaggagac 1441 aagcattggg tgtttgatga ggcgtccctg gaacctggct accccaagca cattaaggag 1501 ctgggccgag ggctgcctac cgacaagatt gatgctgctc tcttctggat gcccaatgga 1561 aagacctact tcttccgtgg aaacaagtac taccgtttca acgaagagct cagggcagtg 1621 gatagcgagt accccaagaa catcaaagtc tgggaaggga tccctgagtc tcccagaggg 1681 tcattcatgg gcagcgatga agtcttcact tacttctaca aggggaacaa atactggaaa 1741 ttcaacaacc agaagctgaa ggtagaaccg ggctacccca agtcagccct gagggactgg 1801 atgggctgcc catcgggagg ccggccggat gaggggactg aggaggagac ggaggtgatc 1861 atcattgagg tggacgagga gggcggcggg gcggtgagcg cggctgccgt ggtgctgccc 1921 gtgctgctgc tgctcctggt gctggcggtg ggccttgcag tcttcttctt cagacgccat 1981 gggaccccca ggcgactgct ctactgccag cgttccctgc tggacaaggt ctgacgccca 2041 ccgccggccc gcccactcct accacaagga ctttgcctct gaaggccagt ggcagcaggt 2101 ggtggtgggt gggctgttcc catcgtcccg agccccctcc ccgcagcctc cttgcttctc 2161 tctgtcccct ggctggcctc cttcaccctg accgcctccc tccctcctgc cccggcattg 2221 catcttccct agataggtcc cctgagggct gagtgggagg gcggcccttt ccagcctctg 2281 cccctcaggg gaaccctgta gctttgtgtc tgtccagccc catctgaatg tgttgggggc 2341 tctgcacttg aaggcaggac cctcagacct cgctggtaaa ggtcaaatgg ggtcatctgc 2401 tccttttcca tcccctgaca taccttaacc tctgaactct gacctcagga ggctctgggc 2461 actccagccc tgaaagcccc aggtgtaccc aattggcagc ctctcactac tctttctggc 2521 taaaaggaat ctaatcttgt tgagggtaga gaccctgaga cagtgtgagg gggtggggac 2581 tgccaagcca ccctaagacc ttgggaggaa aactcagaga gggtcttcgt tgctcagtca 2641 gtcaagttcc tcggagatct gcctctgcct cacctacccc agggaacttc caaggaagga 2701 gcctgagcca ctggggacta agtgggcaga agaaaccctt ggcagccctg tgcctctcga 2761 atgttagcct tggatggggc tttcacagtt agaagagctg aaaccagggg tgcagctgtc 2821 aggtagggtg gggccggtgg gagaggcccg ggtcagagcc ctgggggtga gcctgaaggc 2881 cacagagaaa gaaccttgcc caaactcagg cagctggggc tgaggcccaa aggcagaaca 2941 gccagagggg gcaggagggg accaaaaagg aaaatgagga cgtgcagcag cattggaagg 3001 ctggggccgg gcaggccagg ccaagccaag cagggggcca cagggtgggc tgtggagctc 3061 tcaggaaggg ccctgaggaa ggcacacttg ctcctgttgg tccctgtcct tgctgcccag 3121 gcagcgtgga ggggaagggt agggcagcca gagaaaggag cagagaaggc acacaaacga 3181 ggaatgaggg gcttcacgag aggccacagg gcctggctgg ccacgctgtc ccggcctgct 3241 caccatctca gtgaggggca ggagctgggg ctcgcttagg ctgggtccac gcttccctgg 3301 tgccagcacc cctcaagcct gtctcaccag tggcctgccc tctcgctccc ccacccagcc 3361 cacccattga agtctccttg ggccaccaaa ggtggtggcc atggtaccgg ggacttggga 3421 gagtgagacc cagtggaggg agcaagagga gagggatgtc gggggggtgg ggcacggggt 3481 aggggaaatg gggtgaacgg tgctggcagt tcggctagat ttctgtcttg tttgtttttt 3541 tgttttgttt aatgtatatt tttattataa ttattatata tgaattccat tcaaaaaaaa 3601 aaaaaaaaaa (SEQ ID NO 96) .

[0282] An exemplary amino acid sequence encoding MMP14 (NP 004986.1) comprises or consists of:

MSPAPRPPRCLLLPLLTLGTALASLGSAQSSSFSPEAWLQQYGYLPPGDLRTHTQRSPQSLSAAIAAMQKFYGLQ VTGKADADTMKAMRRPRCGVPDKFGAEIKANVRRKRYAIQGLKWQHNEITFCIQNYTPKVGEYATYEAIRKAFRV WESATPLRFREVPYAYIREGHEKQADIMIFFAEGFHGDSTPFDGEGGFLAHAYFPGPNIGGDTHFDSAEPWTVRN EDLNGNDIFLVAVHELGHALGLEHSSDPSAIMAPFYQWMDTENFVLPDDDRRGIQQLYGGESGFPTKMPPQPRTT SRPSVPDKPKNPTYGPNICDGNFDTVAMLRGEMFVFKERWFWRVRNNQVMDGYPMPIGQFWRGLPASINTAYERK DGKFVFFKGDKH VFDEASLEPGYPKHIKELGRGLPTDKIDAALFWMPNGKTYFFRGNKYYRFNEELRAVDSEYP KNIKVWEGIPESPRGSFMGSDEVFTYFYKGNKYWKFNNQKLKVEPGYPKSALRDWMGCPSGGRPDEGTEEETEVI IIEVDEEGGGAVSAAAWLPVLLLLLVLAVGLAVFFFRRHGTPRRLLYCQRSLLDKV (SEQ ID NO: 97) . [0283] An exemplary nucleic acid sequence encoding MMP2 (NM_004530.5, transcript variant 1) comprises or consists of:

1 acatctggcg gctgccctcc cttgtttccg ctgcatccag acttcctcag gcggtggctg 61 gaggctgcgc atctggggct ttaaacatac aaagggattg ccaggacctg cggcggcggc 121 ggcggcggcg ggggctgggg cgcgggggcc ggaccatgag ccgctgagcc gggcaaaccc 181 caggccaccg agccagcgga ccctcggagc gcagccctgc gccgcggagc aggctccaac 241 caggcggcga ggcggccaca cgcaccgagc cagcgacccc cgggcgacgc gcggggccag 301 ggagcgctac gatggaggcg ctaatggccc ggggcgcgct cacgggtccc ctgagggcgc 361 tctgtctcct gggctgcctg ctgagccacg ccgccgccgc gccgtcgccc atcatcaagt 421 tccccggcga tgtcgccccc aaaacggaca aagagttggc agtgcaatac ctgaacacct 481 tctatggctg ccccaaggag agctgcaacc tgtttgtgct gaaggacaca ctaaagaaga 541 tgcagaagtt ctttggactg ccccagacag gtgatcttga ccagaatacc atcgagacca 601 tgcggaagcc acgctgcggc aacccagatg tggccaacta caacttcttc cctcgcaagc 661 ccaagtggga caagaaccag atcacataca ggatcattgg ctacacacct gatctggacc 721 cagagacagt ggatgatgcc tttgctcgtg ccttccaagt ctggagcgat gtgaccccac 781 tgcggttttc tcgaatccat gatggagagg cagacatcat gatcaacttt ggccgctggg 841 agcatggcga tggatacccc tttgacggta aggacggact cctggctcat gccttcgccc 901 caggcactgg tgttggggga gactcccatt ttgatgacga tgagctatgg accttgggag 961 aaggccaagt ggtccgtgtg aagtatggga acgccgatgg ggagtactgc aagttcccct 1021 tcttgttcaa tggcaaggag tacaacagct gcactgatac cggccgcagc gatggcttcc 1081 tctggtgctc caccacctac aactttgaga aggatggcaa gtacggcttc tgtccccatg 1141 aagccctgtt caccatgggc ggcaacgctg aaggacagcc ctgcaagttt ccattccgct 1201 tccagggcac atcctatgac agctgcacca ctgagggccg cacggatggc taccgctggt 1261 gcggcaccac tgaggactac gaccgcgaca agaagtatgg cttctgccct gagaccgcca 1321 tgtccactgt tggtgggaac tcagaaggtg ccccctgtgt cttccccttc actttcctgg 1381 gcaacaaata tgagagctgc accagcgccg gccgcagtga cggaaagatg tggtgtgcga 1441 ccacagccaa ctacgatgat gaccgcaagt ggggcttctg ccctgaccaa gggtacagcc 1501 tgttcctcgt ggcagcccac gagtttggcc acgccatggg gctggagcac tcccaagacc 1561 ctggggccct gatggcaccc atttacacct acaccaagaa cttccgtctg tcccaggatg 1621 acatcaaggg cattcaggag ctctatgggg cctctcctga cattgacctt ggcaccggcc 1681 ccacccccac gctgggccct gtcactcctg agatctgcaa acaggacatt gtatttgatg 1741 gcatcgctca gatccgtggt gagatcttct tcttcaagga ccggttcatt tggcggactg 1801 tgacgccacg tgacaagccc atggggcccc tgctggtggc cacattctgg cctgagctcc 1861 cggaaaagat tgatgcggta tacgaggccc cacaggagga gaaggctgtg ttctttgcag 1921 ggaatgaata ctggatctac tcagccagca ccctggagcg agggtacccc aagccactga 1981 ccagcctggg actgccccct gatgtccagc gagtggatgc cgcctttaac tggagcaaaa 2041 acaagaagac atacatcttt gctggagaca aattctggag atacaatgag gtgaagaaga 2101 aaatggatcc tggcttcccc aagctcatcg cagatgcctg gaatgccatc cccgataacc 2161 tggatgccgt cgtggacctg cagggcggcg gtcacagcta cttcttcaag ggtgcctatt 2221 acctgaagct ggagaaccaa agtctgaaga gcgtgaagtt tggaagcatc aaatccgact 2281 ggctaggctg ctgagctggc cctggctccc acaggccctt cctctccact gccttcgata 2341 caccgggcct ggagaactag agaaggaccc ggaggggcct ggcagccgtg ccttcagctc 2401 tacagctaat cagcattctc actcctacct ggtaatttaa gattccagag agtggctcct 2461 cccggtgccc aagaatagat gctgactgta ctcctcccag gcgccccttc cccctccaat 2521 cccaccaacc ctcagagcca cccctaaaga gatactttga tattttcaac gcagccctgc 2581 tttgggctgc cctggtgctg ccacacttca ggctcttctc ctttcacaac cttctgtggc 2641 tcacagaacc cttggagcca atggagactg tctcaagagg gcactggtgg cccgacagcc 2701 tggcacaggg cagtgggaca gggcatggcc aggtggccac tccagacccc tggcttttca 2761 ctgctggctg ccttagaacc tttcttacat tagcagtttg ctttgtatgc actttgtttt 2821 tttctttggg tcttgttttt tttttccact tagaaattgc atttcctgac agaaggactc 2881 aggttgtctg aagtcactgc acagtgcatc tcagcccaca tagtgatggt tcccctgttc 2941 actctactta gcatgtccct accgagtctc ttctccactg gatggaggaa aaccaagccg 3001 tggcttcccg ctcagccctc cctgcccctc ccttcaacca ttccccatgg gaaatgtcaa 3061 caagtatgaa taaagacacc tactgagtgg ccgtgtttgc catctgtttt agcagagcct 3121 agacaagggc cacagaccca gccagaagcg gaaacttaaa aagtccgaat ctctgctccc 3181 tgcagggcac aggtgatggt gtctgctgga aaggtcagag cttccaaagt aaacagcaag 3241 agaacctcag ggagagtaag ctctagtccc tctgtcctgt agaaagagcc ctgaagaatc 3301 agcaattttg ttgctttatt gtggcatctg ttcgaggttt gcttcctctt taagtctgtt 3361 tcttcattag caatcatatc agttttaatg ctactactaa caatgaacag taacaataat 3421 atccccctca attaatagag tgctttctat gtgcaaggca cttttcacgt gtcacctatt 3481 ttaacctttc caaccacata aataaaaaag gccattatta gttgaatctt attgatgaag 3541 agaaaaaaaa aaaaaaaa (SEQ ID NO: 98) .

[0284] An exemplary amino acid sequence encoding MMP2 (NP_004521.1 , isoform 1) comprises or consists of:

MEALMARGALTGPLRALCLLGCLLSHAAAAPSPIIKFPGDVAPKTDKELAVQYLNTFYGCPKESCNLFVLKDTLK

KMQKFFGLPQTGDLDQNTIETMRKPRCGNPDVANYNFFPRKPKWDKNQITYRIIGYTPDLDPETVDDAFARAFQV

WSDVTPLRFSRIHDGEADIMINFGRWEHGDGYPFDGKDGLLAHAFAPGTGVGGDSHFDDDELWTLGEGQWRVKY

GNADGEYCKFPFLFNGKEYNSCTDTGRSDGFLWCSTTYNFEKDGKYGFCPHEALFTMGGNAEGQPCKFPFRFQGT

SYDSCTTEGRTDGYRWCGTTEDYDRDKKYGFCPETAMSTVGGNSEGAPCVFPFTFLGNKYESCTSAGRSDGKMWC

ATTANYDDDRKWGFCPDQGYSLFLVAAHEFGHAMGLEHSQDPGALMAPIYTYTKNFRLSQDDIKGIQELYGASPD

IDLGTGPTPTLGPVTPEICKQDIVFDGIAQIRGEIFFFKDRFIWRTVTPRDKPMGPLLVATFWPELPEKIDAVYE

APQEEKAVFFAGNEYWIYSASTLERGYPKPLTSLGLPPDVQRVDAAFNWSKNKKTYIFAGDKFWRYNEVKKKMDP

GFPKLIADAWNAIPDNLDAWDLQGGGHSYFFKGAYYLKLENQSLKSVKFGSIKSDWLGC (SEQ ID NO:

99) .

[0285] An exemplary nucleic acid sequence encoding MMP2 (NM_001 127891.2, transcript variant 2) comprises or consists of:

1 aatgcatgcc tgccctcctg ggaatgaagc acagcaggtc tcagcctcat cttacccagc 61 cccccactca agatggaggt gcctggtttg aacacctctg acaaatggaa gtctgtgttg 121 tccagaggca atgcagtggg ggcttaagaa gataactctg gacttagacc gcttggcttc 181 aaatcaaaga gtgcatgaac caaccagctg gcctagtgat gatgttaggc aagtgacttc 241 tcagtttctt catctgcaaa ctgggaaatt tcctatctca gggttaaaag agaggtaatc 301 ttaggtgctt acctagcaca tgcaatacct gaacaccttc tatggctgcc ccaaggagag 361 ctgcaacctg tttgtgctga aggacacact aaagaagatg cagaagttct ttggactgcc 421 ccagacaggt gatcttgacc agaataccat cgagaccatg cggaagccac gctgcggcaa 481 cccagatgtg gccaactaca acttcttccc tcgcaagccc aagtgggaca agaaccagat 541 cacatacagg atcattggct acacacctga tctggaccca gagacagtgg atgatgcctt 601 tgctcgtgcc ttccaagtct ggagcgatgt gaccccactg cggttttctc gaatccatga 661 tggagaggca gacatcatga tcaactttgg ccgctgggag catggcgatg gatacccctt 721 tgacggtaag gacggactcc tggctcatgc cttcgcccca ggcactggtg ttgggggaga 781 ctcccatttt gatgacgatg agctatggac cttgggagaa ggccaagtgg tccgtgtgaa 841 gtatgggaac gccgatgggg agtactgcaa gttccccttc ttgttcaatg gcaaggagta 901 caacagctgc actgataccg gccgcagcga tggcttcctc tggtgctcca ccacctacaa 961 ctttgagaag gatggcaagt acggcttctg tccccatgaa gccctgttca ccatgggcgg 1021 caacgctgaa ggacagccct gcaagtttcc attccgcttc cagggcacat cctatgacag 1081 ctgcaccact gagggccgca cggatggcta ccgctggtgc ggcaccactg aggactacga 1141 ccgcgacaag aagtatggct tctgccctga gaccgccatg tccactgttg gtgggaactc 1201 agaaggtgcc ccctgtgtct tccccttcac tttcctgggc aacaaatatg agagctgcac 1261 cagcgccggc cgcagtgacg gaaagatgtg gtgtgcgacc acagccaact acgatgatga 1321 ccgcaagtgg ggcttctgcc ctgaccaagg gtacagcctg ttcctcgtgg cagcccacga 1381 gtttggccac gccatggggc tggagcactc ccaagaccct ggggccctga tggcacccat 1441 ttacacctac accaagaact tccgtctgtc ccaggatgac atcaagggca ttcaggagct 1501 ctatggggcc tctcctgaca ttgaccttgg caccggcccc acccccacgc tgggccctgt 1561 cactcctgag atctgcaaac aggacattgt atttgatggc atcgctcaga tccgtggtga 1621 gatcttcttc ttcaaggacc ggttcatttg gcggactgtg acgccacgtg acaagcccat 1681 ggggcccctg ctggtggcca cattctggcc tgagctcccg gaaaagattg atgcggtata 1741 cgaggcccca caggaggaga aggctgtgtt ctttgcaggg aatgaatact ggatctactc 1801 agccagcacc ctggagcgag ggtaccccaa gccactgacc agcctgggac tgccccctga 1861 tgtccagcga gtggatgccg cctttaactg gagcaaaaac aagaagacat acatctttgc 1921 tggagacaaa ttctggagat acaatgaggt gaagaagaaa atggatcctg gcttccccaa 1981 gctcatcgca gatgcctgga atgccatccc cgataacctg gatgccgtcg tggacctgca 2041 gggcggcggt cacagctact tcttcaaggg tgcctattac ctgaagctgg agaaccaaag 2101 tctgaagagc gtgaagtttg gaagcatcaa atccgactgg ctaggctgct gagctggccc 2161 tggctcccac aggcccttcc tctccactgc cttcgataca ccgggcctgg agaactagag 2221 aaggacccgg aggggcctgg cagccgtgcc ttcagctcta cagctaatca gcattctcac 22 1 tcctacctgg taatttaaga ttccagagag tggctcctcc cggtgcccaa gaatagatgc 2341 tgactgtact cctcccaggc gccccttccc cctccaatcc caccaaccct cagagccacc 2401 cctaaagaga tactttgata ttttcaacgc agccctgctt tgggctgccc tggtgctgcc 2461 acacttcagg ctcttctcct ttcacaacct tctgtggctc acagaaccct tggagccaat 2521 ggagactgtc tcaagagggc actggtggcc cgacagcctg gcacagggca gtgggacagg 2581 gcatggccag gtggccactc cagacccctg gcttttcact gctggctgcc ttagaacctt 2641 tcttacatta gcagtttgct ttgtatgcac tttgtttttt tctttgggtc ttgttttttt 2701 tttccactta gaaattgcat ttcctgacag aaggactcag gttgtctgaa gtcactgcac 2761 agtgcatctc agcccacata gtgatggttc ccctgttcac tctacttagc atgtccctac 2821 cgagtctctt ctccactgga tggaggaaaa ccaagccgtg gcttcccgct cagccctccc 2881 tgcccctccc ttcaaccatt ccccatggga aatgtcaaca agtatgaata aagacaccta 2941 ctgagtggcc gtgtttgcca tctgttttag cagagcctag acaagggcca cagacccagc 3001 cagaagcgga aacttaaaaa gtccgaatct ctgctccctg cagggcacag gtgatggtgt 3061 ctgctggaaa ggtcagagct tccaaagtaa acagcaagag aacctcaggg agagtaagct 3121 ctagtccctc tgtcctgtag aaagagccct gaagaatcag caattttgtt gctttattgt 31 1 ggcatctgtt cgaggtttgc ttcctcttta agtctgtttc ttcattagca atcatatcag 3241 ttttaatgct actactaaca atgaacagta acaataatat ccccctcaat taatagagtg 3301 ctttctatgt gcaaggcact tttcacgtgt cacctatttt aacctttcca accacataaa 3361 taaaaaaggc cattattagt tgaatcttat tgatgaagag aaaaaaaaaa aaaaaa (SEQ ID NO: 100) .

[0286] An exemplary amino acid sequence encoding MMP2 (NP_001 121363.1, isoform 2) comprises or consists of:

MQYLNTFYGCPKESCNLFVLKDTLKKMQKFFGLPQTGDLDQNTIETMRKPRCGNPDVANYNFFPRKPKWDKNQIT YRIIGYTPDLDPETVDDAFARAFQVWSDVTPLRFSRIHDGEADIMINFGRWEHGDGYPFDGKDGLLAHAFAPGTG VGGDSHFDDDELWTLGEGQWRVKYGNADGEYCKFPFLFNGKEYNSCTDTGRSDGFLWCSTTYNFEKDGKYGFCP HEALFTMGGNAEGQPCKFPFRFQGTSYDSCTTEGRTDGYRWCGTTEDYDRDKKYGFCPETAMSTVGGNSEGAPCV FPFTFLGNKYESCTSAGRSDGKMWCATTANYDDDRKWGFCPDQGYSLFLVAAHEFGHAMGLEHSQDPGALMAPIY TYTKNFRLSQDDIKGIQELYGASPDIDLGTGPTPTLGPVTPEICKQDIVFDGIAQIRGEIFFFKDRFIWRTVTPR DKPMGPLLVATFWPELPEKIDAVYEAPQEEKAVFFAGNEYWIYSASTLERGYPKPLTSLGLPPDVQRVDAAFNWS KNKKTYIFAGDKFWRYNEVKKKMDPGFPKLIADAWNAIPDNLDAWDLQGGGHSYFFKGAYYLKLENQSLKSVKF GSIKSDWLGC (SEQ ID NO: 101) .

[0287] An exemplary nucleic acid sequence encoding MMP2 (NM_001302508.1 isoform 3) comprises or consists of:

1 gtgcagggtg tcctagccaa gccggcgtcc ctcctagtag taccgctgct ctctaacctc

61 aggacgtcaa gggcctagag cgacagatgt ttcccagcag ggggttctga ggctgtgcgc

121 ccagatcgcg agagagcaat acctgaacac cttctatggc tgccccaagg agagctgcaa

181 cctgtttgtg ctgaaggaca cactaaagaa gatgcagaag ttctttggac tgccccagac

241 aggtgatctt gaccagaata ccatcgagac catgcggaag ccacgctgcg gcaacccaga

301 tgtggccaac tacaacttct tccctcgcaa gcccaagtgg gacaagaacc agatcacata

361 caggatcatt ggctacacac ctgatctgga cccagagaca gtggatgatg cctttgctcg

421 tgccttccaa gtctggagcg atgtgacccc actgcggttt tctcgaatcc atgatggaga

481 ggcagacatc atgatcaact ttggccgctg ggagcatggc gatggatacc cctttgacgg

541 taaggacgga ctcctggctc atgccttcgc cccaggcact ggtgttgggg gagactccca

601 ttttgatgac gatgagctat ggaccttggg agaaggccaa gtggtccgtg tgaagtatgg

661 gaacgccgat ggggagtact gcaagttccc cttcttgttc aatggcaagg agtacaacag 721 ctgcactgat accggccgca gcgatggctt cctctggtgc tccaccacct acaactttga 781 gaaggatggc aagtacggct tctgtcccca tgaagccctg ttcaccatgg gcggcaacgc 841 tgaaggacag ccctgcaagt ttccattccg cttccagggc acatcctatg acagctgcac 901 cactgagggc cgcacggatg gctaccgctg gtgcggcacc actgaggact acgaccgcga 961 caagaagtat ggcttctgcc ctgagaccgc catgtccact gttggtggga actcagaagg 1021 tgccccctgt gtcttcccct tcactttcct gggcaacaaa tatgagagct gcaccagcgc 1081 cggccgcagt gacggaaaga tgtggtgtgc gaccacagcc aactacgatg atgaccgcaa 1141 gtggggcttc tgccctgacc aagggtacag cctgttcctc gtggcagccc acgagtttgg 1201 ccacgccatg gggctggagc actcccaaga ccctggggcc ctgatggcac ccatttacac 1261 ctacaccaag aacttccgtc tgtcccagga tgacatcaag ggcattcagg agctctatgg 1321 ggcctctcct gacattgacc ttggcaccgg ccccaccccc acgctgggcc ctgtcactcc 1381 tgagatctgc aaacaggaca ttgtatttga tggcatcgct cagatccgtg gtgagatctt 1441 cttcttcaag gaccggttca tttggcggac tgtgacgcca cgtgacaagc ccatggggcc 1501 cctgctggtg gccacattct ggcctgagct cccggaaaag attgatgcgg tatacgaggc 1561 cccacaggag gagaaggctg tgttctttgc agggaatgaa tactggatct actcagccag 1621 caccctggag cgagggtacc ccaagccact gaccagcctg ggactgcccc ctgatgtcca 1681 gcgagtggat gccgccttta actggagcaa aaacaagaag acatacatct ttgctggaga 1741 caaattctgg agatacaatg aggtgaagaa gaaaatggat cctggcttcc ccaagctcat 1801 cgcagatgcc tggaatgcca tccccgataa cctggatgcc gtcgtggacc tgcagggcgg 1861 cggtcacagc tacttcttca agggtgccta ttacctgaag ctggagaacc aaagtctgaa 1921 gagcgtgaag tttggaagca tcaaatccga ctggctaggc tgctgagctg gccctggctc 1981 ccacaggccc ttcctctcca ctgccttcga tacaccgggc ctggagaact agagaaggac 2041 ccggaggggc ctggcagccg tgccttcagc tctacagcta atcagcattc tcactcctac 2101 ctggtaattt aagattccag agagtggctc ctcccggtgc ccaagaatag atgctgactg 2161 tactcctccc aggcgcccct tccccctcca atcccaccaa ccctcagagc cacccctaaa 2221 gagatacttt gatattttca acgcagccct gctttgggct gccctggtgc tgccacactt 2281 caggctcttc tcctttcaca accttctgtg gctcacagaa cccttggagc caatggagac 2341 tgtctcaaga gggcactggt ggcccgacag cctggcacag ggcagtggga cagggcatgg 2401 ccaggtggcc actccagacc cctggctttt cactgctggc tgccttagaa cctttcttac 2461 attagcagtt tgctttgtat gcactttgtt tttttctttg ggtcttgttt tttttttcca 2521 cttagaaatt gcatttcctg acagaaggac tcaggttgtc tgaagtcact gcacagtgca 2581 tctcagccca catagtgatg gttcccctgt tcactctact tagcatgtcc ctaccgagtc 2641 tcttctccac tggatggagg aaaaccaagc cgtggcttcc cgctcagccc tccctgcccc 2701 tcccttcaac cattccccat gggaaatgtc aacaagtatg aataaagaca cctactgagt 2761 ggccgtgttt gccatctgtt ttagcagagc ctagacaagg gccacagacc cagccagaag 2821 cggaaactta aaaagtccga atctctgctc cctgcagggc acaggtgatg gtgtctgctg 2881 gaaaggtcag agcttccaaa gtaaacagca agagaacctc agggagagta agctctagtc 2941 cctctgtcct gtagaaagag ccctgaagaa tcagcaattt tgttgcttta ttgtggcatc 3001 tgttcgaggt ttgcttcctc tttaagtctg tttcttcatt agcaatcata tcagttttaa 3061 tgctactact aacaatgaac agtaacaata atatccccct caattaatag agtgctttct 3121 atgtgcaagg cacttttcac gtgtcaccta ttttaacctt tccaaccaca taaataaaaa 3181 aggccattat tagttgaatc ttattgatga agagaaaaaa aaaaaaaaaa (SEQ ID

NO: 102) .

[0288] An exemplary amino acid sequence encoding MMP2 (NP_001289437.1, isoform 3, corresponding to transcript variants 3, 4 and 5) comprises or consists of:

MQKFFGLPQTGDLDQNTIETMRKPRCGNPDVANYNFFPRKPKWDKNQITYRI IGYTPDLDPETVDDAFARAFQVW SDVTPLRFSRIHDGEADIMINFGRWEHGDGYPFDGKDGLLAHAFAPGTGVGGDSHFDDDELWTLGEGQWRVKYG NADGEYCKFPFLFNGKEYNSCTDTGRSDGFLWCSTTYNFEKDGKYGFCPHEALFTMGGNAEGQPCKFPFRFQGTS YDSCTTEGRTDGYRWCGTTEDYDRDKKYGFCPETAMSTVGGNSEGAPCVFPFTFLGNKYESCTSAGRSDGKMWCA TTANYDDDRKWGFCPDQGYSLFLVAAHEFGHAMGLEHSQDPGALMAPIYTYTKNFRLSQDDIKGIQELYGASPDI DLGTGPTPTLGPVTPEICKQDIVFDGIAQIRGEIFFFKDRFIWRTVTPRDKPMGPLLVATFWPELPEKIDAVYEA PQEEKAVFFAGNEYWIYSASTLERGYPKPLTSLGLPPDVQRVDAAFNWSKNKKTYIFAGDKFWRYNEVKKKMDPG FPKLIADAWNAIPDNLDAWDLQGGGHSYFFKGAYYLKLENQSLKSVKFGSIKSDWLGC (SEQ ID NO: 103) . [0289] An exemplary nucleic acid sequence encoding MMP2 (NM_001302509.1 transcript variant 4) comprises or consists of:

1 agatgttgtc ttgtgagcgt gcgcgcgcct ggctggaggg gcactgagcc tggccgcagt 61 gttgccaata cctgaacacc ttctatggct gccccaagga gagctgcaac ctgtttgtgc 121 tgaaggacac actaaagaag atgcagaagt tctttggact gccccagaca ggtgatcttg 181 accagaatac catcgagacc atgcggaagc cacgctgcgg caacccagat gtggccaact 241 acaacttctt ccctcgcaag cccaagtggg acaagaacca gatcacatac aggatcattg 301 gctacacacc tgatctggac ccagagacag tggatgatgc ctttgctcgt gccttccaag 361 tctggagcga tgtgacccca ctgcggtttt ctcgaatcca tgatggagag gcagacatca 421 tgatcaactt tggccgctgg gagcatggcg atggataccc ctttgacggt aaggacggac 481 tcctggctca tgccttcgcc ccaggcactg gtgttggggg agactcccat tttgatgacg 541 atgagctatg gaccttggga gaaggccaag tggtccgtgt gaagtatggg aacgccgatg 601 gggagtactg caagttcccc ttcttgttca atggcaagga gtacaacagc tgcactgata 661 ccggccgcag cgatggcttc ctctggtgct ccaccaccta caactttgag aaggatggca 721 agtacggctt ctgtccccat gaagccctgt tcaccatggg cggcaacgct gaaggacagc 781 cctgcaagtt tccattccgc ttccagggca catcctatga cagctgcacc actgagggcc 841 gcacggatgg ctaccgctgg tgcggcacca ctgaggacta cgaccgcgac aagaagtatg 901 gcttctgccc tgagaccgcc atgtccactg ttggtgggaa ctcagaaggt gccccctgtg 961 tcttcccctt cactttcctg ggcaacaaat atgagagctg caccagcgcc ggccgcagtg 1021 acggaaagat gtggtgtgcg accacagcca actacgatga tgaccgcaag tggggcttct 1081 gccctgacca agggtacagc ctgttcctcg tggcagccca cgagtttggc cacgccatgg 1141 ggctggagca ctcccaagac cctggggccc tgatggcacc catttacacc tacaccaaga 1201 acttccgtct gtcccaggat gacatcaagg gcattcagga gctctatggg gcctctcctg 1261 acattgacct tggcaccggc cccaccccca cgctgggccc tgtcactcct gagatctgca 1321 aacaggacat tgtatttgat ggcatcgctc agatccgtgg tgagatcttc ttcttcaagg 1381 accggttcat ttggcggact gtgacgccac gtgacaagcc catggggccc ctgctggtgg 1441 ccacattctg gcctgagctc ccggaaaaga ttgatgcggt atacgaggcc ccacaggagg 1501 agaaggctgt gttctttgca gggaatgaat actggatcta ctcagccagc accctggagc 1561 gagggtaccc caagccactg accagcctgg gactgccccc tgatgtccag cgagtggatg 1621 ccgcctttaa ctggagcaaa aacaagaaga catacatctt tgctggagac aaattctgga 1681 gatacaatga ggtgaagaag aaaatggatc ctggcttccc caagctcatc gcagatgcct 1741 ggaatgccat ccccgataac ctggatgccg tcgtggacct gcagggcggc ggtcacagct 1801 acttcttcaa gggtgcctat tacctgaagc tggagaacca aagtctgaag agcgtgaagt 1861 ttggaagcat caaatccgac tggctaggct gctgagctgg ccctggctcc cacaggccct 1921 tcctctccac tgccttcgat acaccgggcc tggagaacta gagaaggacc cggaggggcc 1981 tggcagccgt gccttcagct ctacagctaa tcagcattct cactcctacc tggtaattta 2041 agattccaga gagtggctcc tcccggtgcc caagaataga tgctgactgt actcctccca 2101 ggcgcccctt ccccctccaa tcccaccaac cctcagagcc acccctaaag agatactttg 2161 atattttcaa cgcagccctg ctttgggctg ccctggtgct gccacacttc aggctcttct 2221 cctttcacaa ccttctgtgg ctcacagaac ccttggagcc aatggagact gtctcaagag 2281 ggcactggtg gcccgacagc ctggcacagg gcagtgggac agggcatggc caggtggcca 2341 ctccagaccc ctggcttttc actgctggct gccttagaac ctttcttaca ttagcagttt 2401 gctttgtatg cactttgttt ttttctttgg gtcttgtttt ttttttccac ttagaaattg 2461 catttcctga cagaaggact caggttgtct gaagtcactg cacagtgcat ctcagcccac 2521 atagtgatgg ttcccctgtt cactctactt agcatgtccc taccgagtct cttctccact 2581 ggatggagga aaaccaagcc gtggcttccc gctcagccct ccctgcccct cccttcaacc 2641 attccccatg ggaaatgtca acaagtatga ataaagacac ctactgagtg gccgtgtttg 2701 ccatctgttt tagcagagcc tagacaaggg ccacagaccc agccagaagc ggaaacttaa 2761 aaagtccgaa tctctgctcc ctgcagggca caggtgatgg tgtctgctgg aaaggtcaga 2821 gcttccaaag taaacagcaa gagaacctca gggagagtaa gctctagtcc ctctgtcctg 2881 tagaaagagc cctgaagaat cagcaatttt gttgctttat tgtggcatct gttcgaggtt 2941 tgcttcctct ttaagtctgt ttcttcatta gcaatcatat cagttttaat gctactacta 3001 acaatgaaca gtaacaataa tatccccctc aattaataga gtgctttcta tgtgcaaggc 3061 acttttcacg tgtcacctat tttaaccttt ccaaccacat aaataaaaaa ggccattatt 3121 agttgaatct tattgatgaa gagaaaaaaa aaaaaaaaa (SEQ ID NO: 104) .

[0290] An exemplary nucleic acid sequence encoding MMP2 (NM_001302510.1 transcript variant 5) comprises or consists of:

1 tgtaaacaac ttttggacac atctgggcag ttgctaaggg ctcttgccaa gcgtctagca 61 atacctgaac accttctatg gctgccccaa ggagagctgc aacctgtttg tgctgaagga 121 cacactaaag aagatgcaga agttctttgg actgccccag acaggtgatc ttgaccagaa 181 taccatcgag accatgcgga agccacgctg cggcaaccca gatgtggcca actacaactt 241 cttccctcgc aagcccaagt gggacaagaa ccagatcaca tacaggatca ttggctacac 301 acctgatctg gacccagaga cagtggatga tgcctttgct cgtgccttcc aagtctggag 361 cgatgtgacc ccactgcggt tttctcgaat ccatgatgga gaggcagaca tcatgatcaa 421 ctttggccgc tgggagcatg gcgatggata cccctttgac ggtaaggacg gactcctggc 481 tcatgccttc gccccaggca ctggtgttgg gggagactcc cattttgatg acgatgagct 541 atggaccttg ggagaaggcc aagtggtccg tgtgaagtat gggaacgccg atggggagta 601 ctgcaagttc cccttcttgt tcaatggcaa ggagtacaac agctgcactg ataccggccg 661 cagcgatggc ttcctctggt gctccaccac ctacaacttt gagaaggatg gcaagtacgg 721 cttctgtccc catgaagccc tgttcaccat gggcggcaac gctgaaggac agccctgcaa 781 gtttccattc cgcttccagg gcacatccta tgacagctgc accactgagg gccgcacgga 841 tggctaccgc tggtgcggca ccactgagga ctacgaccgc gacaagaagt atggcttctg 901 ccctgagacc gccatgtcca ctgttggtgg gaactcagaa ggtgccccct gtgtcttccc 961 cttcactttc ctgggcaaca aatatgagag ctgcaccagc gccggccgca gtgacggaaa 1021 gatgtggtgt gcgaccacag ccaactacga tgatgaccgc aagtggggct tctgccctga 1081 ccaagggtac agcctgttcc tcgtggcagc ccacgagttt ggccacgcca tggggctgga 1141 gcactcccaa gaccctgggg ccctgatggc acccatttac acctacacca agaacttccg 1201 tctgtcccag gatgacatca agggcattca ggagctctat ggggcctctc ctgacattga 1261 ccttggcacc ggccccaccc ccacgctggg ccctgtcact cctgagatct gcaaacagga 1321 cattgtattt gatggcatcg ctcagatccg tggtgagatc ttcttcttca aggaccggtt 1381 catttggcgg actgtgacgc cacgtgacaa gcccatgggg cccctgctgg tggccacatt 1441 ctggcctgag ctcccggaaa agattgatgc ggtatacgag gccccacagg aggagaaggc 1501 tgtgttcttt gcagggaatg aatactggat ctactcagcc agcaccctgg agcgagggta 1561 ccccaagcca ctgaccagcc tgggactgcc ccctgatgtc cagcgagtgg atgccgcctt 1621 taactggagc aaaaacaaga agacatacat ctttgctgga gacaaattct ggagatacaa 1681 tgaggtgaag aagaaaatgg atcctggctt ccccaagctc atcgcagatg cctggaatgc 1741 catccccgat aacctggatg ccgtcgtgga cctgcagggc ggcggtcaca gctacttctt 1801 caagggtgcc tattacctga agctggagaa ccaaagtctg aagagcgtga agtttggaag 1861 catcaaatcc gactggctag gctgctgagc tggccctggc tcccacaggc ccttcctctc 1921 cactgccttc gatacaccgg gcctggagaa ctagagaagg acccggaggg gcctggcagc 1981 cgtgccttca gctctacagc taatcagcat tctcactcct acctggtaat ttaagattcc 2041 agagagtggc tcctcccggt gcccaagaat agatgctgac tgtactcctc ccaggcgccc 2101 cttccccctc caatcccacc aaccctcaga gccaccccta aagagatact ttgatatttt 2161 caacgcagcc ctgctttggg ctgccctggt gctgccacac ttcaggctct tctcctttca 2221 caaccttctg tggctcacag aacccttgga gccaatggag actgtctcaa gagggcactg 2281 gtggcccgac agcctggcac agggcagtgg gacagggcat ggccaggtgg ccactccaga 2341 cccctggctt ttcactgctg gctgccttag aacctttctt acattagcag tttgctttgt 2401 atgcactttg tttttttctt tgggtcttgt tttttttttc cacttagaaa ttgcatttcc 2461 tgacagaagg actcaggttg tctgaagtca ctgcacagtg catctcagcc cacatagtga 2521 tggttcccct gttcactcta cttagcatgt ccctaccgag tctcttctcc actggatgga 2581 ggaaaaccaa gccgtggctt cccgctcagc cctccctgcc cctcccttca accattcccc 2641 atgggaaatg tcaacaagta tgaataaaga cacctactga gtggccgtgt ttgccatctg 2701 ttttagcaga gcctagacaa gggccacaga cccagccaga agcggaaact taaaaagtcc 2761 gaatctctgc tccctgcagg gcacaggtga tggtgtctgc tggaaaggtc agagcttcca 2821 aagtaaacag caagagaacc tcagggagag taagctctag tccctctgtc ctgtagaaag 2881 agccctgaag aatcagcaat tttgttgctt tattgtggca tctgttcgag gtttgcttcc 2941 tctttaagtc tgtttcttca ttagcaatca tatcagtttt aatgctacta ctaacaatga 3001 acagtaacaa taatatcccc ctcaattaat agagtgcttt ctatgtgcaa ggcacttttc 3061 acgtgtcacc tattttaacc tttccaacca cataaataaa aaaggccatt attagttgaa 3121 tcttattgat gaagagaaaa aaaaaaaaaa aa (SEQ ID NO: 105) .

[0291] An exemplary nucleic acid sequence encoding MMP9 (NM_004994.2 mRNA) comprises or consists of:

1 agacacctct gccctcacca tgagcctctg gcagcccctg gtcctggtgc tcctggtgct 61 gggctgctgc tttgctgccc ccagacagcg ccagtccacc cttgtgctct tccctggaga 121 cctgagaacc aatctcaccg acaggcagct ggcagaggaa tacctgtacc gctatggtta 181 cactcgggtg gcagagatgc gtggagagtc gaaatctctg gggcctgcgc tgctgcttct 241 ccagaagcaa ctgtccctgc ccgagaccgg tgagctggat agcgccacgc tgaaggccat 301 gcgaacccca cggtgcgggg tcccagacct gggcagattc caaacctttg agggcgacct 361 caagtggcac caccacaaca tcacctattg gatccaaaac tactcggaag acttgccgcg 421 ggcggtgatt gacgacgcct ttgcccgcgc cttcgcactg tggagcgcgg tgacgccgct 481 caccttcact cgcgtgtaca gccgggacgc agacatcgtc atccagtttg gtgtcgcgga 541 gcacggagac gggtatccct tcgacgggaa ggacgggctc ctggcacacg cctttcctcc 601 tggccccggc attcagggag acgcccattt cgacgatgac gagttgtggt ccctgggcaa 661 gggcgtcgtg gttccaactc ggtttggaaa cgcagatggc gcggcctgcc acttcccctt 721 catcttcgag ggccgctcct actctgcctg caccaccgac ggtcgctccg acggcttgcc 781 ctggtgcagt accacggcca actacgacac cgacgaccgg tttggcttct gccccagcga 841 gagactctac acccaggacg gcaatgctga tgggaaaccc tgccagtttc cattcatctt 901 ccaaggccaa tcctactccg cctgcaccac ggacggtcgc tccgacggct accgctggtg 961 cgccaccacc gccaactacg accgggacaa gctcttcggc ttctgcccga cccgagctga 1021 ctcgacggtg atggggggca actcggcggg ggagctgtgc gtcttcccct tcactttcct 1081 gggtaaggag tactcgacct gtaccagcga gggccgcgga gatgggcgcc tctggtgcgc 1141 taccacctcg aactttgaca gcgacaagaa gtggggcttc tgcccggacc aaggatacag 1201 tttgttcctc gtggcggcgc atgagttcgg ccacgcgctg ggcttagatc attcctcagt 1261 gccggaggcg ctcatgtacc ctatgtaccg cttcactgag gggcccccct tgcataagga 1321 cgacgtgaat ggcatccggc acctctatgg tcctcgccct gaacctgagc cacggcctcc 1381 aaccaccacc acaccgcagc ccacggctcc cccgacggtc tgccccaccg gaccccccac 1441 tgtccacccc tcagagcgcc ccacagctgg ccccacaggt cccccctcag ctggccccac 1501 aggtcccccc actgctggcc cttctacggc cactactgtg cctttgagtc cggtggacga 1561 tgcctgcaac gtgaacatct tcgacgccat cgcggagatt gggaaccagc tgtatttgtt 1621 caaggatggg aagtactggc gattctctga gggcaggggg agccggccgc agggcccctt 1681 ccttatcgcc gacaagtggc ccgcgctgcc ccgcaagctg gactcggtct ttgaggagcg 1741 gctctccaag aagcttttct tcttctctgg gcgccaggtg tgggtgtaca caggcgcgtc 1801 ggtgctgggc ccgaggcgtc tggacaagct gggcctggga gccgacgtgg cccaggtgac 1861 cggggccctc cggagtggca gggggaagat gctgctgttc agcgggcggc gcctctggag 1921 gttcgacgtg aaggcgcaga tggtggatcc ccggagcgcc agcgaggtgg accggatgtt 1981 ccccggggtg cctttggaca cgcacgacgt cttccagtac cgagagaaag cctatttctg 2041 ccaggaccgc ttctactggc gcgtgagttc ccggagtgag ttgaaccagg tggaccaagt 2101 gggctacgtg acctatgaca tcctgcagtg ccctgaggac tagggctccc gtcctgcttt 2161 ggcagtgcca tgtaaatccc cactgggacc aaccctgggg aaggagccag tttgccggat 2221 acaaactggt attctgttct ggaggaaagg gaggagtgga ggtgggctgg gccctctctt 2281 ctcacctttg ttttttgttg gagtgtttct aataaacttg gattctctaa cctttaaaaa 2341 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaa (SEQ ID NO:

106)

[0292] An exemplary amino acid sequence encoding MMP9 (NP_004985.2) comprises or consists of:

MSLWQPLVLVLLVLGCCFAAPRQRQSTLVLFPGDLRTNLTDRQLAEEYLYRYGYTRVAEMRGESKSLGPALLLLQ KQLSLPETGELDSATLKAMRTPRCGVPDLGRFQTFEGDLKWHHHNITYWIQNYSEDLPRAVIDDAFARAFALWSA VTPLTFTRVYSRDADIVIQFGVAEHGDGYPFDGKDGLLAHAFPPGPGIQGDAHFDDDELWSLGKGVWPTRFGNA DGAACHFPFIFEGRSYSACTTDGRSDGLPWCSTTANYDTDDRFGFCPSERLYTQDGNADGKPCQFPFIFQGQSYS ACTTDGRSDGYRWCATTANYDRDKLFGFCPTRADSTVMGGNSAGELCVFPFTFLGKEYSTCTSEGRGDGRLWCAT TSNFDSDKKWGFCPDQGYSLFLVAAHEFGHALGLDHSSVPEALMYPMYRFTEGPPLHKDDVNGIRHLYGPRPEPE PRPPTTTTPQPTAPPTVCPTGPPTVHPSERPTAGPTGPPSAGPTGPPTAGPSTATTVPLSPVDDACNVNIFDAIA EIGNQLYLFKDGKYWRFSEGRGSRPQGPFLIADKWPALPRKLDSVFEERLSKKLFFFSGRQV VYTGASVLGPRR LDKLGLGADVAQVTGALRSGRGKMLLFSGRRLWRFDVKAQMVDPRSASEVDRMFPGVPLDTHDVFQYREKAYFCQ DRFYWRVSSRSELNQVDQVGYVTYDILQCPED (SEQ ID NO: 107) . [0293] An exemplary nucleic acid sequence encoding MMP9 (HM210695.1, promoter region) comprises or consists of:

1 tggcacatag taggcccttt aaatacagct tattgggccg ggcgccatgg ctcatgcccg

61 taatcctagc actttgggag gccaggtggg cagatcactt gagtcagaag ttcgaaacca

121 gcctggtcaa cgtagtgaaa ccccatctct actaaaaata caaaaaattt agccaggcgt

181 ggtggcgcat gcctataata ccagctactc gggaggctga ggcaggagaa ttgcttgaac

241 ccgggaggca gatgttgcag tgagccgaga tcacgccact gcactccagc ctgggtgata

301 gagtgatact acacccccca aaaataaaat aaaataaata aatacaactt tttgagttgt

361 tagcaggttt ttcccaaata gggctttgaa gaaggtgaat atagaccctg cccgatgccg

421 gctggctagg aagaaaggag tga (SEQ ID NO: 108) .

[0294] An exemplary nucleic acid sequence encoding MMP9 (HM210691.1, promoter

;ion) comprises or consists of:

1 cacatagtag ccctttaaat acagcttatt gggccgggcg ccatggctca tgcccgtaat

61 cctagcactt tgggaggcca ggtgggcaga tcacttgagt cagaagttcg aaaccagcct

121 ggtcaacgta gtgaaacccc atctctacta aaaatacaaa aaatttagcc aggcgtggtg

181 gcgcacgcct ataataccag ctactcggga ggctgaggca ggagaattgc ttgaacccgg

241 gaggcagatg ttgcagtgag ccgagatcac gccactgcac tccagcctgg gtgacagagt

301 gatactacac cccccaaaaa taaaataaaa taaataaata caactttttg agttgttagc

361 aggtttttcc caaatagggc tttgaagaag gtgaatatag accctgcccg atgccggctg

421 gctagg (SEQ ID NO: 109) .

[0295] An exemplary nucleic acid sequence encoding MPL (NM_005373.2 mRNA) comprises or consists of:

1 cctgaaggga ggatgggcta aggcaggcac acagtggcgg agaagatgcc ctcctgggcc 61 ctcttcatgg tcacctcctg cctcctcctg gcccctcaaa acctggccca agtcagcagc 121 caagatgtct ccttgctggc atcagactca gagcccctga agtgtttctc ccgaacattt 181 gaggacctca cttgcttctg ggatgaggaa gaggcagcgc ccagtgggac ataccagctg 241 ctgtatgcct acccgcggga gaagccccgt gcttgccccc tgagttccca gagcatgccc 301 cactttggaa cccgatacgt gtgccagttt ccagaccagg aggaagtgcg tctcttcttt 361 ccgctgcacc tctgggtgaa gaatgtgttc ctaaaccaga ctcggactca gcgagtcctc 421 tttgtggaca gtgtaggcct gccggctccc cccagtatca tcaaggccat gggtgggagc 481 cagccagggg aacttcagat cagctgggag gagccagctc cagaaatcag tgatttcctg 541 aggtacgaac tccgctatgg ccccagagat cccaagaact ccactggtcc cacggtcata 601 cagctgattg ccacagaaac ctgctgccct gctctgcaga ggcctcactc agcctctgct 661 ctggaccagt ctccatgtgc tcagcccaca atgccctggc aagatggacc aaagcagacc 721 tccccaagta gagaagcttc agctctgaca gcagagggtg gaagctgcct catctcagga 781 ctccagcctg gcaactccta ctggctgcag ctgcgcagcg aacctgatgg gatctccctc 841 ggtggctcct ggggatcctg gtccctccct gtgactgtgg acctgcctgg agatgcagtg 901 gcacttggac tgcaatgctt taccttggac ctgaagaatg ttacctgtca atggcagcaa 961 caggaccatg ctagctccca aggcttcttc taccacagca gggcacggtg ctgccccaga 1021 gacaggtacc ccatctggga gaactgcgaa gaggaagaga aaacaaatcc aggactacag 1081 accccacagt tctctcgctg ccacttcaag tcacgaaatg acagcattat tcacatcctt 1141 gtggaggtga ccacagcccc gggtactgtt cacagctacc tgggctcccc tttctggatc 1201 caccaggctg tgcgcctccc caccccaaac ttgcactgga gggagatctc cagtgggcat 1261 ctggaattgg agtggcagca cccatcgtcc tgggcagccc aagagacctg ttatcaactc 1321 cgatacacag gagaaggcca tcaggactgg aaggtgctgg agccgcctct cggggcccga 1381 ggagggaccc tggagctgcg cccgcgatct cgctaccgtt tacagctgcg cgccaggctc 1441 aacggcccca cctaccaagg tccctggagc tcgtggtcgg acccaactag ggtggagacc 1501 gccaccgaga ccgcctggat ctccttggtg accgctctgc atctagtgct gggcctcagc 1561 gccgtcctgg gcctgctgct gctgaggtgg cagtttcctg cacactacag gagactgagg 1621 catgccctgt ggccctcact tccagacctg caccgggtcc taggccagta ccttagggac 1681 actgcagccc tgagcccgcc caaggccaca gtctcagata cctgtgaaga agtggaaccc 1741 agcctccttg aaatcctccc caagtcctca gagaggactc ctttgcccct gtgttcctcc 1801 caggcccaga tggactaccg aagattgcag ccttcttgcc tggggaccat gcccctgtct 1861 gtgtgcccac ccatggctga gtcagggtcc tgctgtacca cccacattgc caaccattcc 1921 tacctaccac taagctattg gcagcagcct tgaggacagg ctcctcactc ccagttccct 1981 ggacagagct aaactctcga gacttctctg tgaacttccc taccctaccc ccacaacaca 2041 agcaccccag acctcacctc catccccctc tgtctgccct cacaattagg cttcattgca 2101 ctgatcttac tctactgctg ctgacataaa accaggaccc tttctccaca ggcaggctca 2161 tttcactaag ctcctccttt actttctctc tcctctttga tgtcaaacgc cttgaaaaca 2221 agcctccact tccccacact tcccatttac tcttgagact acttcaatta gttcccctac 2281 tacactttgc tagtgaaact gcccaggcaa agtgcacctc aaatcttcta attccaagat 2341 ccaataggat ctcgttaatc atcagttcct ttgatctcgc tgtaagattt gtcaaggctg 2401 actactcact tctcctttaa attctttcct accttggtcc tgcctctttg agtatattag 2461 taggtttttt ttatttgttt gagacagggt ctcactctgt cacccaggct gcagtgcaat 2521 ggcgcgatct cagctcactg caacctccac ctccgggttc aagcgattct tgtgcctcgg 2581 cctccctagt agctgggatt acaggcgcac accaccacac acagctaatt tttttttttt 2641 tttttttttt ttttttttag acggagcctt gctctgttgc cagactggag tgcagtggca 2701 cgatctcggc tcactgcaac ctctgcctcc cgggttcaag ccattctgcc tcagcctccc 2761 aagtagctgg gagtacaggc gtctgccacc atgcctaatt tttttctatt tttaggagag 2821 accggttttc accacgttgg ccaggatggt ctcgatatcc tgatctcgtg atccgcctgc 2881 ctctgcctcc caaagtgctg ggattacagg tgtgacccac tgcgcacagc cccagctaat 2941 tttcatattt ttagtagaga cagggttttg ccatgttgcc caggctggtc ttgaactcct 3001 aacctcgggt gatccaccca ccttggcctc ccaaagtgtt aggattacag gcatgagcca 3061 ctgcgcccgg ctgagtgtac tagtagttaa gagaataaac tagatctaga atcagagctg 3121 gattcaattc ctgtccttca catttactag ctgtgcaacc ttgggcacat aacttaatgt 3181 ctttgagcct tagttttttc atctgtaaaa cagggataat aacagcaccc catagagttg 3241 tgacgaggat tgagataatc taagtaaagc acagtcccta ggacatagta aatgattcat 3301 atatccgaac tactgttata attattcctt cttactctcc tcttctagca tttcttccaa 3361 ttattacagt ccttcaagat tccatttctt aacagtctcc aatcccatct attctctgcc 3421 tttactatat gttgaccatt ccaaagttct tatctctagc tcagacatct actacagcac 3481 tgtgatgctt tatgcaacta actgtttaca tatctgtccc ctgctactag attgtgagct 3541 ccttgaggga aaggaacatg atttatttgt ccttttcccc cagcacctag agtagtgctt 3601 ggtgcatgat agtaggcctt caataaattt tttctaaatg aatga (SEQ ID NO:

110)

[0296] An exemplary amino acid sequence encoding MPL (NP 005364.1) comprises or consists of:

MPSWALFMVTSCLLLAPQNLAQVSSQDVSLLASDSEPLKCFSRTFEDLTCFWDEEEAAPSGTYQLLYAYPREKPR ACPLSSQSMPHFGTRYVCQFPDQEEVRLFFPLHLWVKNVFLNQTRTQRVLFVDSVGLPAPPSIIKAMGGSQPGEL QISWEEPAPEISDFLRYELRYGPRDPKNSTGPTVIQLIATETCCPALQRPHSASALDQSPCAQPTMPWQDGPKQT SPSREASALTAEGGSCLISGLQPGNSYWLQLRSEPDGISLGGSWGSWSLPVTVDLPGDAVALGLQCFTLDLKNVT CQWQQQDHASSQGFFYHSRARCCPRDRYPIWENCEEEEKTNPGLQTPQFSRCHFKSRNDSIIHILVEVTTAPGTV HSYLGSPFWIHQAVRLPTPNLHWREISSGHLELEWQHPSSWAAQETCYQLRYTGEGHQDWKVLEPPLGARGGTLE LRPRSRYRLQLRARLNGPTYQGPWSSWSDPTRVETATETAWISLVTALHLVLGLSAVLGLLLLRWQFPAHYRRLR HALWPSLPDLHRVLGQYLRDTAALSPPKATVSDTCEEVEPSLLEILPKSSERTPLPLCSSQAQMDYRRLQPSCLG TMPLSVCPPMAESGSCCTTHIANHSYLPLSYWQQP (SEQ ID NO: 111) .

[0297] An exemplary nucleic acid sequence encoding MPL (AH003655.2 alternatively spliced ) comprises or consists of:

1 caagggggca gggtaaggag tgtgagccat ctccaatctg agcaaacagg ataaaagtac

61 tgaagaccat tgcttctcca actttaagtt acattcaaac catctgggga ttttggcaaa

121 atgcaggttc aactttaata ggcctggggt ggggcctaag attctgcatt tctaataagt

181 gcccacctaa tgctgttgct cctggtctac agaccacatt ttgagtagca agggattaga

241 ggcagccgtg gaggccaccc ataatggaga gggcatttcc agttccaggg agaatgtgtt

301 tattcatgcg caaagtcaca gaactattaa agtggaaata cccaccattt ggcatggttg

361 tggggcagag agttatttct cagcagatta gcctcccaag agcatagcac agcatggctg 421 ttatgcaggt gggttctgaa ggttgaacct cctgagcttt atgtcttagt atgtaatctt 481 gggcaaatct ttaacttctc tgtatctccg tttcctcatc tctataatgg aaataacaag 541 actattgtgc ggattgtcta agtgaatgga tataaagtgc ttaacacacg gcagcatagt 601 aagtgctcag taaaagttgc tattctgatg ctattatacc attctataat cgttagcaca 661 gatacagagg ctgagttgcc ttttggtaca cggtcaaata tacaaccccc atctccctca 721 caccaaaagg cctgtgtcct ctctttcaaa ttcctccttc cctcctgccc actccccctc 781 ccctggcccc tggccccagt gtggtctgga tgggccccag aggggcaggg acagggacag 841 gacgtggggc tgtatctgac aggaacctga ggggctggcc tgggagggga ttggggccca 901 gcttcctgaa gggaggatgg gctaaggcag gcacacagtg gcggagaaga tgccctcctg 961 ggccctcttc atggtcacct cctgcctcct cctggcccct caaaacctgg cccaagtcag 1021 cagccaaggt gaggtgcaca gagggtggag atcacctatg ccccaggaag agggagccct 1081 gggaggtgat gcagggcccc cggaggggag gtagagtaag aggctctcct gctggtcccc 1141 tccccttcca cataaacatg cctgggagga cccagggcca actcaccagc tgttccttag 1201 atgtctcctt gctggcatca gactcagagc ccctgaagtg tttctcccga acatttgagg 1261 acctcacttg cttctgggat gaggaagagg cagcgcccag tgggacatac cagctgctgt 1321 atgcctaccc gcggtaggtg ctggactgtg ccccactccc catgtatctg tccctgcact 1381 tagctgagtc ccactccagc agctttcctg cctgtccgag gaccactctg aatacaagcc 1441 ctaagtacct actttttgaa cagatgtgct ttggatgtat gtgggcccca gctccagccc 1501 tacataaccc ctaatcccac ctatcccagg cagtgagaag aaaaatggca gtactagaga 1561 cagaagttgg gcatgggccc aggtctgggt cctcaggcgt ccgcatggtg gctgtgtagg 1621 agggacctct tctatgccaa cagggagaag ccccgtgctt gccccctgag ttcccagagc 1681 atgccccact ttggaacccg atacgtgtgc cagtttccag accaggagga agtgcgtctc 1741 ttctttccgc tgcacctctg ggtgaagaat gtgttcctaa accagactcg gactcagcga 1801 gtcctctttg tggacagtgt aggtaagagc catcctcctg tcaccctgcc ccctccactt 1861 gctgccccca gtccagctcc cggaatcaga cttgcctgtg cccttccagc tcagcacgga 1921 tacccctatt accagacccc ctgaggcacc ccaagactcc cttgtcattc ctcccagcct 1981 tggcatctag agctagaaat gcccaacaga tcattcacac cctgtnnctc ccatcgtcaa 2041 caaatcattt attcatccat tcaagagtta cagaatacct actgtgtgcc agacactggg 2101 ctaggtgatg gggatatgga gagaaaaagg gatccctgct tacaagaagc actgagtcta 2161 gcaagccatc atactgcaaa gaagtcactg ttctcatgag agaagaacag aatcaggagc 2221 ctcctcagcc tgccctccag gagaatgaca gcctacaatt tttgaatcca gaagctgccc 2281 caattcagcc cccagcaccc ctctctgcag tccagaggct gagccataga ctgtggtact 2341 cagagttctg atgtgccctg tcttgccctc aggcctgccg gctcccccca gtatcatcaa 2401 ggccatgggt gggagccagc caggggaact tcagatcagc tgggaggagc cagctccaga 2461 aatcagtgat ttcctgaggt acgaactccg ctatggcccc agagatccca agaactccac 2521 tggtcccacg gtcatacagc tgattgccac agaaacctgc tgccctgctc tgcagaggcc 2581 tcactcagcc tctgctctgg accagtctcc atgtgctcag cccacaatgc cctggcaaga 2641 tggaccaaag cagacctccc caagtagaga agtatgctga ccttcttctg ccccacctct 2701 tatctcctac cttcaatctt gccccaggaa aggacagacc atactttggg gattccagac 2761 ctaggttcgt ccttggagag ttagtatagg ctcagatatg agcacgccta cttaggggct 2821 tcctactttg ggtcattccc actgacaaaa gcaaggcttt caggcctcca aattaatgga 2881 gatttcgcaa caaaaccctg aacaccacct gaaacccacc aacttagccc ctggtctgtg 2941 tgcatatcta tccagcaagg agctgagctc ctctccacag agatgctgtg caaatataag 3001 ggttggaggc tctctcagct gacaggcaga cctagattgt gaagctggga ttttcctccc 3061 aaggcttcag ctctgacagc agagggtgga agctgcctca tctcaggact ccagcctggc 3121 aactcctact ggctgcagct gcgcagcgaa cctgatggga tctccctcgg tggctcctgg 3181 ggatcctggt ccctccctgt gactgtggac ctgcctggag atgcaggtga gtcaacaaag 3241 gaatagggag atggggagga gataaaagaa tatctctagg gaagcctggg ctagatctga 3301 agctctggga accatggtcc ttcctgatga tctcgaactt gccactggac aggaactatg 3361 ttcagggaaa gaagagagaa taggagtcaa tgttctaagt tatatgtgta gaaattatct 3421 gaaatctgaa caccctatac agtaggggca cacgggccct gatgggactt acttctttga 3481 ctttagtggc acttggactg caatgcttta ccttggacct gaagaatgtt acctgtcaat 3541 ggcagcaaca ggaccatgct agctcccaag gcttcttcta ccacagcagg gcacggtgct 3601 gccccagaga caggtgagag ctgaactgct gattgaggtt ggtgtcatgg gagtgagcca 3661 caatcttgca gaaaaaaaga agagagtgtt cttggtcctc ttcactctcc ttcctttgtc 3721 tccaaaccat acagctttca atgctctctt atctattctg tcatcctcca atcgatattt 3781 tatcttctca acccctctct gttcccattg ggaatgcttt ggtttagttt agccttaatc 3841 atgtcactgg gaccattgca acatcctaca gtctaattca cctccaatgt attccccatg 3901 ctgctaacag agtgatcttt gttaagctca aactgtgcat gaccttnnnn nnnnnnnnnn 3961 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 4021 nnnnnnnnnn nnnnnnnnnn nnnnnnaaaa tgcaaaaaca aacgaacaaa tgaacaaagg 4081 aaaaaacaaa aagaaaacat catggcataa agacagaggg aaagctctgg aggcccctgg 4141 aaggaaggag ttaaatgata atccctgcag gccatcgttc ttgtaggatg ggaagccttg 4201 ggattagtct ctgaggcagg cctgattcaa tgactctgtg gggctgggtc ttaggtaccc 4261 catctgggag aactgcgaag aggaagagaa aacaaatcca ggactacaga ccccacagtt 4321 ctctcgctgc cacttcaagt cacgaaatga cagcattatt cacatccttg tggaggtgac 4381 cacagccccg ggtactgttc acagctacct gggctcccct ttctggatcc accaggctgg 4441 taagaacttt cttcctcatt cttccacata gttcccaccc ccactgaatc tgaccctgtg 4501 cccaggatcc ccaactctga cccttctgac cgatggctct ggtggcacaa tgccttgtgc 4561 acagaaggac ttaagctgct ccctgctgac atccctgtag tgcgcctccc caccccaaac 4621 ttgcactgga gggagatctc cagtgggcat ctggaattgg agtggcagca cccatcgtcc 4681 tgggcagccc aagagacctg ttatcaactc cgatacacag gagaaggcca tcaggactgg 4741 aaggtatggt caagcaacaa atgcccacag acctcactac gcaggggatc cctggggttg 4801 gccatgcctg ttagcaggag tgaaagtgtc tatgtatcca gtctctgcta gtatatctat 4861 gtttatcaga ttcaactggt atcttagtct ctcttgggca tctgatattt ctggctactc 4921 ctacttaaca tttctcttcc ctttgtcttt gggatatcag tcttccccga ttttcctcct 4981 acctctctga ctgaactttc tcactctcct ctcctggctc ctcctttcca gccttccaca 5041 aaatgctgtg cttcctagag tctcatccta ggctcttttc tcctctgata aaataaatat 5101 gttctcccca ggtgagtgct ttaactccat ggtttcaatg tccatacatt aacaatcgca 5161 attttaccat tctaactccc atatggaaag gaatttacaa accacaggca aattaccaaa 5221 atgtttgaag tctgtttcct cattggtgaa atgaggatga agctatctac cttatggagt 5281 tatagtaaag attaaatact atatctaaat acctagcata ctgcctggca taaggaaggt 5341 gctcaatata cattacttaa atattagttt gtctactttt attctcattt gccacacata 5401 tatacaacta tgtacaacat cttatggttn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 5461 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 5521 nnnnnnnnnc cttgcactaa ttaattgttg tgattattta cctgtttgga tgtctttctc 5581 attagatatg taagagacgg tgttttattg ctttctcccc agtgcctaac ccaatgtttg 5641 gagtatcaca cagttcataa atgtttgctg ccttcctgct tgtacacatg atgcttgtac 5701 cccagcgcct aacgcaaatc tggcatcctc tgcagcatga gtattatttg tggcatggtc 5761 tgtgtggctc tgaatatatc tgtttctggg ggtgtccatc gcccgacctg gagttgtgag 5821 aacacccggt agggtgtgcg tgtaccggga tccctgccga gggtgtacct gggtgttggt 5881 gttaggatac gtagctctct gaggtgaggt ctgtgtctca ggaggtgggc ctggcacgtt 5941 tctctcgggc agagcgtgat cccgttaagg aggctctcgg ttagggcgct ctatcctgtt 6001 gctgggaagc gtgttttctg ccggtggggc tctttgtggg aatctccgac cgcctgggga 6061 ttcggagctg caggatttgg gtcaaacaga cgctgggcta tcgaagcccc gacgccgggc 6121 caccgcacgc ttctttgctc aggtgctgga gccgcctctc ggggcccgag gagggaccct 6181 ggagctgcgc ccgcgatctc gctaccgttt acagctgcgc gccaggctca acggccccac 6241 ctaccaaggt ccctggagct cgtggtcgga cccaactagg gtggagaccg ccaccgagac 6301 cggtgaggca agccccggcc gcaccaaagc cgcacagcgc ctgcgcaggg actgggcgcc 6361 gggtgcgagt ggggcggggc tcggagaggg gcgagnnggg gcgnggagag ggcggggccc 6421 tgaccttgcg ggccgacgct gcgcaggtgc ccgcagtccc aggggcggcg aggggcgggg 6481 ccagagtagg ggctggctgg atgagggcgg ggctccggcc cgggtgggcc gaagtctgac 6541 cctttttgtc tcctagcctg gatctccttg gtgaccgctc tgcatctagt gctgggcctc 6601 agcgccgtcc tgggcctgct gctgctgagg tggcagtttc ctgcacacta caggtaccgc 6661 ccccgccagg caggagactg gcggtggacc aggtggagcc gaaccggtgt aaacaggcat 6721 tcttggttcg ctctgtgacc ccagatctcc gtccaccgcc cgtgcgcacc tacggcttcg 6781 cacttcctgc acgtcacctc tgggactcgc cgcggctcct tacactctaa cacgcccact 6841 ataccgccca cctcgaacag ccccgcctcc tgctgctcac ctcggcgact aggccaccgt 6901 ccacccttca gccaaactgc ccactccacc cccatccaat ctgccgtcag tcccacctcc 6961 taaacctagt ccaaacaatg gccccctttc tctagcccta cagacacgac ctgactcact 7021 gaaacagaac ctcttgcccc tccgatctag ctacacagcc accagaataa tctttctaaa 7081 atgcgcacat gaacctatca attccctcct taaatccttt caatagctcc caggatatag 7141 tccaggctcc ctatgatgac aagcgaggct ctgcaaaatc ggcccctgcc agcaagcact 7201 tcagcctgtt ctaccctgtg catcagcctt tccaaactgg ttttctccac aagtcaggtt 7261 ttacttctca gtgcctttgc acataacgtc cgctctgcct gaaatagcct ccctnnnnnn 7321 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 7381 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnctgcag ataaagaggg agtactgtgt 7441 ttcaggcaag gtagtcaggg atgacatttg aacagaggcc tacaatgagg tgagggaatg 7501 aatccagtgt tccagacaga acaaacattg gagtgtttga ggaaactgca gcaccctttg 7561 ttgaacctgc ccaccactga cttccctccc ctacctgagg ttttcttctt actctactcc 7621 cctgcccaac tttattgcct tgaccatgct cttatatctc caagccttac tccccggcct 7681 cactgctccc ccaccccaac tgctgtcctc ctccctgcca atccactgcc atggctcagt 7741 ctgcttctct tccttctccc ccaggagact gaggcatgcc ctgtggccct cacttccaga 7801 cctgcaccgg gtcctaggcc agtaccttag ggacactgca gccctgagcc cggtgagtgt 7861 gcttccctcc cctgtgccca ccaccaaccc tgcctggtac tggatccttg ccccaacaat 7921 acaacttgtt caaggtcctt gccctaccag tgtgccatcc ccaggcacta ccccagcact 7981 accccagccc ttctccttcc tgtacagtcc agcccctcct cccacaggat ctgctttaat 8041 ccagcgcctc tcctcatctc tcccagccca aggccacagt ctcagatacc tgtgaagaag 8101 tggaacccag cctccttgaa atcctcccca agtcctcaga gaggactcct ttgcccctgt 8161 gttcctccca ggcccagatg gactaccgaa gattgcagcc ttcttgcctg gggaccatgc 8221 ccctgtctgt gtgcccaccc atggctgagt cagggtcctg ctgtaccacc cacattgcca 8281 accattccta cctaccacta agctattggc agcagccttg aggacaggct cctcactccc 8341 agttccctgg acagagctaa actctcgaga cttctctgtg aacttcccta ccctaccccc 8401 acaacacaag caccccagac ctcacctcca tccccctctg tctgccctca caattaggct 8461 tcattgcact gatcttactc tactgctgct gacataaaac caggaccctt tctccacagg 8521 caggctcatt tcactaagct cctcctttac ttcctctctc ctctttgatg tcaaacgcct 8581 tgaaaacaag cctccacttc cccacacttc ccatttactc ttgagactac ttcaattagt 8641 tcccctacta cactttgcta gtgaactgcc caggcaaagt gcacctcaaa tcttctaatt 8701 ccaagatcca ataggatctc gttaatcatc agttcctttg atctcgctgt aagatttgtc 8761 aaggctgact actcacttct cctttaaatt ctttcctacc ttggtcctgc ctctttgagt 8821 atattagtag gtttttttta tttgtttgag acagggtctc actctgtcac ccaggctgca 8881 gtgcaatggc gcgatctcag ctcactgcaa cctccacctc cgggttcaag cgattcttgt 8941 gcctcggcct ccctagtagc tgggattaca ggcgcacacc accacacaca gctaattttt 9001 tttttttttt tttttttttt tttttttttt agacggagcc ttgcctgttg ccagactgga 9061 gtgcagtggc acgatctcgg ctcactgcaa cctctgcctc ccgggttcaa gccattctgc 9121 ctcagcctcc caagtagctg ggagtacagc gtctgccacc atgcctaatt tttttctatt 9181 tttaggagag accggttttc accacgttgg ccaggatggt ctcgatatct gatctcgtga 9241 tccgcctgcc tctgcctccc aaagtgctgg gattacaggt gtgacccact gcgcacagcc 9301 ccagctaatt ttcatatttt tagtagagac agggttttgc catgttgccc aggctggtct 9361 tgaactccta acctcgggtg atccacccac cttggcctcc caaagtgtta ggattacagg 9421 catgagccac tgcgcccggc tgagtgtact agtagttaag agaataaact agatctagaa 9481 tcagagctgg attcaattcc tgtccttcac atttactagc tgtgcaacct tgggcacata 9541 acttaatgtc tttgagcctt agttttttca tctgtaaaac agggataata acagcacccc 9601 atagagttgt gacgaggatt gagataatct aagtaaagca cagtccctag gacatagtaa 9661 atgattcata tatccgaact actgttataa ttattccttc ttactctcct cttctagcat 9721 ttcttccaat tattacagtc cttcaagatt ccatttctta acagtctcca atcccatcta 9781 ttctctgcct ttactatatg ttgaccattc caaagttctt atctctagct cagacatcta 9841 ctacagcact gtgatgcttt atgcaactaa ctgtttacat atctgtcccc tgctactaga 9901 ttgtgagctc cttgagggaa aggaacatga tttatttgtc cttttccccc agcacctaga 9961 gtagtgcttg gtgcatgata gtaggccttc aataaatttt ttctaaatga atgaaatctt 10021 tctggacaag gttaccttaa tcccatgcca gctgtcctca tcctctaaac cgttcatagg 10081 cagcagtaaa tgtgccagac agttctgatt atggactctc ctaacacatt ctaattctca 10141 aacaaatggt tttgttgtca ttgtttttnc tggctccaaa tatacccact gtatcagtca 10201 gggtcttgga agaaatagat gacacactca aattgggtaa tatgatgaca gtgtaataaa 10261 ct (SEQ ID NO: 112) .

[0298] An exemplary amino acid sequence encoding MPL (AAB08425.1, alternative initiation codon) comprises or consists of:

MVTSCLLLAPQNLAQVSSQDVSLLASDSEPLKCFSRTFEDLTCFWDEEEAAPSGTYQLLYAYPREKPRACPLSSQ SMPHFGTRYVCQFPDQEEVRLFFPLHLWVKNVFLNQTRTQRVLFVDSVGLPAPPSIIKAMGGSQPGELQISWEEP APEISDFLRYELRYGPRDPKNSTGPTVIQLIATETCCPALQRPHSASALDQSPCAQPTMPWQDGPKQTSPSREAS ALTAEGGSCLISGLQPGNSYWLQLRSEPDGISLGGSWGSWSLPVTVDLPGDAVALGLQCFTLDLKNVTCQWQQQD HASSQGFFYHSRARCCPRDRYPIWENCEEEEKTNPGLQTPQFSRCHFKSRNDSI IHILVEVTTAPGTVHSYLGSP FWIHQAVRLPTPNLHWREISSGHLELEWQHPSSWAAQETCYQLRYTGEGHQDWKVLEPPLGARGGTLELRPRSRY RLQLRARLNGPTYQGPWSSWSDPTRVETATETAWISLVTALHLVLGLSAVLGLLLLRWQFPAHYRRLRHALWPSL PDLHRVLGQYLRDTAALSPPKATVSDTCEEVEPSLLEILPKSSERTPLPLCSSQAQMDYRRLQPSCLGTMPLSVC PPMAESGSCCTTHIANHSYLPLSYWQQP (SEQ ID NO: 113) . [0299] An exemplary nucleic acid sequence encoding PDKl (NM 001278549.1 transcript variant ) comprises or consists of:

1 ctccttcccg ctccgcgtcc cgcccagcgg cgcagggggc cgggctccgg ctaggagggt 61 gggggccgcg ccggtgacag ccgatccccg cccctgctgc ccgccacgtc cctcacgtac 121 cactcggcag aggcgcgggg aaacctggcg tactggctgt ggcttctcta gcgggactcg 181 gcatgaggct ggcgcggctg cttcgcggag ccgccttggc cggcccgggc ccggggctgc 241 gcgccgccgg cttcagccgc agcttcagct cggactcggg ctccagcccg gcgtccgagc 301 gcggcgttcc gggccaggtg gacttctacg cgcgcttctc gccgtccccg ctctccatga 361 agcagttcct ggacttcgga tcagtgaatg cttgtgaaaa gacctcattt atgtttctgc 421 ggcaagagtt gcctgtcaga ctggcaaata taatgaaaga aataagtctc cttccagata 481 atcttctcag gacaccatcc gttcaattgg tacaaagctg gtatatccag agtcttcagg 541 agcttcttga ttttaaggac aaaagtgctg aggatgctaa agctatttat gaaaggccta 601 gaagaacatg gttgcaggtc tctagtttat gctgtatggc ctgcaagatg atctttacag 661 atactgtgat acggatcaga aaccgacaca atgatgtcat tcccacaatg gcccagggtg 721 tgattgaata caaggagagc tttggggtgg atcctgtcac cagccagaat gttcagtact 781 ttttggatcg attctacatg agtcgcattt caattagaat gttactcaat cagcactctt 841 tattgtttgg tggaaaaggc aaaggaagtc catctcatcg aaaacacatt ggaagcataa 901 atccaaactg caatgtactt gaagttatta aagatggcta tgaaaatgct aggcgtctgt 961 gtgatttgta ttatattaac tctcccgaac tagaacttga agaactaaat gcaaaatcac 1021 caggacagcc aatacaagtg gtttatgtac catcccatct ctatcacatg gtgtttgaac 1081 ttttcaagaa tgcaatgaga gccactatgg aacaccatgc caacagaggt gtttaccccc 1141 ctattcaagt tcatgtcacg ctgggtaatg aggatttgac tgtgaagatg agtgaccgag 1201 gaggtggcgt tcctttgagg aaaattgaca gacttttcaa ctacatgtat tcaactgcac 1261 caagacctcg tgttgagacc tcccgcgcag tgcctctggc tggttttggt tatggattgc 1321 ccatatcacg tctttacgca caatacttcc aaggagacct gaagctgtat tccctagagg 1381 gttacgggac agatgcagtt atctacatta aggctctgtc aacagactca atagaaagac 1441 tcccagtgta taacaaagct gcctggaagc attacaacac caaccacgag gctgatgact 1501 ggtgcgtccc cagcagagaa cccaaagaca tgacgacgtt ccgcagtgcc tagacacact 1561 tgggacatcg gaaaatccaa atgtggcttt tgtattaaat ttggaaggta tggtgttcag 1621 aactatatta taccaagtac tttatttatc gttttcacaa aactatttga gtagaataaa 1681 tggaaactga attccatttg tgcccgttaa acctcctaaa ggatgaaatt gcacctattt 1741 tacacttata ttttcacagt taattgaaca tatttttaaa caactgtagt tttgggcaac 1801 ttttcacttt gtggtagact tcagaagtgt ggaaatcttc gggtttctat aggaaactag 1861 tttttttttt ttaagaaata ctttcattta tgtttgctag aaacattttc taaatgatag 1921 tgattagctg gttagccatc ttcctgttat ttggaggagt tctgccatct tttattcggt 1981 agtgacagct gtaatatggt cttcatgttt atcagtgact tgactacaag taaagcagaa 2041 aacagttggc ctgtaatcac agaaccagcc acccttcggc gtctacatgc attgtcttag 2101 ctctgaggtt aatttaccat ttttaaattt tattgtaaag aagtgtaatg actagctctc 2161 tgtggatcta tgccaaaatc atgggccatc ttttctaagt gtacttctga ttaatgcaag 2221 gggaaatttt tatactgaaa acaaacaaac aaactagcag ctactaaaat agagaagaaa 2281 ttgagggcaa agtaatatgt ctccaaaact gaactgattg cttgttgaga ttacctagaa 2341 agcttttgga aaaaaataga gcttttctgc atcctactcc agatacactg aatcggaatc 2401 cctagggcta gagcctagaa atctcacttt ttaaaatgct tccaaggtaa gtctgatgcc 2461 taccctaggt tgggaaccac tctttcaaag taaacagtga tgacacagca tttgctaaag 2521 taacatctgt aggttttggt ttccacctat ttaaagtcag atttatagac tcgaggagac 2581 agaaactgaa tcccacacct ggtgcaatta gaagcataat tagaagcaga agaacaaaat 2641 gccacgtaac caaagcatca gagccatcat tgcacgtgtc tttttttctt ttttcttttt 2701 tttttttcaa gacagggtct cgctcttttg cccaggatgg agtacagtgg catggtcaag 2761 gctcactgca gcttcaatct tctgggctca agtaatcctt ccacctcagc ctcccatata 2821 gctggaacta cagttgtgca ctaccacacc cagctaattt tttgatttct tgtggagatg 2881 aggtctcagt atgttcccag gctagtgttg aactcctgag ctcaagaaat cctcctgcct 2941 gagtctctga aagtgctggg attacaggcg tgagccacca cacatggcct attgcacaag 3001 tcttgacaaa caacatatat tttctaaaac tatccagatt tcattatcag ggaaaagttt 3061 gcttaggttt attacagcag tccttggcat ttgtatggta atttgtactt tacaaatact 3121 ttgatatatt ataactctat tggtctttga aacaaagcga tacagtgtag gtggtatcat 3181 tctctttctc actcagtgtg gcccagagtt gctcagaatt ggagcagagc ctgagacgta 3241 tctgcagatc ctgtcatcag ctggcaagtc caggagactg tgtcatttag agactgtgtt 3301 gttagttatc cctcaacatc ttctaaggtg gcaggaaata atattggaaa taacatttta 3361 aagtaaaaat tttaaagttt aaagaagagt tttgccactt aaacagggga gctttgtctg 342 1 gaaaatacac tgagttgaaa cacttcatcc ttggaaggat tatataagat gaacagttgt 34 1 gataaatgtg tagattagag ggatgtgaat gggcagttag tccagtgccc tcatttaaga 354 1 ggccaagatc ctgattcaga ggaggcatcc tttgcccaga gctgcttagc taatctgacc 360 1 aaatgttggg aaaaatgtct cacctaaccc actattcctt aattatggat tttgtgaaaa 366 1 acaatagaac atgttaatga gtaatttata ttagttcgat gtattacaat tttttagctt 372 1 taaattacag ttttcttata atgttgaaat gttttagaat cctttgaatc taagtatttg 378 1 tttcctaaat gaaacatttg tacaacattt gatgttttta cttatgaaat attctcctcc 384 1 cccaagaaaa tttaaacttt ttctctctat ttaaaagcta agaaatgttt taaaggaaaa 390 1 atgaaattat cttcctttag cttattttta aggtaaaaca gctttttact ctgttattgt 396 1 ggtaatggac agaatattac atacaaaaat attctgggag agctttttcc tagttggttt 402 1 taaatcattg tgccacctga aaggttttta gattttatag gagctaattt gtccaccagc 408 1 attaatgtaa cacagtgtag ttatgaaaat atattgaagg acaggaagtg gacacgaagt 414 1 gatttttgta acctgagcag ttaatgaatg tgccaacatt ttctaggaag ggacagcaag 420 1 aatattctgc tctgtagtta aaatactggc tggcttttga tgtcttcatg cttaattgtg 426 1 atcactttct tgcactgtga tgtttttacg tgaatatgtt gaagtagaag tctaccatat 432 1 tattttataa aatgttttct gtatggcaat aaactgaaaa catggatcaa cccttctttt 43 1 gaaaataaac tgagtcaatt tagcctttta aaaatatagt catctctttt aaatagaatc 444 1 ctcttccacc atcaaggctc aacattttgt aagcatccaa aaaattggta attagggggc 450 1 ttgcactaaa tttcactatc ttcagtagag aggaactgtt tggaacttag atttccaatg 456 1 tgtatattct aatggagaaa gcaagaggta gagtttgtat gtttgactta ccttagattt 462 1 ttattttcca tacatactgc aaatgattga cttgttgcat aaatgaagat cttctgttgt 468 1 gtgcttttca aacactgtaa ataaatttga aatttgaaaa aaaaaaaaaa aaaa (SEQ NO: 114) .

[0300] An exemplary amino acid sequence encoding PDK1 (NP 001265478.1 , isoform 1 precursor) comprises or consists of:

MRLARLLRGAALAGPGPGLRAAGFSRSFSSDSGSSPASERGVPGQVDFYARFSPSPLSMKQFLDFGSVNACEKTS FMFLRQELPVRLANIMKEISLLPDNLLRTPSVQLVQSWYIQSLQELLDFKDKSAEDAKAIYERPRRTWLQVSSLC CMACKMIFTDTVIRIRNRHNDVIPTMAQGVIEYKESFGVDPVTSQNVQYFLDRFYMSRISIRMLLNQHSLLFGGK GKGSPSHRKHIGSINPNCNVLEVIKDGYENARRLCDLYYINSPELELEELNAKSPGQPIQWYVPSHLYHMVFEL FKNAMRATMEHHANRGVYPPIQVHVTLGNEDLTVKMSDRGGGVPLRKIDRLFNYMYSTAPRPRVETSRAVPLAGF GYGLPISRLYAQYFQGDLKLYSLEGYGTDAVIYIKALSTDSIERLPVYNKAAWKHYNTNHEADDWCVPSREPKDM TTFRSA (SEQ ID NO: 115) .

[0301] An exemplary nucleic acid sequence encoding PDK1 (NM 002610.4 transcript variant 2) comprises or consists of:

1 ctccttcccg ctccgcgtcc cgcccagcgg cgcagggggc cgggctccgg ctaggagggt 61 gggggccgcg ccggtgacag ccgatccccg cccctgctgc ccgccacgtc cctcacgtac 121 cactcggcag aggcgcgggg aaacctggcg tactggctgt ggcttctcta gcgggactcg 181 gcatgaggct ggcgcggctg cttcgcggag ccgccttggc cggcccgggc ccggggctgc 241 gcgccgccgg cttcagccgc agcttcagct cggactcggg ctccagcccg gcgtccgagc 301 gcggcgttcc gggccaggtg gacttctacg cgcgcttctc gccgtccccg ctctccatga 361 agcagttcct ggacttcgga tcagtgaatg cttgtgaaaa gacctcattt atgtttctgc 421 ggcaagagtt gcctgtcaga ctggcaaata taatgaaaga aataagtctc cttccagata 481 atcttctcag gacaccatcc gttcaattgg tacaaagctg gtatatccag agtcttcagg 541 agcttcttga ttttaaggac aaaagtgctg aggatgctaa agctatttat gactttacag 601 atactgtgat acggatcaga aaccgacaca atgatgtcat tcccacaatg gcccagggtg 661 tgattgaata caaggagagc tttggggtgg atcctgtcac cagccagaat gttcagtact 721 ttttggatcg attctacatg agtcgcattt caattagaat gttactcaat cagcactctt 781 tattgtttgg tggaaaaggc aaaggaagtc catctcatcg aaaacacatt ggaagcataa 841 atccaaactg caatgtactt gaagttatta aagatggcta tgaaaatgct aggcgtctgt 901 gtgatttgta ttatattaac tctcccgaac tagaacttga agaactaaat gcaaaatcac 961 caggacagcc aatacaagtg gtttatgtac catcccatct ctatcacatg gtgtttgaac 1021 ttttcaagaa tgcaatgaga gccactatgg aacaccatgc caacagaggt gtttaccccc 1081 ctattcaagt tcatgtcacg ctgggtaatg aggatttgac tgtgaagatg agtgaccgag 1141 gaggtggcgt tcctttgagg aaaattgaca gacttttcaa ctacatgtat tcaactgcac 1201 caagacctcg tgttgagacc tcccgcgcag tgcctctggc tggttttggt tatggattgc 1261 ccatatcacg tctttacgca caatacttcc aaggagacct gaagctgtat tccctagagg 1321 gttacgggac agatgcagtt atctacatta aggctctgtc aacagactca atagaaagac 1381 tcccagtgta taacaaagct gcctggaagc attacaacac caaccacgag gctgatgact 1441 ggtgcgtccc cagcagagaa cccaaagaca tgacgacgtt ccgcagtgcc tagacacact 1501 tgggacatcg gaaaatccaa atgtggcttt tgtattaaat ttggaaggta tggtgttcag 1561 aactatatta taccaagtac tttatttatc gttttcacaa aactatttga gtagaataaa 1621 tggaaactga attccatttg tgcccgttaa acctcctaaa ggatgaaatt gcacctattt 1681 tacacttata ttttcacagt taattgaaca tatttttaaa caactgtagt tttgggcaac 1741 ttttcacttt gtggtagact tcagaagtgt ggaaatcttc gggtttctat aggaaactag 1801 tttttttttt ttaagaaata ctttcattta tgtttgctag aaacattttc taaatgatag 1861 tgattagctg gttagccatc ttcctgttat ttggaggagt tctgccatct tttattcggt 1921 agtgacagct gtaatatggt cttcatgttt atcagtgact tgactacaag taaagcagaa 1981 aacagttggc ctgtaatcac agaaccagcc acccttcggc gtctacatgc attgtcttag 2041 ctctgaggtt aatttaccat ttttaaattt tattgtaaag aagtgtaatg actagctctc 2101 tgtggatcta tgccaaaatc atgggccatc ttttctaagt gtacttctga ttaatgcaag 2161 gggaaatttt tatactgaaa acaaacaaac aaactagcag ctactaaaat agagaagaaa 2221 ttgagggcaa agtaatatgt ctccaaaact gaactgattg cttgttgaga ttacctagaa 2281 agcttttgga aaaaaataga gcttttctgc atcctactcc agatacactg aatcggaatc 2341 cctagggcta gagcctagaa atctcacttt ttaaaatgct tccaaggtaa gtctgatgcc 2401 taccctaggt tgggaaccac tctttcaaag taaacagtga tgacacagca tttgctaaag 2461 taacatctgt aggttttggt ttccacctat ttaaagtcag atttatagac tcgaggagac 2521 agaaactgaa tcccacacct ggtgcaatta gaagcataat tagaagcaga agaacaaaat 2581 gccacgtaac caaagcatca gagccatcat tgcacgtgtc tttttttctt ttttcttttt 2641 tttttttcaa gacagggtct cgctcttttg cccaggatgg agtacagtgg catggtcaag 2701 gctcactgca gcttcaatct tctgggctca agtaatcctt ccacctcagc ctcccatata 2761 gctggaacta cagttgtgca ctaccacacc cagctaattt tttgatttct tgtggagatg 2821 aggtctcagt atgttcccag gctagtgttg aactcctgag ctcaagaaat cctcctgcct 2881 gagtctctga aagtgctggg attacaggcg tgagccacca cacatggcct attgcacaag 2941 tcttgacaaa caacatatat tttctaaaac tatccagatt tcattatcag ggaaaagttt 3001 gcttaggttt attacagcag tccttggcat ttgtatggta atttgtactt tacaaatact 3061 ttgatatatt ataactctat tggtctttga aacaaagcga tacagtgtag gtggtatcat 3121 tctctttctc actcagtgtg gcccagagtt gctcagaatt ggagcagagc ctgagacgta 3181 tctgcagatc ctgtcatcag ctggcaagtc caggagactg tgtcatttag agactgtgtt 3241 gttagttatc cctcaacatc ttctaaggtg gcaggaaata atattggaaa taacatttta 3301 aagtaaaaat tttaaagttt aaagaagagt tttgccactt aaacagggga gctttgtctg 3361 gaaaatacac tgagttgaaa cacttcatcc ttggaaggat tatataagat gaacagttgt 3421 gataaatgtg tagattagag ggatgtgaat gggcagttag tccagtgccc tcatttaaga 3481 ggccaagatc ctgattcaga ggaggcatcc tttgcccaga gctgcttagc taatctgacc 3541 aaatgttggg aaaaatgtct cacctaaccc actattcctt aattatggat tttgtgaaaa 3601 acaatagaac atgttaatga gtaatttata ttagttcgat gtattacaat tttttagctt 3661 taaattacag ttttcttata atgttgaaat gttttagaat cctttgaatc taagtatttg 3721 tttcctaaat gaaacatttg tacaacattt gatgttttta cttatgaaat attctcctcc 3781 cccaagaaaa tttaaacttt ttctctctat ttaaaagcta agaaatgttt taaaggaaaa 3841 atgaaattat cttcctttag cttattttta aggtaaaaca gctttttact ctgttattgt 3901 ggtaatggac agaatattac atacaaaaat attctgggag agctttttcc tagttggttt 3961 taaatcattg tgccacctga aaggttttta gattttatag gagctaattt gtccaccagc 4021 attaatgtaa cacagtgtag ttatgaaaat atattgaagg acaggaagtg gacacgaagt 4081 gatttttgta acctgagcag ttaatgaatg tgccaacatt ttctaggaag ggacagcaag 4141 aatattctgc tctgtagtta aaatactggc tggcttttga tgtcttcatg cttaattgtg 4201 atcactttct tgcactgtga tgtttttacg tgaatatgtt gaagtagaag tctaccatat 4261 tattttataa aatgttttct gtatggcaat aaactgaaaa catggatcaa cccttctttt 4321 gaaaataaac tgagtcaatt tagcctttta aaaatatagt catctctttt aaatagaatc 4381 ctcttccacc atcaaggctc aacattttgt aagcatccaa aaaattggta attagggggc 4441 ttgcactaaa tttcactatc ttcagtagag aggaactgtt tggaacttag atttccaatg 4501 tgtatattct aatggagaaa gcaagaggta gagtttgtat gtttgactta ccttagattt 4561 ttattttcca tacatactgc aaatgattga cttgttgcat aaatgaagat cttctgttgt 4621 gtgcttttca aacactgtaa ataaatttga aatttgaaaa aaaaaaaaaa aaaa (SEQ ID NO: 116) .

[0302] An exemplary amino acid sequence encoding PDK1 (NP 002601.1, isoform 2 precursor) comprises or consists of:

MRLARLLRGAALAGPGPGLRAAGFSRSFSSDSGSSPASERGVPGQVDFYARFSPSPLSMKQFLDFGSVNACEKTS FMFLRQELPVRLANIMKEISLLPDNLLRTPSVQLVQSWYIQSLQELLDFKDKSAEDAKAIYDFTDTVIRIRNRHN DVIPTMAQGVIEYKESFGVDPVTSQNVQYFLDRFYMSRISIRMLLNQHSLLFGGKGKGSPSHRKHIGSINPNCNV LEVIKDGYENARRLCDLYYINSPELELEELNAKSPGQPIQWYVPSHLYHMVFELFKNAMRATMEHHANRGVYPP IQVHVTLGNEDLTVKMSDRGGGVPLRKIDRLFNYMYSTAPRPRVETSRAVPLAGFGYGLPISRLYAQYFQGDLKL YSLEGYGTDAVIYIKALSTDSIERLPVYNKAAWKHYNTNHEADDWCVPSREPKDMTTFRSA (SEQ ID NO: 117) .

[0303] An exemplary nucleic acid sequence encoding PDK1 (NR_103731.1, transcript variant 3) comprises or consists of:

1 ataatatgct cctttttcag gtaaagagac ggaggctcag agaggttaaa cagctcactc

61 aaaggcacag agccagtaca tggcagtaca tctcttctcc cggggccgcc gtcgcggtga 121 tactatttag ggccacacgt cccagtgttc agctttcgta tttacgtact actgtttggc 1 1 aagcggggac tcctgaagct ctctgaccct ggaaaatgcg tggcttgcgt cacagaggag

241 cgtttctgga acgcgctcgc agcacgacac cgcggtgtgt gcaagcggaa cgccgccctg 301 tccttgagcc ttttggctga gattgggagg gcagaggaag caggaaggat cagtgaatgc 361 ttgtgaaaag acctcattta tgtttctgcg gcaagagttg cctgtcagac tggcaaatat 421 aatgaaagaa ataagtctcc ttccagataa tcttctcagg acaccatccg ttcaattggt 481 acaaagctgg tatatccaga gtcttcagga gcttcttgat tttaaggaca aaagtgctga 541 ggatgctaaa gctatttatg actttacaga tactgtgata cggatcagaa accgacacaa 601 tgatgtcatt cccacaatgg cccagggtgt gattgaatac aaggagagct ttggggtgga 661 tcctgtcacc agccagaatg ttcagtactt tttggatcga ttctacatga gtcgcatttc 721 aattagaatg ttactcaatc agcactcttt attgtttggt ggaaaaggca aaggaagtcc 781 atctcatcga aaacacattg gaagcataaa tccaaactgc aatgtacttg aagttattaa 841 agatggctat gaaaatgcta ggcgtctgtg tgatttgtat tatattaact ctcccgaact 901 agaacttgaa gaactaaatg caaaatcacc aggacagcca atacaagtgg tttatgtacc 961 atcccatctc tatcacatgg tgtttgaact tttcaagaat gcaatgagag ccactatgga 1021 acaccatgcc aacagaggtg tttacccccc tattcaagtt catgtcacgc tgggtaatga 1081 ggatttgact gtgaagatga gtgaccgagg aggtggcgtt cctttgagga aaattgacag 1141 acttttcaac tacatgtatt caactgcacc aagacctcgt gttgagacct cccgcgcagt 1201 gcctctggct ggttttggtt atggattgcc catatcacgt ctttacgcac aatacttcca 1261 aggagacctg aagctgtatt ccctagaggg ttacgggaca gatgcagtta tctacattaa 1321 ggctctgtca acagactcaa tagaaagact cccagtgtat aacaaagctg cctggaagca 1381 ttacaacacc aaccacgagg ctgatgactg gtgcgtcccc agcagagaac ccaaagacat 1441 gacgacgttc cgcagtgcct agacacactt gggacatcgg aaaatccaaa tgtggctttt 1501 gtattaaatt tggaagattc ttcagttttg ggacttggac tggctttcct tgcccctcag 1561 cttgcagatg gcctgttgtg ggaccttgtg atcatgaact cctcctccca catctgatgg 1621 agctaccaat catcagatct cctctgcctc tggggtgcgt ctcaggctgg ccaatcacgt 1681 tcttcatcca cgtggactat gactggccct agggagaaaa catggagata tgaatgactg 1741 tgtggagcag aacccacctt ctcccagctc agctttggac tgtgaggtga cagaaataaa 1801 catttgttgt gctaagccac tgagattttg agtcataaca gctgttagca tcaatgattc 1861 tgactaatac agtagcccac catatgattg ttcactagta tgtctaaaat tccagggctg 1921 tgatcaacca ctctccccgt ccccactctg acagttaatt gacctgtgaa tttgcctttt 19 1 atgtaaattc tctttctatc cttactgcat tattgtattt cagcctttgg tttcctgaca 2041 gatgtaattg tcctgtgtgt cctttctcca ggcagagtga tgttcctgga atgttcatct 2101 aatcatatca tgcatctgtt tgtaactttc tttcttcaac cttatctcct gctagtccct 2161 gctatacctc tctatgcttg gaacatattt ttctttagcc cttgttttcc aaggactgaa 2221 tctgtctcat cttttggggg ctctgtgtaa atattccttt atccagtaag cctgcc ID NO: 118) . [0304] An exemplary nucleic acid sequence encoding PDKl (NR_103729.1, transcript variant 4) comprises or consists of:

1 ctccttcccg ctccgcgtcc cgcccagcgg cgcagggggc cgggctccgg ctaggagggt 61 gggggccgcg ccggtgacag ccgatccccg cccctgctgc ccgccacgtc cctcacgtac 121 cactcggcag aggcgcgggg aaacctggcg tactggctgt ggcttctcta gcgggactcg 181 gcatgaggct ggcgcggctg cttcgcggag ccgccttggc cggcccgggc ccggggctgc 241 gcgccgccgg cttcagccgc agcttcagct cggactcggg ctccagcccg gcgtccgagc 301 gcggcgttcc gggccaggtg gacttctacg cgcgcttctc gccgtccccg ctctccatga 361 agcagttcct ggacttcgga tcagtgaatg cttgtgaaaa gacctcattt atgtttctgc 421 ggcaagagtt gcctgtcaga ctggcaaata taatgaaaga aataagtctc cttccagata 481 atcttctcag gacaccatcc gttcaattgg tacaaagctg gtatatccag agtcttcagg 541 agcttcttga ttttaaggac aaaagtgctg aggatgctaa agctatttat gactttacag 601 atactgtgat acggatcaga aaccgacaca atgatgtcat tcccacaatg gcccagggtg 661 tgattgaata caaggagagc tttggggtgg atcctgtcac cagccagaat gttcagtact 721 ttttggatcg attctacatg agtcgcattt caattagaat gttactcaat cagcactctt 781 tattgtttgg tggaaaaggc aaaggaagtc catctcatcg aaaacacatt ggaagcataa 841 atccaaactg caatgtactt gaagttatta aagatggcta tgaaaatgct aggcgtctgt 901 gtgatttgta ttatattaac tctcccgaac tagaacttga agaactaaat gcaaaatcac 961 caggacagcc aatacaagtg gtttatgtac catcccatct ctatcacatg gtgtttgaac 1021 ttttcaagaa tgcaatgaga gccactatgg aacaccatgc caacagaggt gtttaccccc 1081 ctattcaagt tcatgtcacg ctgggtaatg aggatttgac tgtgaagatg agtgaccgag 1141 gaggtggcgt tcctttgagg aaaattgaca gacttttcaa ctacatgtat tcaactgcac 1201 caagacctcg tgttgagacc tcccgcgcag tgcctctggc tggttttggt tatggattgc 1261 ccatatcacg tctttacgca caatacttcc aaggagacct gaagctgtat tccctagagg 1321 gttacgggac agatgcagtt atctacatta aggctctgtc aacagactca atagaaagac 1381 tcccagtgta taacaaagct gcctggaagc attacaacac caaccacgag gctgatgact 1441 ggtgcgtccc cagcagagaa cccaaagaca tgacgacgtt ccgcagtgcc tagacacact 1501 tgggacatcg gaaaatccaa atgtggcttt tgtattaaat ttggaagtgt ggcccagagt 1561 tgctcagaat tggagcagag cctgagacgt atctgcagat cctgtcatca gctggcaagt 1621 ccaggagact gtgtcattta gagactgtgt tgttagttat ccctcaacat cttctaaggt 1681 ggcaggaaat aatattggaa ataacatttt aaagtaaaaa ttttaaagtt taaagaagag 1741 ttttgccact taaacagggg agctttgtct ggaaaataca ctgagttgaa acacttcatc 1801 cttggaagga ttatataaga tgaacagttg tgataaatgt gtagattaga gggatgtgaa 1861 tgggcagtta gtccagtgcc ctcatttaag aggccaagat cctgattcag aggaggcatc 1921 ctttgcccag agctgcttag ctaatctgac caaatgttgg gaaaaatgtc tcacctaacc 1981 cactattcct taattatgga ttttgtgaaa aacaatagaa catgttaatg agtaatttat 2041 attagttcga tgtattacaa ttttttagct ttaaattaca gttttcttat aatgttgaaa 2101 tgttttagaa tcctttgaat ctaagtattt gtttcctaaa tgaaacattt gtacaacatt 2161 tgatgttttt acttatgaaa tattctcctc ccccaagaaa atttaaactt tttctctcta 2221 tttaaaagct aagaaatgtt ttaaaggaaa aatgaaatta tcttccttta gcttattttt 2281 aaggtaaaac agctttttac tctgttattg tggtaatgga cagaatatta catacaaaaa 2341 tattctggga gagctttttc ctagttggtt ttaaatcatt gtgccacctg aaaggttttt 2401 agattttata ggagctaatt tgtccaccag cattaatgta acacagtgta gttatgaaaa 2461 tatattgaag gacaggaagt ggacacgaag tgatttttgt aacctgagca gttaatgaat 2521 gtgccaacat tttctaggaa gggacagcaa gaatattctg ctctgtagtt aaaatactgg 2581 ctggcttttg atgtcttcat gcttaattgt gatcactttc ttgcactgtg atgtttttac 2641 gtgaatatgt tgaagtagaa gtctaccata ttattttata aaatgttttc tgtatggcaa 2701 taaactgaaa acatggatca acccttcttt tgaaaataaa ctgagtcaat ttagcctttt 2761 aaaaatatag tcatctcttt taaatagaat cctcttccac catcaaggct caacattttg 2821 taagcatcca aaaaattggt aattaggggg cttgcactaa atttcactat cttcagtaga 2881 gaggaactgt ttggaactta gatttccaat gtgtatattc taatggagaa agcaagaggt 2941 agagtttgta tgtttgactt accttagatt tttattttcc atacatactg caaatgattg 3001 acttgttgca taaatgaaga tcttctgttg tgtgcttttc aaacactgta aataaatttg 3061 aaatttgaaa aaaaaaaaaa aaaaa (SEQ ID NO: 119)

[0305] An exemplary nucleic acid sequence encoding PGR (NM_001202474.3 transcript variant 1) comprises or consists of:

1 agctgaaggc aaagggtccc cgggctcccc acgtggcggg cggcccgccc tcccccgagg 61 tcggatcccc actgctgtgt cgcccagccg caggtccgtt cccggggagc cagacctcgg 121 acaccttgcc tgaagtttcg gccataccta tctccctgga cgggctactc ttccctcggc 181 cctgccaggg acaggacccc tccgacgaaa agacgcagga ccagcagtcg ctgtcggacg 241 tggagggcgc atattccaga gctgaagcta caaggggtgc tggaggcagc agttctagtc 301 ccccagaaaa ggacagcgga ctgctggaca gtgtcttgga cactctgttg gcgccctcag 361 gtcccgggca gagccaaccc agccctcccg cctgcgaggt caccagctct tggtgcctgt 421 ttggccccga acttcccgaa gatccaccgg ctgcccccgc cacccagcgg gtgttgtccc 481 cgctcatgag ccggtccggg tgcaaggttg gagacagctc cgggacggca gctgcccata 541 aagtgctgcc ccggggcctg tcaccagccc ggcagctgct gctcccggcc tctgagagcc 601 ctcactggtc cggggcccca gtgaagccgt ctccgcaggc cgctgcggtg gaggttgagg 661 aggaggatgg ctctgagtcc gaggagtctg cgggtccgct tctgaagggc aaacctcggg 721 ctctgggtgg cgcggcggct ggaggaggag ccgcggctgt cccgccgggg gcggcagcag 781 gaggcgtcgc cctggtcccc aaggaagatt cccgcttctc agcgcccagg gtcgccctgg 841 tggagcagga cgcgccgatg gcgcccgggc gctccccgct ggccaccacg gtgatggatt 901 tcatccacgt gcctatcctg cctctcaatc acgccttatt ggcagcccgc actcggcagc 961 tgctggaaga cgaaagttac gacggcgggg ccggggctgc cagcgccttt gccccgccgc 1021 ggagttcacc ctgtgcctcg tccaccccgg tcgctgtagg cgacttcccc gactgcgcgt 1081 acccgcccga cgccgagccc aaggacgacg cgtaccctct ctatagcgac ttccagccgc 1141 ccgctctaaa gataaaggag gaggaggaag gcgcggaggc ctccgcgcgc tccccgcgtt 1201 cctaccttgt ggccggtgcc aaccccgcag ccttcccgga tttcccgttg gggccaccgc 1261 ccccgctgcc gccgcgagcg accccatcca gacccgggga agcggcggtg acggccgcac 1321 ccgccagtgc ctcagtctcg tctgcgtcct cctcggggtc gaccctggag tgcatcctgt 1381 acaaagcgga gggcgcgccg ccccagcagg gcccgttcgc gccgccgccc tgcaaggcgc 1441 cgggcgcgag cggctgcctg ctcccgcggg acggcctgcc ctccacctcc gcctctgccg 1501 ccgccgccgg ggcggccccc gcgctctacc ctgcactcgg cctcaacggg ctcccgcagc 1561 tcggctacca ggccgccgtg ctcaaggagg gcctgccgca ggtctacccg ccctatctca 1621 actacctgag gccggattca gaagccagcc agagcccaca atacagcttc gagtcattac 1681 ctcagaagat ttgtttaatc tgtggggatg aagcatcagg ctgtcattat ggtgtcctta 1741 cctgtgggag ctgtaaggtc ttctttaaga gggcaatgga agggcagcac aactacttat 1801 gtgctggaag aaatgactgc atcgttgata aaatccgcag aaaaaactgc ccagcatgtc 1861 gccttagaaa gtgctgtcag gctggcatgg tccttggagg tcgaaaattt aaaaagttca 1921 ataaagtcag agttgtgaga gcactggatg ctgttgctct cccacagcca gtgggcgttc 1981 caaatgaaag ccaagcccta agccagagat tcactttttc accaggtcaa gacatacagt 2041 tgattccacc actgatcaac ctgttaatga gcattgaacc agatgtgatc tatgcaggac 2101 atgacaacac aaaacctgac acctccagtt ctttgctgac aagtcttaat caactaggcg 2161 agaggcaact tctttcagta gtcaagtggt ctaaatcatt gccaggtttt cgaaacttac 2221 atattgatga ccagataact ctcattcagt attcttggat gagcttaatg gtgtttggtc 2281 taggatggag atcctacaaa cacgtcagtg ggcagatgct gtattttgca cctgatctaa 2341 tactaaatga acagcggatg aaagaatcat cattctattc attatgcctt accatgtggc 2401 agatcccaca ggagtttgtc aagcttcaag ttagccaaga agagttcctc tgtatgaaag 2461 tattgttact tcttaataca attcctttgg aagggctacg aagtcaaacc cagtttgagg 2521 agatgaggtc aagctacatt agagagctca tcaaggcaat tggtttgagg caaaaaggag 2581 ttgtgtcgag ctcacagcgt ttctatcaac ttacaaaact tcttgataac ttgcatgatc 2641 ttgtcaaaca acttcatctg tactgcttga atacatttat ccagtcccgg gcactgagtg 2701 ttgaatttcc agaaatgatg tctgaagtta ttgctgcaca attacccaag atattggcag 2761 ggatggtgaa accccttctc tttcataaaa agtgaatgtc atctttttct tttaaagaat 2821 taaattttgt ggtatgtctt tttgttttgg tcaggattat gaggtcttga gtttttataa 2881 tgttcttctg aaagccttac atttataaca tcatagtgtg taaatttaaa agaaaaattg 2941 tgaggttcta attattttct tttataaagt ataattagaa tgtttaactg ttttgtttac 3001 ccatattttc ttgaagaatt tacaagattg aaaaagtact aaaattgtta aagtaaacta 3061 tcttatccat attatttcat accatgtagg tgaggatttt taacttttgc atctaacaaa 3121 tcatcgactt aagagaaaaa atcttacatg taataacaca aagctattat atgttatttc 3181 taggtaactc cctttgtgtc aattatattt ccaaaaatga acctttaaaa tggtatgcaa 3241 aattttgtct atatatattt gtgtgaggag gaaattcata actttcctca gattttcaaa 3301 agtattttta atgcaaaaaa tgtagaaaga gtttaaaacc actaaaatag attgatgttc 3361 ttcaaactag gcaaaacaac tcatatgtta agaccatttt ccagattgga aacacaaatc 3421 tcttaggaag ttaataagta gattcatatc attatgcaaa tagtattgtg ggttttgtag 3481 gtttttaaaa taaccttttt tggggagaga attgtcctct aatgaggtat tgcgagtgga 3541 cataagaaat cagaagatta tggcctaact gtactcctta ccaactgtgg catgctgaaa 3601 gttagtcact cttactgatt ctcaattctc tcacctttga aagtagtaaa atatctttcc 3661 tgccaattgc tcctttgggt cagagcttat taacatcttt tcaaatcaaa ggaaagaaga 3721 aagggagagg aggaggaggg aggtatcaat tcacatacct ttctcctctt tatcctccac 3781 tatcatgaat tcatattatg tttcagccat gcaaatcttt ttaccatgaa atttcttcca 3841 gaattttccc cctttgacac aaattccatg catgtttcaa ccttcgagac tcagccaaat 3901 gtcatttctg taaaatcttc cctgagtctt ccaagcagta atttgccttc tcctagagtt 3961 tacctgccat tttgtgcaca tttgagttac agtagcatgt tattttacaa ttgtgactct 4021 cctgggagtc tgggagccat ataaagtggt caatagtgtt tgctgactga gagttgaatg 4081 acattttctc tctgtcttgg tattactgta gatttcgatc attctttggt tacatttctg 4141 catatttctg tacccatgac tttatcactt tcttctccca tgctttatct ccatcaatta 4201 tcttcattac ttttaaattt tccacctttg cttcctactt tgtgagatct ctccctttac 4261 tgactataac atagaagaat agaagtgtat tttatgtgtc ttaaggacaa tactttagat 4321 tccttgttct aagtttttaa actgaatgaa tggaatatta tttctctccc taagcaaaat 4381 tccacaaaac aattatttct tatgtttatg tagccttaaa ttgttttgta ctgtaaacct 4441 cagcataaaa actttcttca tttctaattt cattcaacaa atattgattg aatacctggt 4501 attagcacaa gaaaaatgtg ctaataagcc ttatgagaat ttggagctga agaaagacat 4561 ataactcagg aaagttacag tccagtagta ggtataaatt acagtgcctg ataaataggc 4621 attttaatat ttgtacactc aacgtatact aggtaggtgc aaaacattta catataattt 4681 tactgatacc catgcagcac aaaggtacta actttaaata ttaaataaca cctttatgtg 4741 tcagtaattc atttgcatta aatcttattg aaaaggcttt caatatattt tccccacaaa 4801 tgtcatccca agaaaaaagt atttttaaca tctcccaaat ataatagtta caggaaatct 4861 acctctgtga gagtgacacc tctcagaatg aactgtgtga cacaagaaaa tgaatgtagg 4921 tctatccaaa aaaaacccca agaaacaaaa acaatattat tagcccttta tgcttaagtg 4981 atggactcag ggaacagttg atgttgtgat cattttatta tctgattctt gttactttga 5041 attaaaccaa tattttgatg atataaatca tttccaccag catatattta atttccataa 5101 taactttaaa attttctaat ttcactcaac tatgagggaa tagaatgtgg tggccacagg 5161 tttggctttt gttaaaatgt ttgatatctt cgatgttgat ctctgtctgc aatgtagatg 5221 tctaaacact aggatttaat atttaaggct aagctttaaa aataaagtac ctttttaaaa 5281 agaatatggc ttcaccaaat ggaaaatacc taatttctaa atctttttct ctacaaagtc 5341 ctatctacta atgtctccat tactatttag tcatcataac cattatcttc attttacatg 5401 tcgtgttctt tctggtagct ctaaaatgac actaaatcat aagaagacag gttacatatc 5461 aggaaatact tgaaggttac tgaaatagat tcttgagtta atgaaaatat tttctgtaaa 5521 aaggtttgaa aagccatttg agtctaaagc attatacctc cattatcagt agttatgtga 5581 caattgtgtg tgtgtttaat gtttaaagat gtggcacttt ttaataaggc aatgctatgc 5641 tattttttcc catttaacat taagataatt tattgctata cagatgatat ggaaatatga 5701 tgaacaatat tttttttgcc aaaactatgc cttgtaagta gccatggaat gtcaacctgt 5761 aacttaaatt atccacagat agtcatgtgt ttgatgatgg gcactgtgga gataactgac 5821 ataggactgt gccccccttc tctgccactt actagctgga tgagattaag caagtcattt 5881 aactgctctg attaaacctg cctttcccaa gtgctttgta atgaatagaa atggaaacca 5941 aaaaaaacgt atacaggcct tcagaaatag taattgctac tattttgttt tcattaagcc 6001 atagttctgg ctataatttt atcaaactca ccagctatat tctacagtga aagcaggatt 6061 ctagaaagtc tcactgtttt atttatgtca ccatgtgcta tgatatattt ggttgaattc 6121 atttgaaatt agggctggaa gtattcaagt aatttcttct gctgaaaaaa tacagtgttt 6181 tgagtttagg gcctgtttta tcaaagttct aaagagccta tcactcttcc attgtagaca 6241 ttttaaaata atgacactga ttttaacatt tttaagtgtc tttttagaac agagagcctg 6301 actagaacac agcccctcca aaaacccatg ctcaaattat ttttactatg gcagcaattc 6361 cacaaaaggg aacaatgggt ttagaaatta caatgaagtc atcaacccaa aaaacatccc 6421 tatccctaag aaggttatga tataaaatgc ccacaagaaa tctatgtctg ctttaatctg 6481 tcttttattg ctttggaagg atggctatta catttttagt ttttgctgtg aatacctgag 6541 cagtttctct catccatact tatccttcac acatcagaag tcaggataga atatgaatca 6601 ttttaaaaac ttttacaact ccagagccat gtgcataaga agcattcaaa acttgccaaa 6661 acatacattt tttttcaaat ttaaagatac tctatttttg tattcaatag ctcaacaact 6721 gtggtcccca ctgataaagt gaagtggaca aggagacaag taatggcata agtttgtttt 6781 tcccaaagta tgcctgttca atagccattg gatgtgggaa atttctacat ctcttaaaat 6841 tttacagaaa atacatagcc agatagtcta gcaaaagttc accaagtcct aaattgctta 6901 tccttacttc actaagtcat gaaatcattt taatgaaaag aacatcacct aggttttgtg 6961 gtttcttttt ttcttattca tggctgagtg aaaacaacaa tctctgtttc tccctagcat 7021 ctgtggacta tttaatgtac cattattcca cactctatgg tccttactaa atacaaaatt 7081 gaacaaaaag cagtaaaaca actgactctt cacccatatt ataaaatata atccaagcca 7141 gattagtcaa catccataag atgaatccaa gctgaactgg gcctagatta ttgagttcag 7201 gttggatcac atccctattt attaataaac ttaggaaaga aggccttaca gaccatcagt 7261 tagctggagc taatagaacc tacacttcta aagttcggcc tagaatcaat gtggccttaa 7321 aagctgaaaa gaagcaggaa agaacagttt tcttcaataa tttgtccacc ctgtcactgg 7381 agaaaattta agaatttggg ggtgttggta gtaagttaaa cacagcagct gttcatggca 7441 gaaattattc aatacatacc ttctctgaat atcctataac caaagcaaag aaaaacacca 7501 aggggtttgt tctcctcctt ggagttgacc tcattccaag gcagagctca ggtcacaggc 7561 acaggggctg cgcccaagct tgtccgcagc cttatgcagc tgtggagtct ggaagactgt 7621 tgcaggactg ctggcctagt cccagaatgt cagcctcatt ttcgatttac tggctcttgt 7681 tgctgtatgt catgctgacc ttattgttaa acacaggttt gtttgctttt tttccactca 7741 tggagacatg ggagaggcat tatttttaag ctggttgaaa gctttaaccg ataaagcatt 7801 tttagagaaa tgtgaatcag gcagctaaga aagcatactc tgtccattac ggtaaagaaa 7861 atgcacagat tattaactct gcagtgtggc attagtgtcc tggtcaatat tcggatagat 7921 atgaataaaa tatttaaatg gtattgtaaa tagttttcag gacatatgct atagcttatt 7981 tttattatct tttgaaattg ctcttaatac atcaaatcct gatgtattca atttatcaga 8041 tataaattat tctaaatgaa gcccagttaa atgtttttgt cttgtcagtt atatgttaag 8101 tttctgatct ctttgtctat gacgtttact aatctgcatt tttactgtta tgaattattt 8161 tagacagcag tggtttcaag ctttttgcca ctaaaaatac cttttatttt ctcctccccc 8221 agaaaagtct ataccttgaa gtatctatcc accaaactgt acttctatta agaaatagtt 8281 attgtgtttt cttaatgttt tgttattcaa agacatatca atgaaagctg ctgagcagca 8341 tgaataacaa ttatatccac acagatttga tatattttgt gcagccttaa cttgatagta 8401 taaaatgtca ttgcttttta aataatagtt agtcaatgga cttctatcat agctttccta 8461 aactaggtta agatccagag ctttggggtc ataatatatt acatacaatt aagttatctt 8521 tttctaaggg ctttaaaatt catgagaata accaaaaaag gtatgtggag agttaataca 8581 aacataccat attcttgttg aaacagagat gtggctctgc ttgttctcca taaggtagaa 8641 atactttcca gaatttgcct aaactagtaa gccctgaatt tgctatgatt agggatagga 8701 agagattttc acatggcaga ctttagaatt cttcacttta gccagtaaag tatctccttt 8761 tgatcttagt attctgtgta ttttaacttt tctgagttgt gcatgtttat aagaaaaatc 8821 agcacaaagg gtttaagtta aagccttttt actgaaattt gaaagaaaca gaagaaaata 8881 tcaaagttct ttgtattttg agaggattaa atatgattta caaaagttac atggagggct 8941 ctctaaaaca ttaaattaat tattttttgt tgaaaagtct tactttaggc atcattttat 9001 tcctcagcaa ctagctgtga agcctttact gtgctgtatg ccagtcactc tgctagattg 9061 tggagattac cagtgttccc gtcttctccg agcttagagt tggatgggga ataaagacag 9121 gtaaacagat agctacaata ttgtactgtg aatgcttatg ctggaggaag tacagggaac 9181 tattggagca cctaagagga gcacctacct tgaatttagg ggttagcaga ggcatcctga 9241 aaaaagtcaa agctaagcca caatctataa gcagtttagg aattagcaga acgtgcgtgg 9301 tgaggagatg ccaaaggcaa gaagagaaga gtattccaaa caggagggat tccaaagaga 9361 gaagagtatc ccaaacaaca tttgcacaaa cctgatgggg agagagaatg tggggtgggg 9421 atggatgatg agactgaaga agaaagccag gtctagataa tcagtggcct tgtacaccat 9481 gttaaagagt gtagacttga ttctgttgta aacaggaaag cagcacaatt catatgaata 9541 ttttagaaga ctcccactgg aatatggaga ataaagttgg agatgactaa tcctggaagc 9601 agggagaaca tttttgagga agttgcacta ttttggtgaa aatgatgatc ataaacatga 9661 agaattgtag gtgatcatga cctcctctct aattttccag aagggttttg gaagatataa 9721 cataggaaca ttgacaggac tgacgaaagg agatgaaata caccatataa attgtcaaac 9781 acaaggccag atgtctaatt attttgctta tgtgttgaaa ttacaaattt ttcatcagga 9841 aaccaaaaac tacaaaactt agttttccca agtcccagaa ttctatctgt ccaaacaatc 9901 tgtaccactc cacctatatc cctacctttg catgtctgtc caacctcaaa gtccaggtct 9961 atacacacgg gtaagactag agcagttcaa gtttcagaaa atgagaaaga ggaactgagt 10021 tgtgctgaac ccatacaaaa taaacacatt ctttgtatag attcttggaa cctcgagagg 10081 aattcaccta actcataggt atttgatggt atgaatccat ggctgggctc ggcttttaaa 10141 aagccttatc tgggattcct tctatggaac caagttccat caaagcccat ttaaaagcct 10201 acattaaaaa caaaattctt gctgcattgt atacaaataa tgatgtcatg atcaaataat 10261 cagatgccat tatcaagtgg aattacaaaa tggtataccc actccaaaaa aaaaaaaaaa 10321 gctaaattct cagtagaaca ttgtgacttc atgagccctc cacagccttg gagctgagga 10381 gggagcactg gtgagcagta ggttgaagag aaaacttggc gcttaataat ctatccatgt 10441 tttttcatct aaaagagcct tctttttgga ttaccttatt caatttccat caaggaaatt 10501 gttagttcca ctaaccagac agcagctggg aaggcagaag cttactgtat gtacatggta 10561 gctgtgggaa ggaggtttct ttctccaggt cctcactggc catacaccag tcccttgtta 10621 gttatgcctg gtcatagacc cccgttgcta tcatctcata tttaagtctt tggcttgtga 10681 atttatctat tctttcagct tcagcactgc agagtgctgg gactttgcta acttccattt 10741 cttgctggct tagcacattc ctcataggcc cagctctttt ctcatctggc cctgctgtgg 10801 agtcaccttg ccccttcagg agagccatgg cttaccactg cctgctaagc ctccactcag 10861 ctgccaccac actaaatcca agcttctcta agatgttgca gactttacag gcaagcataa 10921 aaggcttgat cttcctggac ttccctttac ttgtctgaat ctcacctcct tcaactttca 10981 gtctcagaat gtaggcattt gtcctctttg ccctacatct tccttcttct gaatcatgaa 11041 agcctctcac ttcctcttgc tatgtgctgg aggcttctgt caggttttag aatgagttct 11101 catctagtcc tagtagcttt tgatgcttaa gtccaccttt taaggatacc tttgagattt 11161 agaccatgtt tttcgcttga gaaagcccta atctccagac ttgcctttct gtggatttca 11221 aagaccaact gaggaagtca aaagctgaat gttgactttc tttgaacatt tccgctataa 11281 caattccaat tctcctcaga gcaatatgcc tgcctccaac tgaccaggag aaaggtccag 11341 tgccaaagag aaaaacacaa agattaatta tttcagttga gcacatactt tcaaagtggt 11401 ttgggtattc atatgaggtt ttctgtcaag agggtgagac tcttcatcta tccatgtgtg 11461 cctgacagtt ctcctggcac tggctggtaa cagatgcaaa actgtaaaaa ttaagtgatc 11521 atgtatttta acgatatcat cacatactta ttttctatgt aatgttttaa atttccccta 11581 acatactttg actgttttgc acatggtaga tattcacatt tttttgtgtt gaagttgatg 11641 caatcttcaa agttatctac cccgttgctt attagtaaaa ctagtgttaa tacttggcaa 11701 gagatgcagg gaatctttct catgactcac gccctattta gttattaatg ctactaccct 11761 attttgagta agtagtaggt ccctaagtac attgtccaga gttatacttt taaagatatt 11821 tagccccata tacttcttga atctaaagtc atacaccttg ctcctcattt ctgagtggga 11881 aagacatttg agagtatgtt gacaattgtt ctgaaggttt ttgccaagaa ggtgaaactg 11941 tcctttcatc tgtgtatgcc tggggctggg tccctggcag tgatggggtg acaatgcaaa 12001 gctgtaaaaa ctaggtgcta gtgggcacct aatatcatca tcatatactt attttcaagc 12061 taatatgcaa aatcccatct ctgtttttaa actaagtgta gatttcagag aaaatatttt 12121 gtggttcaca taagaaaaca gtctactcag cttgacaagt gttttatgtt aaattggctg 12181 gtggtttgaa atgaatcatc ttcacataat gttttcttta aaaatattgt gaatttaact 12241 ctaattcttg ttattctgtg tgataataaa gaataaacta atttcta (S: IQ ID NO:

120)

[0306] An exemplary amino acid sequence encoding PGR (NP 001 189403.1 , isoform A) comprises or consists of:

MSRSGCKVGDSSGTAAAHKVLPRGLSPARQLLLPASESPHWSGAPVKPSPQAAAVEVEEEDGSESEESAGPLLKG KPRALGGAAAGGGAAAVPPGAAAGGVALVPKEDSRFSAPRVALVEQDAPMAPGRSPLATTVMDFIHVPILPLNHA LLAARTRQLLEDESYDGGAGAASAFAPPRSSPCASSTPVAVGDFPDCAYPPDAEPKDDAYPLYSDFQPPALKIKE EEEGAEASARSPRSYLVAGANPAAFPDFPLGPPPPLPPRATPSRPGEAAVTAAPASASVSSASSSGSTLECILYK AEGAPPQQGPFAPPPCKAPGASGCLLPRDGLPSTSASAAAAGAAPALYPALGLNGLPQLGYQAAVLKEGLPQVYP PYLNYLRPDSEASQSPQYSFESLPQKICLICGDEASGCHYGVLTCGSCKVFFKRAMEGQHNYLCAGRNDCIVDKI RRKNCPACRLRKCCQAGMVLGGRKFKKFNKVRWRALDAVALPQPVGVPNESQALSQRFTFSPGQDIQLIPPLIN LLMSIEPDVIYAGHDNTKPDTSSSLLTSLNQLGERQLLSVVKWSKSLPGFRNLHIDDQITLIQYSWMSLMVFGLG WRSYKHVSGQMLYFAPDLILNEQRMKESSFYSLCLTMWQIPQEFVKLQVSQEEFLCMKVLLLLNTIPLEGLRSQT QFEEMRSSYIRELIKAIGLRQKGWSSSQRFYQLTKLLDNLHDLVKQLHLYCLNTFIQSRALSVEFPE MSEVIA AQLPKILAGMVKPLLFHKK (SEQ ID NO: 121) .

[0307] An exemplary nucleic acid sequence encoding PGR (NM 000926.4 transcript variant 2) comprises or consists of:

1 agtccacagc tgtcactaat cggggtaagc cttgttgtat ttgtgcgtgt gggtggcatt

61 ctcaatgaga actagcttca cttgtcattt gagtgaaatc tacaacccga ggcggctagt

121 gctcccgcac tactgggatc tgagatcttc ggagatgact gtcgcccgca gtacggagcc

181 agcagaagtc cgacccttcc tgggaatggg ctgtaccgag aggtccgact agccccaggg

241 ttttagtgag ggggcagtgg aactcagcga gggactgaga gcttcacagc atgcacgagt

301 ttgatgccag agaaaaagtc gggagataaa ggagccgcgt gtcactaaat tgccgtcgca

361 gccgcagcca ctcaagtgcc ggacttgtga gtactctgcg tctccagtcc tcggacagaa

421 gttggagaac tctcttggag aactccccga gttaggagac gagatctcct aacaattact

481 actttttctt gcgctcccca cttgccgctc gctgggacaa acgacagcca cagttcccct

541 gacgacagga tggaggccaa gggcaggagc tgaccagcgc cgccctcccc cgcccccgac

601 ccaggaggtg gagatccctc cggtccagcc acattcaaca cccactttct cctccctctg

661 cccctatatt cccgaaaccc cctcctcctt cccttttccc tcctcctgga gacgggggag

721 gagaaaaggg gagtccagtc gtcatgactg agctgaaggc aaagggtccc cgggctcccc 781 acgtggcggg cggcccgccc tcccccgagg tcggatcccc actgctgtgt cgcccagccg 841 caggtccgtt cccggggagc cagacctcgg acaccttgcc tgaagtttcg gccataccta 901 tctccctgga cgggctactc ttccctcggc cctgccaggg acaggacccc tccgacgaaa 961 agacgcagga ccagcagtcg ctgtcggacg tggagggcgc atattccaga gctgaagcta 1021 caaggggtgc tggaggcagc agttctagtc ccccagaaaa ggacagcgga ctgctggaca 1081 gtgtcttgga cactctgttg gcgccctcag gtcccgggca gagccaaccc agccctcccg 1141 cctgcgaggt caccagctct tggtgcctgt ttggccccga acttcccgaa gatccaccgg 1201 ctgcccccgc cacccagcgg gtgttgtccc cgctcatgag ccggtccggg tgcaaggttg 1261 gagacagctc cgggacggca gctgcccata aagtgctgcc ccggggcctg tcaccagccc 1321 ggcagctgct gctcccggcc tctgagagcc ctcactggtc cggggcccca gtgaagccgt 1381 ctccgcaggc cgctgcggtg gaggttgagg aggaggatgg ctctgagtcc gaggagtctg 1441 cgggtccgct tctgaagggc aaacctcggg ctctgggtgg cgcggcggct ggaggaggag 1501 ccgcggctgt cccgccgggg gcggcagcag gaggcgtcgc cctggtcccc aaggaagatt 1561 cccgcttctc agcgcccagg gtcgccctgg tggagcagga cgcgccgatg gcgcccgggc 1621 gctccccgct ggccaccacg gtgatggatt tcatccacgt gcctatcctg cctctcaatc 1681 acgccttatt ggcagcccgc actcggcagc tgctggaaga cgaaagttac gacggcgggg 1741 ccggggctgc cagcgccttt gccccgccgc ggagttcacc ctgtgcctcg tccaccccgg 1801 tcgctgtagg cgacttcccc gactgcgcgt acccgcccga cgccgagccc aaggacgacg 1861 cgtaccctct ctatagcgac ttccagccgc ccgctctaaa gataaaggag gaggaggaag 1921 gcgcggaggc ctccgcgcgc tccccgcgtt cctaccttgt ggccggtgcc aaccccgcag 1981 ccttcccgga tttcccgttg gggccaccgc ccccgctgcc gccgcgagcg accccatcca 2041 gacccgggga agcggcggtg acggccgcac ccgccagtgc ctcagtctcg tctgcgtcct 2101 cctcggggtc gaccctggag tgcatcctgt acaaagcgga gggcgcgccg ccccagcagg 2161 gcccgttcgc gccgccgccc tgcaaggcgc cgggcgcgag cggctgcctg ctcccgcggg 2221 acggcctgcc ctccacctcc gcctctgccg ccgccgccgg ggcggccccc gcgctctacc 2281 ctgcactcgg cctcaacggg ctcccgcagc tcggctacca ggccgccgtg ctcaaggagg 2341 gcctgccgca ggtctacccg ccctatctca actacctgag gccggattca gaagccagcc 2401 agagcccaca atacagcttc gagtcattac ctcagaagat ttgtttaatc tgtggggatg 2461 aagcatcagg ctgtcattat ggtgtcctta cctgtgggag ctgtaaggtc ttctttaaga 2521 gggcaatgga agggcagcac aactacttat gtgctggaag aaatgactgc atcgttgata 2581 aaatccgcag aaaaaactgc ccagcatgtc gccttagaaa gtgctgtcag gctggcatgg 2641 tccttggagg tcgaaaattt aaaaagttca ataaagtcag agttgtgaga gcactggatg 2701 ctgttgctct cccacagcca gtgggcgttc caaatgaaag ccaagcccta agccagagat 2761 tcactttttc accaggtcaa gacatacagt tgattccacc actgatcaac ctgttaatga 2821 gcattgaacc agatgtgatc tatgcaggac atgacaacac aaaacctgac acctccagtt 2881 ctttgctgac aagtcttaat caactaggcg agaggcaact tctttcagta gtcaagtggt 2941 ctaaatcatt gccaggtttt cgaaacttac atattgatga ccagataact ctcattcagt 3001 attcttggat gagcttaatg gtgtttggtc taggatggag atcctacaaa cacgtcagtg 3061 ggcagatgct gtattttgca cctgatctaa tactaaatga acagcggatg aaagaatcat 3121 cattctattc attatgcctt accatgtggc agatcccaca ggagtttgtc aagcttcaag 3181 ttagccaaga agagttcctc tgtatgaaag tattgttact tcttaataca attcctttgg 3241 aagggctacg aagtcaaacc cagtttgagg agatgaggtc aagctacatt agagagctca 3301 tcaaggcaat tggtttgagg caaaaaggag ttgtgtcgag ctcacagcgt ttctatcaac 3361 ttacaaaact tcttgataac ttgcatgatc ttgtcaaaca acttcatctg tactgcttga 3421 atacatttat ccagtcccgg gcactgagtg ttgaatttcc agaaatgatg tctgaagtta 3481 ttgctgcaca attacccaag atattggcag ggatggtgaa accccttctc tttcataaaa 3541 agtgaatgtc atctttttct tttaaagaat taaattttgt ggtatgtctt tttgttttgg 3601 tcaggattat gaggtcttga gtttttataa tgttcttctg aaagccttac atttataaca 3661 tcatagtgtg taaatttaaa agaaaaattg tgaggttcta attattttct tttataaagt 3721 ataattagaa tgtttaactg ttttgtttac ccatattttc ttgaagaatt tacaagattg 3781 aaaaagtact aaaattgtta aagtaaacta tcttatccat attatttcat accatgtagg 3841 tgaggatttt taacttttgc atctaacaaa tcatcgactt aagagaaaaa atcttacatg 3901 taataacaca aagctattat atgttatttc taggtaactc cctttgtgtc aattatattt 3961 ccaaaaatga acctttaaaa tggtatgcaa aattttgtct atatatattt gtgtgaggag 4021 gaaattcata actttcctca gattttcaaa agtattttta atgcaaaaaa tgtagaaaga 4081 gtttaaaacc actaaaatag attgatgttc ttcaaactag gcaaaacaac tcatatgtta 4141 agaccatttt ccagattgga aacacaaatc tcttaggaag ttaataagta gattcatatc 4201 attatgcaaa tagtattgtg ggttttgtag gtttttaaaa taaccttttt tggggagaga 4261 attgtcctct aatgaggtat tgcgagtgga cataagaaat cagaagatta tggcctaact 4321 gtactcctta ccaactgtgg catgctgaaa gttagtcact cttactgatt ctcaattctc 4381 tcacctttga aagtagtaaa atatctttcc tgccaattgc tcctttgggt cagagcttat 4441 taacatcttt tcaaatcaaa ggaaagaaga aagggagagg aggaggaggg aggtatcaat 4501 tcacatacct ttctcctctt tatcctccac tatcatgaat tcatattatg tttcagccat 4561 gcaaatcttt ttaccatgaa atttcttcca gaattttccc cctttgacac aaattccatg 4621 catgtttcaa ccttcgagac tcagccaaat gtcatttctg taaaatcttc cctgagtctt 4681 ccaagcagta atttgccttc tcctagagtt tacctgccat tttgtgcaca tttgagttac 4741 agtagcatgt tattttacaa ttgtgactct cctgggagtc tgggagccat ataaagtggt 4801 caatagtgtt tgctgactga gagttgaatg acattttctc tctgtcttgg tattactgta 4861 gatttcgatc attctttggt tacatttctg catatttctg tacccatgac tttatcactt 4921 tcttctccca tgctttatct ccatcaatta tcttcattac ttttaaattt tccacctttg 4981 cttcctactt tgtgagatct ctccctttac tgactataac atagaagaat agaagtgtat 5041 tttatgtgtc ttaaggacaa tactttagat tccttgttct aagtttttaa actgaatgaa 5101 tggaatatta tttctctccc taagcaaaat tccacaaaac aattatttct tatgtttatg 5161 tagccttaaa ttgttttgta ctgtaaacct cagcataaaa actttcttca tttctaattt 5221 cattcaacaa atattgattg aatacctggt attagcacaa gaaaaatgtg ctaataagcc 5281 ttatgagaat ttggagctga agaaagacat ataactcagg aaagttacag tccagtagta 5341 ggtataaatt acagtgcctg ataaataggc attttaatat ttgtacactc aacgtatact 5401 aggtaggtgc aaaacattta catataattt tactgatacc catgcagcac aaaggtacta 5461 actttaaata ttaaataaca cctttatgtg tcagtaattc atttgcatta aatcttattg 5521 aaaaggcttt caatatattt tccccacaaa tgtcatccca agaaaaaagt atttttaaca 5581 tctcccaaat ataatagtta caggaaatct acctctgtga gagtgacacc tctcagaatg 5641 aactgtgtga cacaagaaaa tgaatgtagg tctatccaaa aaaaacccca agaaacaaaa 5701 acaatattat tagcccttta tgcttaagtg atggactcag ggaacagttg atgttgtgat 5761 cattttatta tctgattctt gttactttga attaaaccaa tattttgatg atataaatca 5821 tttccaccag catatattta atttccataa taactttaaa attttctaat ttcactcaac 5881 tatgagggaa tagaatgtgg tggccacagg tttggctttt gttaaaatgt ttgatatctt 5941 cgatgttgat ctctgtctgc aatgtagatg tctaaacact aggatttaat atttaaggct 6001 aagctttaaa aataaagtac ctttttaaaa agaatatggc ttcaccaaat ggaaaatacc 6061 taatttctaa atctttttct ctacaaagtc ctatctacta atgtctccat tactatttag 6121 tcatcataac cattatcttc attttacatg tcgtgttctt tctggtagct ctaaaatgac 6181 actaaatcat aagaagacag gttacatatc aggaaatact tgaaggttac tgaaatagat 6241 tcttgagtta atgaaaatat tttctgtaaa aaggtttgaa aagccatttg agtctaaagc 6301 attatacctc cattatcagt agttatgtga caattgtgtg tgtgtttaat gtttaaagat 6361 gtggcacttt ttaataaggc aatgctatgc tattttttcc catttaacat taagataatt 6421 tattgctata cagatgatat ggaaatatga tgaacaatat tttttttgcc aaaactatgc 6481 cttgtaagta gccatggaat gtcaacctgt aacttaaatt atccacagat agtcatgtgt 6541 ttgatgatgg gcactgtgga gataactgac ataggactgt gccccccttc tctgccactt 6601 actagctgga tgagattaag caagtcattt aactgctctg attaaacctg cctttcccaa 6661 gtgctttgta atgaatagaa atggaaacca aaaaaaacgt atacaggcct tcagaaatag 6721 taattgctac tattttgttt tcattaagcc atagttctgg ctataatttt atcaaactca 6781 ccagctatat tctacagtga aagcaggatt ctagaaagtc tcactgtttt atttatgtca 6841 ccatgtgcta tgatatattt ggttgaattc atttgaaatt agggctggaa gtattcaagt 6901 aatttcttct gctgaaaaaa tacagtgttt tgagtttagg gcctgtttta tcaaagttct 6961 aaagagccta tcactcttcc attgtagaca ttttaaaata atgacactga ttttaacatt 7021 tttaagtgtc tttttagaac agagagcctg actagaacac agcccctcca aaaacccatg 7081 ctcaaattat ttttactatg gcagcaattc cacaaaaggg aacaatgggt ttagaaatta 7141 caatgaagtc atcaacccaa aaaacatccc tatccctaag aaggttatga tataaaatgc 7201 ccacaagaaa tctatgtctg ctttaatctg tcttttattg ctttggaagg atggctatta 7261 catttttagt ttttgctgtg aatacctgag cagtttctct catccatact tatccttcac 7321 acatcagaag tcaggataga atatgaatca ttttaaaaac ttttacaact ccagagccat 7381 gtgcataaga agcattcaaa acttgccaaa acatacattt tttttcaaat ttaaagatac 7441 tctatttttg tattcaatag ctcaacaact gtggtcccca ctgataaagt gaagtggaca 7501 aggagacaag taatggcata agtttgtttt tcccaaagta tgcctgttca atagccattg 7561 gatgtgggaa atttctacat ctcttaaaat tttacagaaa atacatagcc agatagtcta 7621 gcaaaagttc accaagtcct aaattgctta tccttacttc actaagtcat gaaatcattt 7681 taatgaaaag aacatcacct aggttttgtg gtttcttttt ttcttattca tggctgagtg 7741 aaaacaacaa tctctgtttc tccctagcat ctgtggacta tttaatgtac cattattcca 7801 cactctatgg tccttactaa atacaaaatt gaacaaaaag cagtaaaaca actgactctt 7861 cacccatatt ataaaatata atccaagcca gattagtcaa catccataag atgaatccaa 7921 gctgaactgg gcctagatta ttgagttcag gttggatcac atccctattt attaataaac 7981 ttaggaaaga aggccttaca gaccatcagt tagctggagc taatagaacc tacacttcta 8041 aagttcggcc tagaatcaat gtggccttaa aagctgaaaa gaagcaggaa agaacagttt 8101 tcttcaataa tttgtccacc ctgtcactgg agaaaattta agaatttggg ggtgttggta 8161 gtaagttaaa cacagcagct gttcatggca gaaattattc aatacatacc ttctctgaat 8221 atcctataac caaagcaaag aaaaacacca aggggtttgt tctcctcctt ggagttgacc 8281 tcattccaag gcagagctca ggtcacaggc acaggggctg cgcccaagct tgtccgcagc 8341 cttatgcagc tgtggagtct ggaagactgt tgcaggactg ctggcctagt cccagaatgt 8401 cagcctcatt ttcgatttac tggctcttgt tgctgtatgt catgctgacc ttattgttaa 8461 acacaggttt gtttgctttt tttccactca tggagacatg ggagaggcat tatttttaag 8521 ctggttgaaa gctttaaccg ataaagcatt tttagagaaa tgtgaatcag gcagctaaga 8581 aagcatactc tgtccattac ggtaaagaaa atgcacagat tattaactct gcagtgtggc 8641 attagtgtcc tggtcaatat tcggatagat atgaataaaa tatttaaatg gtattgtaaa 8701 tagttttcag gacatatgct atagcttatt tttattatct tttgaaattg ctcttaatac 8761 atcaaatcct gatgtattca atttatcaga tataaattat tctaaatgaa gcccagttaa 8821 atgtttttgt cttgtcagtt atatgttaag tttctgatct ctttgtctat gacgtttact 8881 aatctgcatt tttactgtta tgaattattt tagacagcag tggtttcaag ctttttgcca 8941 ctaaaaatac cttttatttt ctcctccccc agaaaagtct ataccttgaa gtatctatcc 9001 accaaactgt acttctatta agaaatagtt attgtgtttt cttaatgttt tgttattcaa 9061 agacatatca atgaaagctg ctgagcagca tgaataacaa ttatatccac acagatttga 9121 tatattttgt gcagccttaa cttgatagta taaaatgtca ttgcttttta aataatagtt 9181 agtcaatgga cttctatcat agctttccta aactaggtta agatccagag ctttggggtc 9241 ataatatatt acatacaatt aagttatctt tttctaaggg ctttaaaatt catgagaata 9301 accaaaaaag gtatgtggag agttaataca aacataccat attcttgttg aaacagagat 9361 gtggctctgc ttgttctcca taaggtagaa atactttcca gaatttgcct aaactagtaa 9421 gccctgaatt tgctatgatt agggatagga agagattttc acatggcaga ctttagaatt 9481 cttcacttta gccagtaaag tatctccttt tgatcttagt attctgtgta ttttaacttt 9541 tctgagttgt gcatgtttat aagaaaaatc agcacaaagg gtttaagtta aagccttttt 9601 actgaaattt gaaagaaaca gaagaaaata tcaaagttct ttgtattttg agaggattaa 9661 atatgattta caaaagttac atggagggct ctctaaaaca ttaaattaat tattttttgt 9721 tgaaaagtct tactttaggc atcattttat tcctcagcaa ctagctgtga agcctttact 9781 gtgctgtatg ccagtcactc tgctagattg tggagattac cagtgttccc gtcttctccg 9841 agcttagagt tggatgggga ataaagacag gtaaacagat agctacaata ttgtactgtg 9901 aatgcttatg ctggaggaag tacagggaac tattggagca cctaagagga gcacctacct 9961 tgaatttagg ggttagcaga ggcatcctga aaaaagtcaa agctaagcca caatctataa 10021 gcagtttagg aattagcaga acgtgcgtgg tgaggagatg ccaaaggcaa gaagagaaga 10081 gtattccaaa caggagggat tccaaagaga gaagagtatc ccaaacaaca tttgcacaaa 10141 cctgatgggg agagagaatg tggggtgggg atggatgatg agactgaaga agaaagccag 10201 gtctagataa tcagtggcct tgtacaccat gttaaagagt gtagacttga ttctgttgta 10261 aacaggaaag cagcacaatt catatgaata ttttagaaga ctcccactgg aatatggaga 10321 ataaagttgg agatgactaa tcctggaagc agggagaaca tttttgagga agttgcacta 10381 ttttggtgaa aatgatgatc ataaacatga agaattgtag gtgatcatga cctcctctct 10441 aattttccag aagggttttg gaagatataa cataggaaca ttgacaggac tgacgaaagg 10501 agatgaaata caccatataa attgtcaaac acaaggccag atgtctaatt attttgctta 10561 tgtgttgaaa ttacaaattt ttcatcagga aaccaaaaac tacaaaactt agttttccca 10621 agtcccagaa ttctatctgt ccaaacaatc tgtaccactc cacctatatc cctacctttg 10681 catgtctgtc caacctcaaa gtccaggtct atacacacgg gtaagactag agcagttcaa 10741 gtttcagaaa atgagaaaga ggaactgagt tgtgctgaac ccatacaaaa taaacacatt 10801 ctttgtatag attcttggaa cctcgagagg aattcaccta actcataggt atttgatggt 10861 atgaatccat ggctgggctc ggcttttaaa aagccttatc tgggattcct tctatggaac 10921 caagttccat caaagcccat ttaaaagcct acattaaaaa caaaattctt gctgcattgt 10981 atacaaataa tgatgtcatg atcaaataat cagatgccat tatcaagtgg aattacaaaa 11041 tggtataccc actccaaaaa aaaaaaaaaa gctaaattct cagtagaaca ttgtgacttc 11101 atgagccctc cacagccttg gagctgagga gggagcactg gtgagcagta ggttgaagag 11161 aaaacttggc gcttaataat ctatccatgt tttttcatct aaaagagcct tctttttgga 11221 ttaccttatt caatttccat caaggaaatt gttagttcca ctaaccagac agcagctggg 11281 aaggcagaag cttactgtat gtacatggta gctgtgggaa ggaggtttct ttctccaggt 11341 cctcactggc catacaccag tcccttgtta gttatgcctg gtcatagacc cccgttgcta 11401 tcatctcata tttaagtctt tggcttgtga atttatctat tctttcagct tcagcactgc 11461 agagtgctgg gactttgcta acttccattt cttgctggct tagcacattc ctcataggcc 11521 cagctctttt ctcatctggc cctgctgtgg agtcaccttg ccccttcagg agagccatgg 11581 cttaccactg cctgctaagc ctccactcag ctgccaccac actaaatcca agcttctcta 11641 agatgttgca gactttacag gcaagcataa aaggcttgat cttcctggac ttccctttac 11701 ttgtctgaat ctcacctcct tcaactttca gtctcagaat gtaggcattt gtcctctttg 11761 ccctacatct tccttcttct gaatcatgaa agcctctcac ttcctcttgc tatgtgctgg 11821 aggcttctgt caggttttag aatgagttct catctagtcc tagtagcttt tgatgcttaa 11881 gtccaccttt taaggatacc tttgagattt agaccatgtt tttcgcttga gaaagcccta 11941 atctccagac ttgcctttct gtggatttca aagaccaact gaggaagtca aaagctgaat 12001 gttgactttc tttgaacatt tccgctataa caattccaat tctcctcaga gcaatatgcc 12061 tgcctccaac tgaccaggag aaaggtccag tgccaaagag aaaaacacaa agattaatta 12121 tttcagttga gcacatactt tcaaagtggt ttgggtattc atatgaggtt ttctgtcaag 12181 agggtgagac tcttcatcta tccatgtgtg cctgacagtt ctcctggcac tggctggtaa 12241 cagatgcaaa actgtaaaaa ttaagtgatc atgtatttta acgatatcat cacatactta 12301 ttttctatgt aatgttttaa atttccccta acatactttg actgttttgc acatggtaga 12361 tattcacatt tttttgtgtt gaagttgatg caatcttcaa agttatctac cccgttgctt 12421 attagtaaaa ctagtgttaa tacttggcaa gagatgcagg gaatctttct catgactcac 12481 gccctattta gttattaatg ctactaccct attttgagta agtagtaggt ccctaagtac 12541 attgtccaga gttatacttt taaagatatt tagccccata tacttcttga atctaaagtc 12601 atacaccttg ctcctcattt ctgagtggga aagacatttg agagtatgtt gacaattgtt 12661 ctgaaggttt ttgccaagaa ggtgaaactg tcctttcatc tgtgtatgcc tggggctggg 12721 tccctggcag tgatggggtg acaatgcaaa gctgtaaaaa ctaggtgcta gtgggcacct 12781 aatatcatca tcatatactt attttcaagc taatatgcaa aatcccatct ctgtttttaa 12841 actaagtgta gatttcagag aaaatatttt gtggttcaca taagaaaaca gtctactcag 12901 cttgacaagt gttttatgtt aaattggctg gtggtttgaa atgaatcatc ttcacataat 12961 gttttcttta aaaatattgt gaatttaact ctaattcttg ttattctgtg tgataataaa 13021 gaataaacta atttcta (SEQ ID NO: 122) .

[0308] An exemplary amino acid sequence encoding PGR (NP 000917.3, isoform B) comprises or consists of:

MTELKAKGPRAPHVAGGPPSPEVGSPLLCRPAAGPFPGSQTSDTLPEVSAIPISLDGLLFPRPCQGQDPSDEKTQ DQQSLSDVEGAYSRAEATRGAGGSSSSPPEKDSGLLDSVLDTLLAPSGPGQSQPSPPACEVTSSWCLFGPELPED PPAAPATQRVLSPLMSRSGCKVGDSSGTAAAHKVLPRGLSPARQLLLPASESPHWSGAPVKPSPQAAAVEVEEED GSESEESAGPLLKGKPRALGGAAAGGGAAAVPPGAAAGGVALVPKEDSRFSAPRVALVEQDAPMAPGRSPLATTV MDFIHVPILPLNHALLAARTRQLLEDESYDGGAGAASAFAPPRSSPCASSTPVAVGDFPDCAYPPDAEPKDDAYP LYSDFQPPALKIKEEEEGAEASARSPRSYLVAGANPAAFPDFPLGPPPPLPPRATPSRPGEAAVTAAPASASVSS ASSSGSTLECILYKAEGAPPQQGPFAPPPCKAPGASGCLLPRDGLPSTSASAAAAGAAPALYPALGLNGLPQLGY QAAVLKEGLPQVYPPYLNYLRPDSEASQSPQYSFESLPQKICLICGDEASGCHYGVLTCGSCKVFFKRAMEGQHN YLCAGRNDCIVDKIRRKNCPACRLRKCCQAGMVLGGRKFKKFNKVRWRALDAVALPQPVGVPNESQALSQRFTF SPGQDIQLIPPLINLLMSIEPDVIYAGHDNTKPDTSSSLLTSLNQLGERQLLSWKWSKSLPGFRNLHIDDQITL IQYSWMSLMVFGLGWRSYKHVSGQMLYFAPDLILNEQRMKESSFYSLCLTMWQIPQEFVKLQVSQEEFLCMKVLL LLNTIPLEGLRSQTQFEEMRSSYIRELIKAIGLRQKGWSSSQRFYQLTKLLDNLHDLVKQLHLYCLNTFIQSRA LSVEFPEMMSEVIAAQLPKILAGMVKPLLFHKK (SEQ ID NO: 123) .

[0309] An exemplary nucleic acid sequence encoding PGR (NM 001271161.2 transcript variant 3) comprises or consists of:

1 agctgaaggc aaagggtccc cgggctcccc acgtggcggg cggcccgccc tcccccgagg

61 tcggatcccc actgctgtgt cgcccagccg caggtccgtt cccggggagc cagacctcgg

121 acaccttgcc tgaagtttcg gccataccta tctccctgga cgggctactc ttccctcggc

181 cctgccaggg acaggacccc tccgacgaaa agacgcagga ccagcagtcg ctgtcggacg

241 tggagggcgc atattccaga gctgaagcta caaggggtgc tggaggcagc agttctagtc

301 ccccagaaaa ggacagcgga ctgctggaca gtgtcttgga cactctgttg gcgccctcag

361 gtcccgggca gagccaaccc agccctcccg cctgcgaggt caccagctct tggtgcctgt

421 ttggccccga acttcccgaa gatccaccgg ctgcccccgc cacccagcgg gtgttgtccc

481 cgctcatgag ccggtccggg tgcaaggttg gagacagctc cgggacggca gctgcccata

541 aagtgctgcc ccggggcctg tcaccagccc ggcagctgct gctcccggcc tctgagagcc 601 ctcactggtc cggggcccca gtgaagccgt ctccgcaggc cgctgcggtg gaggttgagg 661 aggaggatgg ctctgagtcc gaggagtctg cgggtccgct tctgaagggc aaacctcggg 721 ctctgggtgg cgcggcggct ggaggaggag ccgcggctgt cccgccgggg gcggcagcag 781 gaggcgtcgc cctggtcccc aaggaagatt cccgcttctc agcgcccagg gtcgccctgg 841 tggagcagga cgcgccgatg gcgcccgggc gctccccgct ggccaccacg gtgatggatt 901 tcatccacgt gcctatcctg cctctcaatc acgccttatt ggcagcccgc actcggcagc 961 tgctggaaga cgaaagttac gacggcgggg ccggggctgc cagcgccttt gccccgccgc 1021 ggagttcacc ctgtgcctcg tccaccccgg tcgctgtagg cgacttcccc gactgcgcgt 1081 acccgcccga cgccgagccc aaggacgacg cgtaccctct ctatagcgac ttccagccgc 1141 ccgctctaaa gataaaggag gaggaggaag gcgcggaggc ctccgcgcgc tccccgcgtt 1201 cctaccttgt ggccggtgcc aaccccgcag ccttcccgga tttcccgttg gggccaccgc 1261 ccccgctgcc gccgcgagcg accccatcca gacccgggga agcggcggtg acggccgcac 1321 ccgccagtgc ctcagtctcg tctgcgtcct cctcggggtc gaccctggag tgcatcctgt 1381 acaaagcgga gggcgcgccg ccccagcagg gcccgttcgc gccgccgccc tgcaaggcgc 1441 cgggcgcgag cggctgcctg ctcccgcggg acggcctgcc ctccacctcc gcctctgccg 1501 ccgccgccgg ggcggccccc gcgctctacc ctgcactcgg cctcaacggg ctcccgcagc 1561 tcggctacca ggccgccgtg ctcaaggagg gcctgccgca ggtctacccg ccctatctca 1621 actacctgag gccggattca gaagccagcc agagcccaca atacagcttc gagtcattac 1681 ctcagaagat ttgtttaatc tgtggggatg aagcatcagg ctgtcattat ggtgtcctta 1741 cctgtgggag ctgtaaggtc ttctttaaga gggcaatgga agggcagcac aactacttat 1801 gtgctggaag aaatgactgc atcgttgata aaatccgcag aaaaaactgc ccagcatgtc 1861 gccttagaaa gtgctgtcag gctggcatgg tccttggagg ttttcgaaac ttacatattg 1921 atgaccagat aactctcatt cagtattctt ggatgagctt aatggtgttt ggtctaggat 1981 ggagatccta caaacacgtc agtgggcaga tgctgtattt tgcacctgat ctaatactaa 2041 atgaacagcg gatgaaagaa tcatcattct attcattatg ccttaccatg tggcagatcc 2101 cacaggagtt tgtcaagctt caagttagcc aagaagagtt cctctgtatg aaagtattgt 2161 tacttcttaa tacaattcct ttggaagggc tacgaagtca aacccagttt gaggagatga 2221 ggtcaagcta cattagagag ctcatcaagg caattggttt gaggcaaaaa ggagttgtgt 2281 cgagctcaca gcgtttctat caacttacaa aacttcttga taacttgcat gatcttgtca 2341 aacaacttca tctgtactgc ttgaatacat ttatccagtc ccgggcactg agtgttgaat 2401 ttccagaaat gatgtctgaa gttattgctg cacaattacc caagatattg gcagggatgg 2461 tgaaacccct tctctttcat aaaaagtgaa tgtcatcttt ttcttttaaa gaattaaatt 2521 ttgtggtatg tctttttgtt ttggtcagga ttatgaggtc ttgagttttt ataatgttct 2581 tctgaaagcc ttacatttat aacatcatag tgtgtaaatt taaaagaaaa attgtgaggt 2641 tctaattatt ttcttttata aagtataatt agaatgttta actgttttgt ttacccatat 2701 tttcttgaag aatttacaag attgaaaaag tactaaaatt gttaaagtaa actatcttat 2761 ccatattatt tcataccatg taggtgagga tttttaactt ttgcatctaa caaatcatcg 2821 acttaagaga aaaaatctta catgtaataa cacaaagcta ttatatgtta tttctaggta 2881 actccctttg tgtcaattat atttccaaaa atgaaccttt aaaatggtat gcaaaatttt 2941 gtctatatat atttgtgtga ggaggaaatt cataactttc ctcagatttt caaaagtatt 3001 tttaatgcaa aaaatgtaga aagagtttaa aaccactaaa atagattgat gttcttcaaa 3061 ctaggcaaaa caactcatat gttaagacca ttttccagat tggaaacaca aatctcttag 3121 gaagttaata agtagattca tatcattatg caaatagtat tgtgggtttt gtaggttttt 3181 aaaataacct tttttgggga gagaattgtc ctctaatgag gtattgcgag tggacataag 3241 aaatcagaag attatggcct aactgtactc cttaccaact gtggcatgct gaaagttagt 3301 cactcttact gattctcaat tctctcacct ttgaaagtag taaaatatct ttcctgccaa 3361 ttgctccttt gggtcagagc ttattaacat cttttcaaat caaaggaaag aagaaaggga 3421 gaggaggagg agggaggtat caattcacat acctttctcc tctttatcct ccactatcat 3481 gaattcatat tatgtttcag ccatgcaaat ctttttacca tgaaatttct tccagaattt 3541 tccccctttg acacaaattc catgcatgtt tcaaccttcg agactcagcc aaatgtcatt 3601 tctgtaaaat cttccctgag tcttccaagc agtaatttgc cttctcctag agtttacctg 3661 ccattttgtg cacatttgag ttacagtagc atgttatttt acaattgtga ctctcctggg 3721 agtctgggag ccatataaag tggtcaatag tgtttgctga ctgagagttg aatgacattt 3781 tctctctgtc ttggtattac tgtagatttc gatcattctt tggttacatt tctgcatatt 3841 tctgtaccca tgactttatc actttcttct cccatgcttt atctccatca attatcttca 3901 ttacttttaa attttccacc tttgcttcct actttgtgag atctctccct ttactgacta 3961 taacatagaa gaatagaagt gtattttatg tgtcttaagg acaatacttt agattccttg 4021 ttctaagttt ttaaactgaa tgaatggaat attatttctc tccctaagca aaattccaca 4081 aaacaattat ttcttatgtt tatgtagcct taaattgttt tgtactgtaa acctcagcat 4141 aaaaactttc ttcatttcta atttcattca acaaatattg attgaatacc tggtattagc 4201 acaagaaaaa tgtgctaata agccttatga gaatttggag ctgaagaaag acatataact 4261 caggaaagtt acagtccagt agtaggtata aattacagtg cctgataaat aggcatttta 4321 atatttgtac actcaacgta tactaggtag gtgcaaaaca tttacatata attttactga 4381 tacccatgca gcacaaaggt actaacttta aatattaaat aacaccttta tgtgtcagta 4441 attcatttgc attaaatctt attgaaaagg ctttcaatat attttcccca caaatgtcat 4501 cccaagaaaa aagtattttt aacatctccc aaatataata gttacaggaa atctacctct 4561 gtgagagtga cacctctcag aatgaactgt gtgacacaag aaaatgaatg taggtctatc 4621 caaaaaaaac cccaagaaac aaaaacaata ttattagccc tttatgctta agtgatggac 4681 tcagggaaca gttgatgttg tgatcatttt attatctgat tcttgttact ttgaattaaa 4741 ccaatatttt gatgatataa atcatttcca ccagcatata tttaatttcc ataataactt 4801 taaaattttc taatttcact caactatgag ggaatagaat gtggtggcca caggtttggc 4861 ttttgttaaa atgtttgata tcttcgatgt tgatctctgt ctgcaatgta gatgtctaaa 4921 cactaggatt taatatttaa ggctaagctt taaaaataaa gtaccttttt aaaaagaata 4981 tggcttcacc aaatggaaaa tacctaattt ctaaatcttt ttctctacaa agtcctatct 5041 actaatgtct ccattactat ttagtcatca taaccattat cttcatttta catgtcgtgt 5101 tctttctggt agctctaaaa tgacactaaa tcataagaag acaggttaca tatcaggaaa 5161 tacttgaagg ttactgaaat agattcttga gttaatgaaa atattttctg taaaaaggtt 5221 tgaaaagcca tttgagtcta aagcattata cctccattat cagtagttat gtgacaattg 5281 tgtgtgtgtt taatgtttaa agatgtggca ctttttaata aggcaatgct atgctatttt 5341 ttcccattta acattaagat aatttattgc tatacagatg atatggaaat atgatgaaca 5401 atattttttt tgccaaaact atgccttgta agtagccatg gaatgtcaac ctgtaactta 5461 aattatccac agatagtcat gtgtttgatg atgggcactg tggagataac tgacatagga 5521 ctgtgccccc cttctctgcc acttactagc tggatgagat taagcaagtc atttaactgc 5581 tctgattaaa cctgcctttc ccaagtgctt tgtaatgaat agaaatggaa accaaaaaaa 5641 acgtatacag gccttcagaa atagtaattg ctactatttt gttttcatta agccatagtt 5701 ctggctataa ttttatcaaa ctcaccagct atattctaca gtgaaagcag gattctagaa 5761 agtctcactg ttttatttat gtcaccatgt gctatgatat atttggttga attcatttga 5821 aattagggct ggaagtattc aagtaatttc ttctgctgaa aaaatacagt gttttgagtt 5881 tagggcctgt tttatcaaag ttctaaagag cctatcactc ttccattgta gacattttaa 5941 aataatgaca ctgattttaa catttttaag tgtcttttta gaacagagag cctgactaga 6001 acacagcccc tccaaaaacc catgctcaaa ttatttttac tatggcagca attccacaaa 6061 agggaacaat gggtttagaa attacaatga agtcatcaac ccaaaaaaca tccctatccc 6121 taagaaggtt atgatataaa atgcccacaa gaaatctatg tctgctttaa tctgtctttt 6181 attgctttgg aaggatggct attacatttt tagtttttgc tgtgaatacc tgagcagttt 6241 ctctcatcca tacttatcct tcacacatca gaagtcagga tagaatatga atcattttaa 6301 aaacttttac aactccagag ccatgtgcat aagaagcatt caaaacttgc caaaacatac 6361 attttttttc aaatttaaag atactctatt tttgtattca atagctcaac aactgtggtc 6421 cccactgata aagtgaagtg gacaaggaga caagtaatgg cataagtttg tttttcccaa 6481 agtatgcctg ttcaatagcc attggatgtg ggaaatttct acatctctta aaattttaca 6541 gaaaatacat agccagatag tctagcaaaa gttcaccaag tcctaaattg cttatcctta 6601 cttcactaag tcatgaaatc attttaatga aaagaacatc acctaggttt tgtggtttct 6661 ttttttctta ttcatggctg agtgaaaaca acaatctctg tttctcccta gcatctgtgg 6721 actatttaat gtaccattat tccacactct atggtcctta ctaaatacaa aattgaacaa 6781 aaagcagtaa aacaactgac tcttcaccca tattataaaa tataatccaa gccagattag 6841 tcaacatcca taagatgaat ccaagctgaa ctgggcctag attattgagt tcaggttgga 6901 tcacatccct atttattaat aaacttagga aagaaggcct tacagaccat cagttagctg 6961 gagctaatag aacctacact tctaaagttc ggcctagaat caatgtggcc ttaaaagctg 7021 aaaagaagca ggaaagaaca gttttcttca ataatttgtc caccctgtca ctggagaaaa 7081 tttaagaatt tgggggtgtt ggtagtaagt taaacacagc agctgttcat ggcagaaatt 7141 attcaataca taccttctct gaatatccta taaccaaagc aaagaaaaac accaaggggt 7201 ttgttctcct ccttggagtt gacctcattc caaggcagag ctcaggtcac aggcacaggg 7261 gctgcgccca agcttgtccg cagccttatg cagctgtgga gtctggaaga ctgttgcagg 7321 actgctggcc tagtcccaga atgtcagcct cattttcgat ttactggctc ttgttgctgt 7381 atgtcatgct gaccttattg ttaaacacag gtttgtttgc tttttttcca ctcatggaga 7441 catgggagag gcattatttt taagctggtt gaaagcttta accgataaag catttttaga 7501 gaaatgtgaa tcaggcagct aagaaagcat actctgtcca ttacggtaaa gaaaatgcac 7561 agattattaa ctctgcagtg tggcattagt gtcctggtca atattcggat agatatgaat 7621 aaaatattta aatggtattg taaatagttt tcaggacata tgctatagct tatttttatt 7681 atcttttgaa attgctctta atacatcaaa tcctgatgta ttcaatttat cagatataaa 7741 ttattctaaa tgaagcccag ttaaatgttt ttgtcttgtc agttatatgt taagtttctg 7801 atctctttgt ctatgacgtt tactaatctg catttttact gttatgaatt attttagaca 7861 gcagtggttt caagcttttt gccactaaaa atacctttta ttttctcctc ccccagaaaa 7921 gtctatacct tgaagtatct atccaccaaa ctgtacttct attaagaaat agttattgtg 7981 ttttcttaat gttttgttat tcaaagacat atcaatgaaa gctgctgagc agcatgaata 8041 acaattatat ccacacagat ttgatatatt ttgtgcagcc ttaacttgat agtataaaat 8101 gtcattgctt tttaaataat agttagtcaa tggacttcta tcatagcttt cctaaactag 8161 gttaagatcc agagctttgg ggtcataata tattacatac aattaagtta tctttttcta 8221 agggctttaa aattcatgag aataaccaaa aaaggtatgt ggagagttaa tacaaacata 8281 ccatattctt gttgaaacag agatgtggct ctgcttgttc tccataaggt agaaatactt 8341 tccagaattt gcctaaacta gtaagccctg aatttgctat gattagggat aggaagagat 8401 tttcacatgg cagactttag aattcttcac tttagccagt aaagtatctc cttttgatct 8461 tagtattctg tgtattttaa cttttctgag ttgtgcatgt ttataagaaa aatcagcaca 8521 aagggtttaa gttaaagcct ttttactgaa atttgaaaga aacagaagaa aatatcaaag 8581 ttctttgtat tttgagagga ttaaatatga tttacaaaag ttacatggag ggctctctaa 8641 aacattaaat taattatttt ttgttgaaaa gtcttacttt aggcatcatt ttattcctca 8701 gcaactagct gtgaagcctt tactgtgctg tatgccagtc actctgctag attgtggaga 8761 ttaccagtgt tcccgtcttc tccgagctta gagttggatg gggaataaag acaggtaaac 8821 agatagctac aatattgtac tgtgaatgct tatgctggag gaagtacagg gaactattgg 8881 agcacctaag aggagcacct accttgaatt taggggttag cagaggcatc ctgaaaaaag 8941 tcaaagctaa gccacaatct ataagcagtt taggaattag cagaacgtgc gtggtgagga 9001 gatgccaaag gcaagaagag aagagtattc caaacaggag ggattccaaa gagagaagag 9061 tatcccaaac aacatttgca caaacctgat ggggagagag aatgtggggt ggggatggat 9121 gatgagactg aagaagaaag ccaggtctag ataatcagtg gccttgtaca ccatgttaaa 9181 gagtgtagac ttgattctgt tgtaaacagg aaagcagcac aattcatatg aatattttag 9241 aagactccca ctggaatatg gagaataaag ttggagatga ctaatcctgg aagcagggag 9301 aacatttttg aggaagttgc actattttgg tgaaaatgat gatcataaac atgaagaatt 9361 gtaggtgatc atgacctcct ctctaatttt ccagaagggt tttggaagat ataacatagg 9421 aacattgaca ggactgacga aaggagatga aatacaccat ataaattgtc aaacacaagg 9481 ccagatgtct aattattttg cttatgtgtt gaaattacaa atttttcatc aggaaaccaa 9541 aaactacaaa acttagtttt cccaagtccc agaattctat ctgtccaaac aatctgtacc 9601 actccaccta tatccctacc tttgcatgtc tgtccaacct caaagtccag gtctatacac 9661 acgggtaaga ctagagcagt tcaagtttca gaaaatgaga aagaggaact gagttgtgct 9721 gaacccatac aaaataaaca cattctttgt atagattctt ggaacctcga gaggaattca 9781 cctaactcat aggtatttga tggtatgaat ccatggctgg gctcggcttt taaaaagcct 9841 tatctgggat tccttctatg gaaccaagtt ccatcaaagc ccatttaaaa gcctacatta 9901 aaaacaaaat tcttgctgca ttgtatacaa ataatgatgt catgatcaaa taatcagatg 9961 ccattatcaa gtggaattac aaaatggtat acccactcca aaaaaaaaaa aaaagctaaa 10021 ttctcagtag aacattgtga cttcatgagc cctccacagc cttggagctg aggagggagc 10081 actggtgagc agtaggttga agagaaaact tggcgcttaa taatctatcc atgttttttc 10141 atctaaaaga gccttctttt tggattacct tattcaattt ccatcaagga aattgttagt 10201 tccactaacc agacagcagc tgggaaggca gaagcttact gtatgtacat ggtagctgtg 10261 ggaaggaggt ttctttctcc aggtcctcac tggccataca ccagtccctt gttagttatg 10321 cctggtcata gacccccgtt gctatcatct catatttaag tctttggctt gtgaatttat 10381 ctattctttc agcttcagca ctgcagagtg ctgggacttt gctaacttcc atttcttgct 10441 ggcttagcac attcctcata ggcccagctc ttttctcatc tggccctgct gtggagtcac 10501 cttgcccctt caggagagcc atggcttacc actgcctgct aagcctccac tcagctgcca 10561 ccacactaaa tccaagcttc tctaagatgt tgcagacttt acaggcaagc ataaaaggct 10621 tgatcttcct ggacttccct ttacttgtct gaatctcacc tccttcaact ttcagtctca 10681 gaatgtaggc atttgtcctc tttgccctac atcttccttc ttctgaatca tgaaagcctc 10741 tcacttcctc ttgctatgtg ctggaggctt ctgtcaggtt ttagaatgag ttctcatcta 10801 gtcctagtag cttttgatgc ttaagtccac cttttaagga tacctttgag atttagacca 10861 tgtttttcgc ttgagaaagc cctaatctcc agacttgcct ttctgtggat ttcaaagacc 10921 aactgaggaa gtcaaaagct gaatgttgac tttctttgaa catttccgct ataacaattc 10981 caattctcct cagagcaata tgcctgcctc caactgacca ggagaaaggt ccagtgccaa 11041 agagaaaaac acaaagatta attatttcag ttgagcacat actttcaaag tggtttgggt 11101 attcatatga ggttttctgt caagagggtg agactcttca tctatccatg tgtgcctgac 11161 agttctcctg gcactggctg gtaacagatg caaaactgta aaaattaagt gatcatgtat 11221 tttaacgata tcatcacata cttattttct atgtaatgtt ttaaatttcc cctaacatac 11281 tttgactgtt ttgcacatgg tagatattca catttttttg tgttgaagtt gatgcaatct 11341 tcaaagttat ctaccccgtt gcttattagt aaaactagtg ttaatacttg gcaagagatg 11401 cagggaatct ttctcatgac tcacgcccta tttagttatt aatgctacta ccctattttg 11461 agtaagtagt aggtccctaa gtacattgtc cagagttata cttttaaaga tatttagccc 11521 catatacttc ttgaatctaa agtcatacac cttgctcctc atttctgagt gggaaagaca 11581 tttgagagta tgttgacaat tgttctgaag gtttttgcca agaaggtgaa actgtccttt 11641 catctgtgta tgcctggggc tgggtccctg gcagtgatgg ggtgacaatg caaagctgta 11701 aaaactaggt gctagtgggc acctaatatc atcatcatat acttattttc aagctaatat 11761 gcaaaatccc atctctgttt ttaaactaag tgtagatttc agagaaaata ttttgtggtt 11821 cacataagaa aacagtctac tcagcttgac aagtgtttta tgttaaattg gctggtggtt 11881 tgaaatgaat catcttcaca taatgttttc tttaaaaata ttgtgaattt aactctaatt 11941 cttgttattc tgtgtgataa taaagaataa actaatttct a (SEQ ID NO: 124) .

[0310] An exemplary amino acid sequence encoding PGR (NP 001258090.1, isoform C) comprises or consists of:

MSRSGCKVGDSSGTAAAHKVLPRGLSPARQLLLPASESPHWSGAPVKPSPQAAAVEVEEEDGSESEESAGPLLKG KPRALGGAAAGGGAAAVPPGAAAGGVALVPKEDSRFSAPRVALVEQDAPMAPGRSPLATTVMDFIHVPILPLNHA LLAARTRQLLEDESYDGGAGAASAFAPPRSSPCASSTPVAVGDFPDCAYPPDAEPKDDAYPLYSDFQPPALKIKE EEEGAEASARSPRSYLVAGANPAAFPDFPLGPPPPLPPRATPSRPGEAAVTAAPASASVSSASSSGSTLECILYK AEGAPPQQGPFAPPPCKAPGASGCLLPRDGLPSTSASAAAAGAAPALYPALGLNGLPQLGYQAAVLKEGLPQVYP PYLNYLRPDSEASQSPQYSFESLPQKICLICGDEASGCHYGVLTCGSCKVFFKRAMEGQHNYLCAGRNDCIVDKI RRKNCPACRLRKCCQAGMVLGGFRNLHIDDQITLIQYSWMSLMVFGLGWRSYKHVSGQMLYFAPDLILNEQRMKE SSFYSLCLTMWQIPQEFVKLQVSQEEFLCMKVLLLLNTIPLEGLRSQTQFEEMRSSYIRELIKAIGLRQKGWSS SQRFYQLTKLLDNLHDLVKQLHLYCLNTFIQSRALSVEFPEiMSEVIAAQLPKILAGMVKPLLFHKK (SEQ ID NO: 125) .

[0311] An exemplary nucleic acid sequence encoding PGR (NR 073141.2 transcript variant

4 ) comprises or consists of:

1 agctgaaggc aaagggtccc cgggctcccc acgtggcggg cggcccgccc tcccccgagg 61 tcggatcccc actgctgtgt cgcccagccg caggtccgtt cccggggagc cagacctcgg 121 acaccttgcc tgaagtttcg gccataccta tctccctgga cgggctactc ttccctcggc 181 cctgccaggg acaggacccc tccgacgaaa agacgcagga ccagcagtcg ctgtcggacg 241 tggagggcgc atattccaga gctgaagcta caaggggtgc tggaggcagc agttctagtc 301 ccccagaaaa ggacagcgga ctgctggaca gtgtcttgga cactctgttg gcgccctcag 361 gtcccgggca gagccaaccc agccctcccg cctgcgaggt caccagctct tggtgcctgt 421 ttggccccga acttcccgaa gatccaccgg ctgcccccgc cacccagcgg gtgttgtccc 481 cgctcatgag ccggtccggg tgcaaggttg gagacagctc cgggacggca gctgcccata 541 aagtgctgcc ccggggcctg tcaccagccc ggcagctgct gctcccggcc tctgagagcc 601 ctcactggtc cggggcccca gtgaagccgt ctccgcaggc cgctgcggtg gaggttgagg 661 aggaggatgg ctctgagtcc gaggagtctg cgggtccgct tctgaagggc aaacctcggg 721 ctctgggtgg cgcggcggct ggaggaggag ccgcggctgt cccgccgggg gcggcagcag 781 gaggcgtcgc cctggtcccc aaggaagatt cccgcttctc agcgcccagg gtcgccctgg 841 tggagcagga cgcgccgatg gcgcccgggc gctccccgct ggccaccacg gtgatggatt 901 tcatccacgt gcctatcctg cctctcaatc acgccttatt ggcagcccgc actcggcagc 961 tgctggaaga cgaaagttac gacggcgggg ccggggctgc cagcgccttt gccccgccgc 1021 ggagttcacc ctgtgcctcg tccaccccgg tcgctgtagg cgacttcccc gactgcgcgt 1081 acccgcccga cgccgagccc aaggacgacg cgtaccctct ctatagcgac ttccagccgc 1141 ccgctctaaa gataaaggag gaggaggaag gcgcggaggc ctccgcgcgc tccccgcgtt 1201 cctaccttgt ggccggtgcc aaccccgcag ccttcccgga tttcccgttg gggccaccgc 1261 ccccgctgcc gccgcgagcg accccatcca gacccgggga agcggcggtg acggccgcac 1321 ccgccagtgc ctcagtctcg tctgcgtcct cctcggggtc gaccctggag tgcatcctgt 1381 acaaagcgga gggcgcgccg ccccagcagg gcccgttcgc gccgccgccc tgcaaggcgc 1441 cgggcgcgag cggctgcctg ctcccgcggg acggcctgcc ctccacctcc gcctctgccg 1501 ccgccgccgg ggcggccccc gcgctctacc ctgcactcgg cctcaacggg ctcccgcagc 1561 tcggctacca ggccgccgtg ctcaaggagg gcctgccgca ggtctacccg ccctatctca 1621 actacctgag gccggattca gaagccagcc agagcccaca atacagcttc gagtcattac 1681 ctcagaagat ttgtttaatc tgtggggatg aagcatcagg ctgtcattat ggtgtcctta 1741 cctgtgggag ctgtaaggtc ttctttaaga gggcaatgga agggcagcac aactacttat 1801 gtgctggaag aaatgactgc atcgttgata aaatccgcag aaaaaactgc ccagcatgtc 1861 gccttagaaa gtgctgtcag gctggcatgg tccttggagg tcgaaaattt aaaaagttca 1921 ataaagtcag agttgtgaga gcactggatg ctgttgctct cccacagcca gtgggcgttc 1981 caaatgaaag ccaagcccta agccagagat tcactttttc accaggtcaa gacatacagt 2041 tgattccacc actgatcaac ctgttaatga gcattgaacc agatgtgatc tatgcaggac 2101 atgacaacac aaaacctgac acctccagtt ctttgctgac aagtcttaat caactaggcg 2161 agaggcaact tctttcagta gtcaagtggt ctaaatcatt gccaggtttt cgaaacttac 2221 atattgatga ccagataact ctcattcagt attcttggat gagcttaatg gtgtttggtc 2281 taggatggag atcctacaaa cacgtcagtg ggcagatgct gtattttgca cctgatctaa 2341 tactaaatga atcccacagg agtttgtcaa gcttcaagtt agccaagaag agttcctctg 2401 tatgaaagta ttgttacttc ttaatacaat tcctttggaa gggctacgaa gtcaaaccca 2461 gtttgaggag atgaggtcaa gctacattag agagctcatc aaggcaattg gtttgaggca 2521 aaaaggagtt gtgtcgagct cacagcgttt ctatcaactt acaaaacttc ttgataactt 2581 gcatgatctt gtcaaacaac ttcatctgta ctgcttgaat acatttatcc agtcccgggc 2641 actgagtgtt gaatttccag aaatgatgtc tgaagttatt gctgcacaat tacccaagat 2701 attggcaggg atggtgaaac cccttctctt tcataaaaag tgaatgtcat ctttttcttt 2761 taaagaatta aattttgtgg tatgtctttt tgttttggtc aggattatga ggtcttgagt 2821 ttttataatg ttcttctgaa agccttacat ttataacatc atagtgtgta aatttaaaag 2881 aaaaattgtg aggttctaat tattttcttt tataaagtat aattagaatg tttaactgtt 2941 ttgtttaccc atattttctt gaagaattta caagattgaa aaagtactaa aattgttaaa 3001 gtaaactatc ttatccatat tatttcatac catgtaggtg aggattttta acttttgcat 3061 ctaacaaatc atcgacttaa gagaaaaaat cttacatgta ataacacaaa gctattatat 3121 gttatttcta ggtaactccc tttgtgtcaa ttatatttcc aaaaatgaac ctttaaaatg 3181 gtatgcaaaa ttttgtctat atatatttgt gtgaggagga aattcataac tttcctcaga 3241 ttttcaaaag tatttttaat gcaaaaaatg tagaaagagt ttaaaaccac taaaatagat 3301 tgatgttctt caaactaggc aaaacaactc atatgttaag accattttcc agattggaaa 3361 cacaaatctc ttaggaagtt aataagtaga ttcatatcat tatgcaaata gtattgtggg 3421 ttttgtaggt ttttaaaata accttttttg gggagagaat tgtcctctaa tgaggtattg 3481 cgagtggaca taagaaatca gaagattatg gcctaactgt actccttacc aactgtggca 3541 tgctgaaagt tagtcactct tactgattct caattctctc acctttgaaa gtagtaaaat 3601 atctttcctg ccaattgctc ctttgggtca gagcttatta acatcttttc aaatcaaagg 3661 aaagaagaaa gggagaggag gaggagggag gtatcaattc acataccttt ctcctcttta 3721 tcctccacta tcatgaattc atattatgtt tcagccatgc aaatcttttt accatgaaat 3781 ttcttccaga attttccccc tttgacacaa attccatgca tgtttcaacc ttcgagactc 3841 agccaaatgt catttctgta aaatcttccc tgagtcttcc aagcagtaat ttgccttctc 3901 ctagagttta cctgccattt tgtgcacatt tgagttacag tagcatgtta ttttacaatt 3961 gtgactctcc tgggagtctg ggagccatat aaagtggtca atagtgtttg ctgactgaga 4021 gttgaatgac attttctctc tgtcttggta ttactgtaga tttcgatcat tctttggtta 4081 catttctgca tatttctgta cccatgactt tatcactttc ttctcccatg ctttatctcc 4141 atcaattatc ttcattactt ttaaattttc cacctttgct tcctactttg tgagatctct 4201 ccctttactg actataacat agaagaatag aagtgtattt tatgtgtctt aaggacaata 4261 ctttagattc cttgttctaa gtttttaaac tgaatgaatg gaatattatt tctctcccta 4321 agcaaaattc cacaaaacaa ttatttctta tgtttatgta gccttaaatt gttttgtact 4381 gtaaacctca gcataaaaac tttcttcatt tctaatttca ttcaacaaat attgattgaa 4441 tacctggtat tagcacaaga aaaatgtgct aataagcctt atgagaattt ggagctgaag 4501 aaagacatat aactcaggaa agttacagtc cagtagtagg tataaattac agtgcctgat 4561 aaataggcat tttaatattt gtacactcaa cgtatactag gtaggtgcaa aacatttaca 4621 tataatttta ctgataccca tgcagcacaa aggtactaac tttaaatatt aaataacacc 4681 tttatgtgtc agtaattcat ttgcattaaa tcttattgaa aaggctttca atatattttc 4741 cccacaaatg tcatcccaag aaaaaagtat ttttaacatc tcccaaatat aatagttaca 4801 ggaaatctac ctctgtgaga gtgacacctc tcagaatgaa ctgtgtgaca caagaaaatg 4861 aatgtaggtc tatccaaaaa aaaccccaag aaacaaaaac aatattatta gccctttatg 4921 cttaagtgat ggactcaggg aacagttgat gttgtgatca ttttattatc tgattcttgt 4981 tactttgaat taaaccaata ttttgatgat ataaatcatt tccaccagca tatatttaat 5041 ttccataata actttaaaat tttctaattt cactcaacta tgagggaata gaatgtggtg 5101 gccacaggtt tggcttttgt taaaatgttt gatatcttcg atgttgatct ctgtctgcaa 5161 tgtagatgtc taaacactag gatttaatat ttaaggctaa gctttaaaaa taaagtacct 5221 ttttaaaaag aatatggctt caccaaatgg aaaataccta atttctaaat ctttttctct 5281 acaaagtcct atctactaat gtctccatta ctatttagtc atcataacca ttatcttcat 5341 tttacatgtc gtgttctttc tggtagctct aaaatgacac taaatcataa gaagacaggt 5401 tacatatcag gaaatacttg aaggttactg aaatagattc ttgagttaat gaaaatattt 5461 tctgtaaaaa ggtttgaaaa gccatttgag tctaaagcat tatacctcca ttatcagtag 5521 ttatgtgaca attgtgtgtg tgtttaatgt ttaaagatgt ggcacttttt aataaggcaa 5581 tgctatgcta ttttttccca tttaacatta agataattta ttgctataca gatgatatgg 5641 aaatatgatg aacaatattt tttttgccaa aactatgcct tgtaagtagc catggaatgt 5701 caacctgtaa cttaaattat ccacagatag tcatgtgttt gatgatgggc actgtggaga 5761 taactgacat aggactgtgc cccccttctc tgccacttac tagctggatg agattaagca 5821 agtcatttaa ctgctctgat taaacctgcc tttcccaagt gctttgtaat gaatagaaat 5881 ggaaaccaaa aaaaacgtat acaggccttc agaaatagta attgctacta ttttgttttc 5941 attaagccat agttctggct ataattttat caaactcacc agctatattc tacagtgaaa 6001 gcaggattct agaaagtctc actgttttat ttatgtcacc atgtgctatg atatatttgg 6061 ttgaattcat ttgaaattag ggctggaagt attcaagtaa tttcttctgc tgaaaaaata 6121 cagtgttttg agtttagggc ctgttttatc aaagttctaa agagcctatc actcttccat 6181 tgtagacatt ttaaaataat gacactgatt ttaacatttt taagtgtctt tttagaacag 6241 agagcctgac tagaacacag cccctccaaa aacccatgct caaattattt ttactatggc 6301 agcaattcca caaaagggaa caatgggttt agaaattaca atgaagtcat caacccaaaa 6361 aacatcccta tccctaagaa ggttatgata taaaatgccc acaagaaatc tatgtctgct 6421 ttaatctgtc ttttattgct ttggaaggat ggctattaca tttttagttt ttgctgtgaa 6481 tacctgagca gtttctctca tccatactta tccttcacac atcagaagtc aggatagaat 6541 atgaatcatt ttaaaaactt ttacaactcc agagccatgt gcataagaag cattcaaaac 6601 ttgccaaaac atacattttt tttcaaattt aaagatactc tatttttgta ttcaatagct 6661 caacaactgt ggtccccact gataaagtga agtggacaag gagacaagta atggcataag 6721 tttgtttttc ccaaagtatg cctgttcaat agccattgga tgtgggaaat ttctacatct 6781 cttaaaattt tacagaaaat acatagccag atagtctagc aaaagttcac caagtcctaa 6841 attgcttatc cttacttcac taagtcatga aatcatttta atgaaaagaa catcacctag 6901 gttttgtggt ttcttttttt cttattcatg gctgagtgaa aacaacaatc tctgtttctc 6961 cctagcatct gtggactatt taatgtacca ttattccaca ctctatggtc cttactaaat 7021 acaaaattga acaaaaagca gtaaaacaac tgactcttca cccatattat aaaatataat 7081 ccaagccaga ttagtcaaca tccataagat gaatccaagc tgaactgggc ctagattatt 7141 gagttcaggt tggatcacat ccctatttat taataaactt aggaaagaag gccttacaga 7201 ccatcagtta gctggagcta atagaaccta cacttctaaa gttcggccta gaatcaatgt 7261 ggccttaaaa gctgaaaaga agcaggaaag aacagttttc ttcaataatt tgtccaccct 7321 gtcactggag aaaatttaag aatttggggg tgttggtagt aagttaaaca cagcagctgt 7381 tcatggcaga aattattcaa tacatacctt ctctgaatat cctataacca aagcaaagaa 7441 aaacaccaag gggtttgttc tcctccttgg agttgacctc attccaaggc agagctcagg 7501 tcacaggcac aggggctgcg cccaagcttg tccgcagcct tatgcagctg tggagtctgg 7561 aagactgttg caggactgct ggcctagtcc cagaatgtca gcctcatttt cgatttactg 7621 gctcttgttg ctgtatgtca tgctgacctt attgttaaac acaggtttgt ttgctttttt 7681 tccactcatg gagacatggg agaggcatta tttttaagct ggttgaaagc tttaaccgat 7741 aaagcatttt tagagaaatg tgaatcaggc agctaagaaa gcatactctg tccattacgg 7801 taaagaaaat gcacagatta ttaactctgc agtgtggcat tagtgtcctg gtcaatattc 7861 ggatagatat gaataaaata tttaaatggt attgtaaata gttttcagga catatgctat 7921 agcttatttt tattatcttt tgaaattgct cttaatacat caaatcctga tgtattcaat 7981 ttatcagata taaattattc taaatgaagc ccagttaaat gtttttgtct tgtcagttat 8041 atgttaagtt tctgatctct ttgtctatga cgtttactaa tctgcatttt tactgttatg 8101 aattatttta gacagcagtg gtttcaagct ttttgccact aaaaatacct tttattttct 8161 cctcccccag aaaagtctat accttgaagt atctatccac caaactgtac ttctattaag 8221 aaatagttat tgtgttttct taatgttttg ttattcaaag acatatcaat gaaagctgct 8281 gagcagcatg aataacaatt atatccacac agatttgata tattttgtgc agccttaact 8341 tgatagtata aaatgtcatt gctttttaaa taatagttag tcaatggact tctatcatag 8401 ctttcctaaa ctaggttaag atccagagct ttggggtcat aatatattac atacaattaa 8461 gttatctttt tctaagggct ttaaaattca tgagaataac caaaaaaggt atgtggagag 8521 ttaatacaaa cataccatat tcttgttgaa acagagatgt ggctctgctt gttctccata 8581 aggtagaaat actttccaga atttgcctaa actagtaagc cctgaatttg ctatgattag 8641 ggataggaag agattttcac atggcagact ttagaattct tcactttagc cagtaaagta 8701 tctccttttg atcttagtat tctgtgtatt ttaacttttc tgagttgtgc atgtttataa 8761 gaaaaatcag cacaaagggt ttaagttaaa gcctttttac tgaaatttga aagaaacaga 8821 agaaaatatc aaagttcttt gtattttgag aggattaaat atgatttaca aaagttacat 8881 ggagggctct ctaaaacatt aaattaatta ttttttgttg aaaagtctta ctttaggcat 8941 cattttattc ctcagcaact agctgtgaag cctttactgt gctgtatgcc agtcactctg 9001 ctagattgtg gagattacca gtgttcccgt cttctccgag cttagagttg gatggggaat 9061 aaagacaggt aaacagatag ctacaatatt gtactgtgaa tgcttatgct ggaggaagta 912 1 cagggaacta ttggagcacc taagaggagc acctaccttg aatttagggg ttagcagagg 918 1 catcctgaaa aaagtcaaag ctaagccaca atctataagc agtttaggaa ttagcagaac 924 1 gtgcgtggtg aggagatgcc aaaggcaaga agagaagagt attccaaaca ggagggattc 930 1 caaagagaga agagtatccc aaacaacatt tgcacaaacc tgatggggag agagaatgtg 936 1 gggtggggat ggatgatgag actgaagaag aaagccaggt ctagataatc agtggccttg 942 1 tacaccatgt taaagagtgt agacttgatt ctgttgtaaa caggaaagca gcacaattca 948 1 tatgaatatt ttagaagact cccactggaa tatggagaat aaagttggag atgactaatc 954 1 ctggaagcag ggagaacatt tttgaggaag ttgcactatt ttggtgaaaa tgatgatcat 960 1 aaacatgaag aattgtaggt gatcatgacc tcctctctaa ttttccagaa gggttttgga 966 1 agatataaca taggaacatt gacaggactg acgaaaggag atgaaataca ccatataaat 972 1 tgtcaaacac aaggccagat gtctaattat tttgcttatg tgttgaaatt acaaattttt 978 1 catcaggaaa ccaaaaacta caaaacttag ttttcccaag tcccagaatt ctatctgtcc 984 1 aaacaatctg taccactcca cctatatccc tacctttgca tgtctgtcca acctcaaagt 990 1 ccaggtctat acacacgggt aagactagag cagttcaagt ttcagaaaat gagaaagagg 996 1 aactgagttg tgctgaaccc atacaaaata aacacattct ttgtatagat tcttggaacc 1002 1 tcgagaggaa ttcacctaac tcataggtat ttgatggtat gaatccatgg ctgggctcgg 1008 1 cttttaaaaa gccttatctg ggattccttc tatggaacca agttccatca aagcccattt 1014 1 aaaagcctac attaaaaaca aaattcttgc tgcattgtat acaaataatg atgtcatgat 1020 1 caaataatca gatgccatta tcaagtggaa ttacaaaatg gtatacccac tccaaaaaaa 1026 1 aaaaaaaagc taaattctca gtagaacatt gtgacttcat gagccctcca cagccttgga 1032 1 gctgaggagg gagcactggt gagcagtagg ttgaagagaa aacttggcgc ttaataatct 1038 1 atccatgttt tttcatctaa aagagccttc tttttggatt accttattca atttccatca 1044 1 aggaaattgt tagttccact aaccagacag cagctgggaa ggcagaagct tactgtatgt 1050 1 acatggtagc tgtgggaagg aggtttcttt ctccaggtcc tcactggcca tacaccagtc 1056 1 ccttgttagt tatgcctggt catagacccc cgttgctatc atctcatatt taagtctttg 1062 1 gcttgtgaat ttatctattc tttcagcttc agcactgcag agtgctggga ctttgctaac 1068 1 ttccatttct tgctggctta gcacattcct cataggccca gctcttttct catctggccc 1074 1 tgctgtggag tcaccttgcc ccttcaggag agccatggct taccactgcc tgctaagcct 1080 1 ccactcagct gccaccacac taaatccaag cttctctaag atgttgcaga ctttacaggc 1086 1 aagcataaaa ggcttgatct tcctggactt ccctttactt gtctgaatct cacctccttc 1092 1 aactttcagt ctcagaatgt aggcatttgt cctctttgcc ctacatcttc cttcttctga 1098 1 atcatgaaag cctctcactt cctcttgcta tgtgctggag gcttctgtca ggttttagaa 1104 1 tgagttctca tctagtccta gtagcttttg atgcttaagt ccacctttta aggatacctt 1110 1 tgagatttag accatgtttt tcgcttgaga aagccctaat ctccagactt gcctttctgt 1116 1 ggatttcaaa gaccaactga ggaagtcaaa agctgaatgt tgactttctt tgaacatttc 1122 1 cgctataaca attccaattc tcctcagagc aatatgcctg cctccaactg accaggagaa 1128 1 aggtccagtg ccaaagagaa aaacacaaag attaattatt tcagttgagc acatactttc 1134 1 aaagtggttt gggtattcat atgaggtttt ctgtcaagag ggtgagactc ttcatctatc 1140 1 catgtgtgcc tgacagttct cctggcactg gctggtaaca gatgcaaaac tgtaaaaatt 1146 1 aagtgatcat gtattttaac gatatcatca catacttatt ttctatgtaa tgttttaaat 1152 1 ttcccctaac atactttgac tgttttgcac atggtagata ttcacatttt tttgtgttga 115 1 agttgatgca atcttcaaag ttatctaccc cgttgcttat tagtaaaact agtgttaata 1164 1 cttggcaaga gatgcaggga atctttctca tgactcacgc cctatttagt tattaatgct 1170 1 actaccctat tttgagtaag tagtaggtcc ctaagtacat tgtccagagt tatactttta 1176 1 aagatattta gccccatata cttcttgaat ctaaagtcat acaccttgct cctcatttct 1182 1 gagtgggaaa gacatttgag agtatgttga caattgttct gaaggttttt gccaagaagg 1188 1 tgaaactgtc ctttcatctg tgtatgcctg gggctgggtc cctggcagtg atggggtgac 1194 1 aatgcaaagc tgtaaaaact aggtgctagt gggcacctaa tatcatcatc atatacttat 1200 1 tttcaagcta atatgcaaaa tcccatctct gtttttaaac taagtgtaga tttcagagaa 1206 1 aatattttgt ggttcacata agaaaacagt ctactcagct tgacaagtgt tttatgttaa 1212 1 attggctggt ggtttgaaat gaatcatctt cacataatgt tttctttaaa aatattgtga 121 1 atttaactct aattcttgtt attctgtgtg ataataaaga ataaactaat ttcta (SEQ NO: 126) .

[0312] An exemplary nucleic acid sequence encoding PGR (NR 073142.2 transcript variant 5) comprises or consists of:

1 agctgaaggc aaagggtccc cgggctcccc acgtggcggg cggcccgccc tcccccgagg 61 tcggatcccc actgctgtgt cgcccagccg caggtccgtt cccggggagc cagacctcgg 121 acaccttgcc tgaagtttcg gccataccta tctccctgga cgggctactc ttccctcggc 181 cctgccaggg acaggacccc tccgacgaaa agacgcagga ccagcagtcg ctgtcggacg 241 tggagggcgc atattccaga gctgaagcta caaggggtgc tggaggcagc agttctagtc 301 ccccagaaaa ggacagcgga ctgctggaca gtgtcttgga cactctgttg gcgccctcag 361 gtcccgggca gagccaaccc agccctcccg cctgcgaggt caccagctct tggtgcctgt 421 ttggccccga acttcccgaa gatccaccgg ctgcccccgc cacccagcgg gtgttgtccc 481 cgctcatgag ccggtccggg tgcaaggttg gagacagctc cgggacggca gctgcccata 541 aagtgctgcc ccggggcctg tcaccagccc ggcagctgct gctcccggcc tctgagagcc 601 ctcactggtc cggggcccca gtgaagccgt ctccgcaggc cgctgcggtg gaggttgagg 661 aggaggatgg ctctgagtcc gaggagtctg cgggtccgct tctgaagggc aaacctcggg 721 ctctgggtgg cgcggcggct ggaggaggag ccgcggctgt cccgccgggg gcggcagcag 781 gaggcgtcgc cctggtcccc aaggaagatt cccgcttctc agcgcccagg gtcgccctgg 841 tggagcagga cgcgccgatg gcgcccgggc gctccccgct ggccaccacg gtgatggatt 901 tcatccacgt gcctatcctg cctctcaatc acgccttatt ggcagcccgc actcggcagc 961 tgctggaaga cgaaagttac gacggcgggg ccggggctgc cagcgccttt gccccgccgc 1021 ggagttcacc ctgtgcctcg tccaccccgg tcgctgtagg cgacttcccc gactgcgcgt 1081 acccgcccga cgccgagccc aaggacgacg cgtaccctct ctatagcgac ttccagccgc 1141 ccgctctaaa gataaaggag gaggaggaag gcgcggaggc ctccgcgcgc tccccgcgtt 1201 cctaccttgt ggccggtgcc aaccccgcag ccttcccgga tttcccgttg gggccaccgc 1261 ccccgctgcc gccgcgagcg accccatcca gacccgggga agcggcggtg acggccgcac 1321 ccgccagtgc ctcagtctcg tctgcgtcct cctcggggtc gaccctggag tgcatcctgt 1381 acaaagcgga gggcgcgccg ccccagcagg gcccgttcgc gccgccgccc tgcaaggcgc 1441 cgggcgcgag cggctgcctg ctcccgcggg acggcctgcc ctccacctcc gcctctgccg 1501 ccgccgccgg ggcggccccc gcgctctacc ctgcactcgg cctcaacggg ctcccgcagc 1561 tcggctacca ggccgccgtg ctcaaggagg gcctgccgca ggtctacccg ccctatctca 1621 actacctgag gccggattca gaagccagcc agagcccaca atacagcttc gagtcattac 1681 ctcagaagat ttgtttaatc tgtggggatg aagcatcagg ctgtcattat ggtgtcctta 1741 cctgtgggag ctgtaaggtc ttctttaaga gggcaatgga aggtcgaaaa tttaaaaagt 1801 tcaataaagt cagagttgtg agagcactgg atgctgttgc tctcccacag ccagtgggcg 1861 ttccaaatga aagccaagcc ctaagccaga gattcacttt ttcaccaggt caagacatac 1921 agttgattcc accactgatc aacctgttaa tgagcattga accagatgtg atctatgcag 1981 gacatgacaa cacaaaacct gacacctcca gttctttgct gacaagtctt aatcaactag 2041 gcgagaggca acttctttca gtagtcaagt ggtctaaatc attgccaggt tttcgaaact 2101 tacatattga tgaccagata actctcattc agtattcttg gatgagctta atggtgtttg 2161 gtctaggatg gagatcctac aaacacgtca gtgggcagat gctgtatttt gcacctgatc 2221 taatactaaa tgaatcccac aggagtttgt caagcttcaa gttagccaag aagagttcct 2281 ctgtatgaaa gtattgttac ttcttaatac aattcctttg gaagggctac gaagtcaaac 2341 ccagtttgag gagatgaggt caagctacat tagagagctc atcaaggcaa ttggtttgag 2401 gcaaaaagga gttgtgtcga gctcacagcg tttctatcaa cttacaaaac ttcttgataa 2461 cttgcatgat cttgtcaaac aacttcatct gtactgcttg aatacattta tccagtcccg 2521 ggcactgagt gttgaatttc cagaaatgat gtctgaagtt attgctgcac aattacccaa 2581 gatattggca gggatggtga aaccccttct ctttcataaa aagtgaatgt catctttttc 2641 ttttaaagaa ttaaattttg tggtatgtct ttttgttttg gtcaggatta tgaggtcttg 2701 agtttttata atgttcttct gaaagcctta catttataac atcatagtgt gtaaatttaa 2761 aagaaaaatt gtgaggttct aattattttc ttttataaag tataattaga atgtttaact 2821 gttttgttta cccatatttt cttgaagaat ttacaagatt gaaaaagtac taaaattgtt 2881 aaagtaaact atcttatcca tattatttca taccatgtag gtgaggattt ttaacttttg 2941 catctaacaa atcatcgact taagagaaaa aatcttacat gtaataacac aaagctatta 3001 tatgttattt ctaggtaact ccctttgtgt caattatatt tccaaaaatg aacctttaaa 3061 atggtatgca aaattttgtc tatatatatt tgtgtgagga ggaaattcat aactttcctc 3121 agattttcaa aagtattttt aatgcaaaaa atgtagaaag agtttaaaac cactaaaata 3181 gattgatgtt cttcaaacta ggcaaaacaa ctcatatgtt aagaccattt tccagattgg 3241 aaacacaaat ctcttaggaa gttaataagt agattcatat cattatgcaa atagtattgt 3301 gggttttgta ggtttttaaa ataacctttt ttggggagag aattgtcctc taatgaggta 3361 ttgcgagtgg acataagaaa tcagaagatt atggcctaac tgtactcctt accaactgtg 3421 gcatgctgaa agttagtcac tcttactgat tctcaattct ctcacctttg aaagtagtaa 3481 aatatctttc ctgccaattg ctcctttggg tcagagctta ttaacatctt ttcaaatcaa 3541 aggaaagaag aaagggagag gaggaggagg gaggtatcaa ttcacatacc tttctcctct 3601 ttatcctcca ctatcatgaa ttcatattat gtttcagcca tgcaaatctt tttaccatga 3661 aatttcttcc agaattttcc ccctttgaca caaattccat gcatgtttca accttcgaga 3721 ctcagccaaa tgtcatttct gtaaaatctt ccctgagtct tccaagcagt aatttgcctt 3781 ctcctagagt ttacctgcca ttttgtgcac atttgagtta cagtagcatg ttattttaca 3841 attgtgactc tcctgggagt ctgggagcca tataaagtgg tcaatagtgt ttgctgactg 3901 agagttgaat gacattttct ctctgtcttg gtattactgt agatttcgat cattctttgg 3961 ttacatttct gcatatttct gtacccatga ctttatcact ttcttctccc atgctttatc 4021 tccatcaatt atcttcatta cttttaaatt ttccaccttt gcttcctact ttgtgagatc 4081 tctcccttta ctgactataa catagaagaa tagaagtgta ttttatgtgt cttaaggaca 4141 atactttaga ttccttgttc taagttttta aactgaatga atggaatatt atttctctcc 4201 ctaagcaaaa ttccacaaaa caattatttc ttatgtttat gtagccttaa attgttttgt 4261 actgtaaacc tcagcataaa aactttcttc atttctaatt tcattcaaca aatattgatt 4321 gaatacctgg tattagcaca agaaaaatgt gctaataagc cttatgagaa tttggagctg 4381 aagaaagaca tataactcag gaaagttaca gtccagtagt aggtataaat tacagtgcct 4441 gataaatagg cattttaata tttgtacact caacgtatac taggtaggtg caaaacattt 4501 acatataatt ttactgatac ccatgcagca caaaggtact aactttaaat attaaataac 4561 acctttatgt gtcagtaatt catttgcatt aaatcttatt gaaaaggctt tcaatatatt 4621 ttccccacaa atgtcatccc aagaaaaaag tatttttaac atctcccaaa tataatagtt 4681 acaggaaatc tacctctgtg agagtgacac ctctcagaat gaactgtgtg acacaagaaa 4741 atgaatgtag gtctatccaa aaaaaacccc aagaaacaaa aacaatatta ttagcccttt 4801 atgcttaagt gatggactca gggaacagtt gatgttgtga tcattttatt atctgattct 4861 tgttactttg aattaaacca atattttgat gatataaatc atttccacca gcatatattt 4921 aatttccata ataactttaa aattttctaa tttcactcaa ctatgaggga atagaatgtg 4981 gtggccacag gtttggcttt tgttaaaatg tttgatatct tcgatgttga tctctgtctg 5041 caatgtagat gtctaaacac taggatttaa tatttaaggc taagctttaa aaataaagta 5101 cctttttaaa aagaatatgg cttcaccaaa tggaaaatac ctaatttcta aatctttttc 5161 tctacaaagt cctatctact aatgtctcca ttactattta gtcatcataa ccattatctt 5221 cattttacat gtcgtgttct ttctggtagc tctaaaatga cactaaatca taagaagaca 5281 ggttacatat caggaaatac ttgaaggtta ctgaaataga ttcttgagtt aatgaaaata 5341 ttttctgtaa aaaggtttga aaagccattt gagtctaaag cattatacct ccattatcag 5401 tagttatgtg acaattgtgt gtgtgtttaa tgtttaaaga tgtggcactt tttaataagg 5461 caatgctatg ctattttttc ccatttaaca ttaagataat ttattgctat acagatgata 5521 tggaaatatg atgaacaata ttttttttgc caaaactatg ccttgtaagt agccatggaa 5581 tgtcaacctg taacttaaat tatccacaga tagtcatgtg tttgatgatg ggcactgtgg 5641 agataactga cataggactg tgcccccctt ctctgccact tactagctgg atgagattaa 5701 gcaagtcatt taactgctct gattaaacct gcctttccca agtgctttgt aatgaataga 5761 aatggaaacc aaaaaaaacg tatacaggcc ttcagaaata gtaattgcta ctattttgtt 5821 ttcattaagc catagttctg gctataattt tatcaaactc accagctata ttctacagtg 5881 aaagcaggat tctagaaagt ctcactgttt tatttatgtc accatgtgct atgatatatt 5941 tggttgaatt catttgaaat tagggctgga agtattcaag taatttcttc tgctgaaaaa 6001 atacagtgtt ttgagtttag ggcctgtttt atcaaagttc taaagagcct atcactcttc 6061 cattgtagac attttaaaat aatgacactg attttaacat ttttaagtgt ctttttagaa 6121 cagagagcct gactagaaca cagcccctcc aaaaacccat gctcaaatta tttttactat 6181 ggcagcaatt ccacaaaagg gaacaatggg tttagaaatt acaatgaagt catcaaccca 6241 aaaaacatcc ctatccctaa gaaggttatg atataaaatg cccacaagaa atctatgtct 6301 gctttaatct gtcttttatt gctttggaag gatggctatt acatttttag tttttgctgt 6361 gaatacctga gcagtttctc tcatccatac ttatccttca cacatcagaa gtcaggatag 6421 aatatgaatc attttaaaaa cttttacaac tccagagcca tgtgcataag aagcattcaa 6481 aacttgccaa aacatacatt ttttttcaaa tttaaagata ctctattttt gtattcaata 6541 gctcaacaac tgtggtcccc actgataaag tgaagtggac aaggagacaa gtaatggcat 6601 aagtttgttt ttcccaaagt atgcctgttc aatagccatt ggatgtggga aatttctaca 6661 tctcttaaaa ttttacagaa aatacatagc cagatagtct agcaaaagtt caccaagtcc 6721 taaattgctt atccttactt cactaagtca tgaaatcatt ttaatgaaaa gaacatcacc 6781 taggttttgt ggtttctttt tttcttattc atggctgagt gaaaacaaca atctctgttt 6841 ctccctagca tctgtggact atttaatgta ccattattcc acactctatg gtccttacta 6901 aatacaaaat tgaacaaaaa gcagtaaaac aactgactct tcacccatat tataaaatat 6961 aatccaagcc agattagtca acatccataa gatgaatcca agctgaactg ggcctagatt 7021 attgagttca ggttggatca catccctatt tattaataaa cttaggaaag aaggccttac 7081 agaccatcag ttagctggag ctaatagaac ctacacttct aaagttcggc ctagaatcaa 7141 tgtggcctta aaagctgaaa agaagcagga aagaacagtt ttcttcaata atttgtccac 7201 cctgtcactg gagaaaattt aagaatttgg gggtgttggt agtaagttaa acacagcagc 7261 tgttcatggc agaaattatt caatacatac cttctctgaa tatcctataa ccaaagcaaa 7321 gaaaaacacc aaggggtttg ttctcctcct tggagttgac ctcattccaa ggcagagctc 7381 aggtcacagg cacaggggct gcgcccaagc ttgtccgcag ccttatgcag ctgtggagtc 7441 tggaagactg ttgcaggact gctggcctag tcccagaatg tcagcctcat tttcgattta 7501 ctggctcttg ttgctgtatg tcatgctgac cttattgtta aacacaggtt tgtttgcttt 7561 ttttccactc atggagacat gggagaggca ttatttttaa gctggttgaa agctttaacc 7621 gataaagcat ttttagagaa atgtgaatca ggcagctaag aaagcatact ctgtccatta 7681 cggtaaagaa aatgcacaga ttattaactc tgcagtgtgg cattagtgtc ctggtcaata 7741 ttcggataga tatgaataaa atatttaaat ggtattgtaa atagttttca ggacatatgc 7801 tatagcttat ttttattatc ttttgaaatt gctcttaata catcaaatcc tgatgtattc 7861 aatttatcag atataaatta ttctaaatga agcccagtta aatgtttttg tcttgtcagt 7921 tatatgttaa gtttctgatc tctttgtcta tgacgtttac taatctgcat ttttactgtt 7981 atgaattatt ttagacagca gtggtttcaa gctttttgcc actaaaaata ccttttattt 8041 tctcctcccc cagaaaagtc tataccttga agtatctatc caccaaactg tacttctatt 8101 aagaaatagt tattgtgttt tcttaatgtt ttgttattca aagacatatc aatgaaagct 8161 gctgagcagc atgaataaca attatatcca cacagatttg atatattttg tgcagcctta 8221 acttgatagt ataaaatgtc attgcttttt aaataatagt tagtcaatgg acttctatca 8281 tagctttcct aaactaggtt aagatccaga gctttggggt cataatatat tacatacaat 8341 taagttatct ttttctaagg gctttaaaat tcatgagaat aaccaaaaaa ggtatgtgga 8401 gagttaatac aaacatacca tattcttgtt gaaacagaga tgtggctctg cttgttctcc 8461 ataaggtaga aatactttcc agaatttgcc taaactagta agccctgaat ttgctatgat 8521 tagggatagg aagagatttt cacatggcag actttagaat tcttcacttt agccagtaaa 8581 gtatctcctt ttgatcttag tattctgtgt attttaactt ttctgagttg tgcatgttta 8641 taagaaaaat cagcacaaag ggtttaagtt aaagcctttt tactgaaatt tgaaagaaac 8701 agaagaaaat atcaaagttc tttgtatttt gagaggatta aatatgattt acaaaagtta 8761 catggagggc tctctaaaac attaaattaa ttattttttg ttgaaaagtc ttactttagg 8821 catcatttta ttcctcagca actagctgtg aagcctttac tgtgctgtat gccagtcact 8881 ctgctagatt gtggagatta ccagtgttcc cgtcttctcc gagcttagag ttggatgggg 8941 aataaagaca ggtaaacaga tagctacaat attgtactgt gaatgcttat gctggaggaa 9001 gtacagggaa ctattggagc acctaagagg agcacctacc ttgaatttag gggttagcag 9061 aggcatcctg aaaaaagtca aagctaagcc acaatctata agcagtttag gaattagcag 9121 aacgtgcgtg gtgaggagat gccaaaggca agaagagaag agtattccaa acaggaggga 9181 ttccaaagag agaagagtat cccaaacaac atttgcacaa acctgatggg gagagagaat 9241 gtggggtggg gatggatgat gagactgaag aagaaagcca ggtctagata atcagtggcc 9301 ttgtacacca tgttaaagag tgtagacttg attctgttgt aaacaggaaa gcagcacaat 9361 tcatatgaat attttagaag actcccactg gaatatggag aataaagttg gagatgacta 9421 atcctggaag cagggagaac atttttgagg aagttgcact attttggtga aaatgatgat 9481 cataaacatg aagaattgta ggtgatcatg acctcctctc taattttcca gaagggtttt 9541 ggaagatata acataggaac attgacagga ctgacgaaag gagatgaaat acaccatata 9601 aattgtcaaa cacaaggcca gatgtctaat tattttgctt atgtgttgaa attacaaatt 9661 tttcatcagg aaaccaaaaa ctacaaaact tagttttccc aagtcccaga attctatctg 9721 tccaaacaat ctgtaccact ccacctatat ccctaccttt gcatgtctgt ccaacctcaa 9781 agtccaggtc tatacacacg ggtaagacta gagcagttca agtttcagaa aatgagaaag 9841 aggaactgag ttgtgctgaa cccatacaaa ataaacacat tctttgtata gattcttgga 9901 acctcgagag gaattcacct aactcatagg tatttgatgg tatgaatcca tggctgggct 9961 cggcttttaa aaagccttat ctgggattcc ttctatggaa ccaagttcca tcaaagccca 10021 tttaaaagcc tacattaaaa acaaaattct tgctgcattg tatacaaata atgatgtcat 10081 gatcaaataa tcagatgcca ttatcaagtg gaattacaaa atggtatacc cactccaaaa 10141 aaaaaaaaaa agctaaattc tcagtagaac attgtgactt catgagccct ccacagcctt 10201 ggagctgagg agggagcact ggtgagcagt aggttgaaga gaaaacttgg cgcttaataa 10261 tctatccatg ttttttcatc taaaagagcc ttctttttgg attaccttat tcaatttcca 10321 tcaaggaaat tgttagttcc actaaccaga cagcagctgg gaaggcagaa gcttactgta 10381 tgtacatggt agctgtggga aggaggtttc tttctccagg tcctcactgg ccatacacca 10441 gtcccttgtt agttatgcct ggtcatagac ccccgttgct atcatctcat atttaagtct 10501 ttggcttgtg aatttatcta ttctttcagc ttcagcactg cagagtgctg ggactttgct 10561 aacttccatt tcttgctggc ttagcacatt cctcataggc ccagctcttt tctcatctgg 10621 ccctgctgtg gagtcacctt gccccttcag gagagccatg gcttaccact gcctgctaag 10681 cctccactca gctgccacca cactaaatcc aagcttctct aagatgttgc agactttaca 10741 ggcaagcata aaaggcttga tcttcctgga cttcccttta cttgtctgaa tctcacctcc 10801 ttcaactttc agtctcagaa tgtaggcatt tgtcctcttt gccctacatc ttccttcttc 10861 tgaatcatga aagcctctca cttcctcttg ctatgtgctg gaggcttctg tcaggtttta 10921 gaatgagttc tcatctagtc ctagtagctt ttgatgctta agtccacctt ttaaggatac 10981 ctttgagatt tagaccatgt ttttcgcttg agaaagccct aatctccaga cttgcctttc 11041 tgtggatttc aaagaccaac tgaggaagtc aaaagctgaa tgttgacttt ctttgaacat 11101 ttccgctata acaattccaa ttctcctcag agcaatatgc ctgcctccaa ctgaccagga 11161 gaaaggtcca gtgccaaaga gaaaaacaca aagattaatt atttcagttg agcacatact 11221 ttcaaagtgg tttgggtatt catatgaggt tttctgtcaa gagggtgaga ctcttcatct 11281 atccatgtgt gcctgacagt tctcctggca ctggctggta acagatgcaa aactgtaaaa 11341 attaagtgat catgtatttt aacgatatca tcacatactt attttctatg taatgtttta 11401 aatttcccct aacatacttt gactgttttg cacatggtag atattcacat ttttttgtgt 11461 tgaagttgat gcaatcttca aagttatcta ccccgttgct tattagtaaa actagtgtta 11521 atacttggca agagatgcag ggaatctttc tcatgactca cgccctattt agttattaat 11581 gctactaccc tattttgagt aagtagtagg tccctaagta cattgtccag agttatactt 11641 ttaaagatat ttagccccat atacttcttg aatctaaagt catacacctt gctcctcatt 11701 tctgagtggg aaagacattt gagagtatgt tgacaattgt tctgaaggtt tttgccaaga 11761 aggtgaaact gtcctttcat ctgtgtatgc ctggggctgg gtccctggca gtgatggggt 11821 gacaatgcaa agctgtaaaa actaggtgct agtgggcacc taatatcatc atcatatact 11881 tattttcaag ctaatatgca aaatcccatc tctgttttta aactaagtgt agatttcaga 11941 gaaaatattt tgtggttcac ataagaaaac agtctactca gcttgacaag tgttttatgt 12001 taaattggct ggtggtttga aatgaatcat cttcacataa tgttttcttt aaaaatattg 12061 tgaatttaac tctaattctt gttattctgt gtgataataa agaataaact aatttcta (SEQ ID NO: 127) .

[0313] An exemplary nucleic acid sequence encoding PGR (NR 073143.2 transcript variant

6) comprises or consists of:

1 agctgaaggc aaagggtccc cgggctcccc acgtggcggg cggcccgccc tcccccgagg 61 tcggatcccc actgctgtgt cgcccagccg caggtccgtt cccggggagc cagacctcgg 121 acaccttgcc tgaagtttcg gccataccta tctccctgga cgggctactc ttccctcggc 181 cctgccaggg acaggacccc tccgacgaaa agacgcagga ccagcagtcg ctgtcggacg 241 tggagggcgc atattccaga gctgaagcta caaggggtgc tggaggcagc agttctagtc 301 ccccagaaaa ggacagcgga ctgctggaca gtgtcttgga cactctgttg gcgccctcag 361 gtcccgggca gagccaaccc agccctcccg cctgcgaggt caccagctct tggtgcctgt 421 ttggccccga acttcccgaa gatccaccgg ctgcccccgc cacccagcgg gtgttgtccc 481 cgctcatgag ccggtccggg tgcaaggttg gagacagctc cgggacggca gctgcccata 541 aagtgctgcc ccggggcctg tcaccagccc ggcagctgct gctcccggcc tctgagagcc 601 ctcactggtc cggggcccca gtgaagccgt ctccgcaggc cgctgcggtg gaggttgagg 661 aggaggatgg ctctgagtcc gaggagtctg cgggtccgct tctgaagggc aaacctcggg 721 ctctgggtgg cgcggcggct ggaggaggag ccgcggctgt cccgccgggg gcggcagcag 781 gaggcgtcgc cctggtcccc aaggaagatt cccgcttctc agcgcccagg gtcgccctgg 841 tggagcagga cgcgccgatg gcgcccgggc gctccccgct ggccaccacg gtgatggatt 901 tcatccacgt gcctatcctg cctctcaatc acgccttatt ggcagcccgc actcggcagc 961 tgctggaaga cgaaagttac gacggcgggg ccggggctgc cagcgccttt gccccgccgc 1021 ggagttcacc ctgtgcctcg tccaccccgg tcgctgtagg cgacttcccc gactgcgcgt 1081 acccgcccga cgccgagccc aaggacgacg cgtaccctct ctatagcgac ttccagccgc 1141 ccgctctaaa gataaaggag gaggaggaag gcgcggaggc ctccgcgcgc tccccgcgtt 1201 cctaccttgt ggccggtgcc aaccccgcag ccttcccgga tttcccgttg gggccaccgc 1261 ccccgctgcc gccgcgagcg accccatcca gacccgggga agcggcggtg acggccgcac 1321 ccgccagtgc ctcagtctcg tctgcgtcct cctcggggtc gaccctggag tgcatcctgt 1381 acaaagcgga gggcgcgccg ccccagcagg gcccgttcgc gccgccgccc tgcaaggcgc 1441 cgggcgcgag cggctgcctg ctcccgcggg acggcctgcc ctccacctcc gcctctgccg 1501 ccgccgccgg ggcggccccc gcgctctacc ctgcactcgg cctcaacggg ctcccgcagc 1561 tcggctacca ggccgccgtg ctcaaggagg gcctgccgca ggtctacccg ccctatctca 1621 actacctgag gccggattca gaagccagcc agagcccaca atacagcttc gagtcattac 1681 ctcagaagat ttgtttaatc tgtggggatg aagcatcagg ctgtcattat ggtgtcctta 1741 cctgtgggag ctgtaaggtc ttctttaaga gggcaatgga agggcagcac aactacttat 1801 gtgctggaag aaatgactgc atcgttgata aaatccgcag aaaaaactgc ccagcatgtc 1861 gccttagaaa gtgctgtcag gctggcatgg tccttggagg ttttcgaaac ttacatattg 1921 atgaccagat aactctcatt cagtattctt ggatgagctt aatggtgttt ggtctaggat 1981 ggagatccta caaacacgtc agtgggcaga tgctgtattt tgcacctgat ctaatactaa 2041 atgattcctt tggaagggct acgaagtcaa acccagtttg aggagatgag gtcaagctac 2101 attagagagc tcatcaaggc aattggtttg aggcaaaaag gagttgtgtc gagctcacag 2161 cgtttctatc aacttacaaa acttcttgat aacttgcatg atcttgtcaa acaacttcat 2221 ctgtactgct tgaatacatt tatccagtcc cgggcactga gtgttgaatt tccagaaatg 2281 atgtctgaag ttattgctgc acaattaccc aagatattgg cagggatggt gaaacccctt 2341 ctctttcata aaaagtgaat gtcatctttt tcttttaaag aattaaattt tgtggtatgt 2401 ctttttgttt tggtcaggat tatgaggtct tgagttttta taatgttctt ctgaaagcct 2461 tacatttata acatcatagt gtgtaaattt aaaagaaaaa ttgtgaggtt ctaattattt 2521 tcttttataa agtataatta gaatgtttaa ctgttttgtt tacccatatt ttcttgaaga 2581 atttacaaga ttgaaaaagt actaaaattg ttaaagtaaa ctatcttatc catattattt 2641 cataccatgt aggtgaggat ttttaacttt tgcatctaac aaatcatcga cttaagagaa 2701 aaaatcttac atgtaataac acaaagctat tatatgttat ttctaggtaa ctccctttgt 2761 gtcaattata tttccaaaaa tgaaccttta aaatggtatg caaaattttg tctatatata 2821 tttgtgtgag gaggaaattc ataactttcc tcagattttc aaaagtattt ttaatgcaaa 2881 aaatgtagaa agagtttaaa accactaaaa tagattgatg ttcttcaaac taggcaaaac 2941 aactcatatg ttaagaccat tttccagatt ggaaacacaa atctcttagg aagttaataa 3001 gtagattcat atcattatgc aaatagtatt gtgggttttg taggttttta aaataacctt 3061 ttttggggag agaattgtcc tctaatgagg tattgcgagt ggacataaga aatcagaaga 3121 ttatggccta actgtactcc ttaccaactg tggcatgctg aaagttagtc actcttactg 3181 attctcaatt ctctcacctt tgaaagtagt aaaatatctt tcctgccaat tgctcctttg 3241 ggtcagagct tattaacatc ttttcaaatc aaaggaaaga agaaagggag aggaggagga 3301 gggaggtatc aattcacata cctttctcct ctttatcctc cactatcatg aattcatatt 3361 atgtttcagc catgcaaatc tttttaccat gaaatttctt ccagaatttt ccccctttga 3421 cacaaattcc atgcatgttt caaccttcga gactcagcca aatgtcattt ctgtaaaatc 3481 ttccctgagt cttccaagca gtaatttgcc ttctcctaga gtttacctgc cattttgtgc 3541 acatttgagt tacagtagca tgttatttta caattgtgac tctcctggga gtctgggagc 3601 catataaagt ggtcaatagt gtttgctgac tgagagttga atgacatttt ctctctgtct 3661 tggtattact gtagatttcg atcattcttt ggttacattt ctgcatattt ctgtacccat 3721 gactttatca ctttcttctc ccatgcttta tctccatcaa ttatcttcat tacttttaaa 3781 ttttccacct ttgcttccta ctttgtgaga tctctccctt tactgactat aacatagaag 3841 aatagaagtg tattttatgt gtcttaagga caatacttta gattccttgt tctaagtttt 3901 taaactgaat gaatggaata ttatttctct ccctaagcaa aattccacaa aacaattatt 3961 tcttatgttt atgtagcctt aaattgtttt gtactgtaaa cctcagcata aaaactttct 4021 tcatttctaa tttcattcaa caaatattga ttgaatacct ggtattagca caagaaaaat 4081 gtgctaataa gccttatgag aatttggagc tgaagaaaga catataactc aggaaagtta 4141 cagtccagta gtaggtataa attacagtgc ctgataaata ggcattttaa tatttgtaca 4201 ctcaacgtat actaggtagg tgcaaaacat ttacatataa ttttactgat acccatgcag 4261 cacaaaggta ctaactttaa atattaaata acacctttat gtgtcagtaa ttcatttgca 4321 ttaaatctta ttgaaaaggc tttcaatata ttttccccac aaatgtcatc ccaagaaaaa 4381 agtattttta acatctccca aatataatag ttacaggaaa tctacctctg tgagagtgac 4441 acctctcaga atgaactgtg tgacacaaga aaatgaatgt aggtctatcc aaaaaaaacc 4501 ccaagaaaca aaaacaatat tattagccct ttatgcttaa gtgatggact cagggaacag 4561 ttgatgttgt gatcatttta ttatctgatt cttgttactt tgaattaaac caatattttg 4621 atgatataaa tcatttccac cagcatatat ttaatttcca taataacttt aaaattttct 4681 aatttcactc aactatgagg gaatagaatg tggtggccac aggtttggct tttgttaaaa 4741 tgtttgatat cttcgatgtt gatctctgtc tgcaatgtag atgtctaaac actaggattt 4801 aatatttaag gctaagcttt aaaaataaag taccttttta aaaagaatat ggcttcacca 4861 aatggaaaat acctaatttc taaatctttt tctctacaaa gtcctatcta ctaatgtctc 4921 cattactatt tagtcatcat aaccattatc ttcattttac atgtcgtgtt ctttctggta 4981 gctctaaaat gacactaaat cataagaaga caggttacat atcaggaaat acttgaaggt 5041 tactgaaata gattcttgag ttaatgaaaa tattttctgt aaaaaggttt gaaaagccat 5101 ttgagtctaa agcattatac ctccattatc agtagttatg tgacaattgt gtgtgtgttt 5161 aatgtttaaa gatgtggcac tttttaataa ggcaatgcta tgctattttt tcccatttaa 5221 cattaagata atttattgct atacagatga tatggaaata tgatgaacaa tatttttttt 5281 gccaaaacta tgccttgtaa gtagccatgg aatgtcaacc tgtaacttaa attatccaca 5341 gatagtcatg tgtttgatga tgggcactgt ggagataact gacataggac tgtgcccccc 5401 ttctctgcca cttactagct ggatgagatt aagcaagtca tttaactgct ctgattaaac 5461 ctgcctttcc caagtgcttt gtaatgaata gaaatggaaa ccaaaaaaaa cgtatacagg 5521 ccttcagaaa tagtaattgc tactattttg ttttcattaa gccatagttc tggctataat 5581 tttatcaaac tcaccagcta tattctacag tgaaagcagg attctagaaa gtctcactgt 5641 tttatttatg tcaccatgtg ctatgatata tttggttgaa ttcatttgaa attagggctg 5701 gaagtattca agtaatttct tctgctgaaa aaatacagtg ttttgagttt agggcctgtt 5761 ttatcaaagt tctaaagagc ctatcactct tccattgtag acattttaaa ataatgacac 5821 tgattttaac atttttaagt gtctttttag aacagagagc ctgactagaa cacagcccct 5881 ccaaaaaccc atgctcaaat tatttttact atggcagcaa ttccacaaaa gggaacaatg 5941 ggtttagaaa ttacaatgaa gtcatcaacc caaaaaacat ccctatccct aagaaggtta 6001 tgatataaaa tgcccacaag aaatctatgt ctgctttaat ctgtctttta ttgctttgga 6061 aggatggcta ttacattttt agtttttgct gtgaatacct gagcagtttc tctcatccat 6121 acttatcctt cacacatcag aagtcaggat agaatatgaa tcattttaaa aacttttaca 6181 actccagagc catgtgcata agaagcattc aaaacttgcc aaaacataca ttttttttca 6241 aatttaaaga tactctattt ttgtattcaa tagctcaaca actgtggtcc ccactgataa 6301 agtgaagtgg acaaggagac aagtaatggc ataagtttgt ttttcccaaa gtatgcctgt 6361 tcaatagcca ttggatgtgg gaaatttcta catctcttaa aattttacag aaaatacata 6421 gccagatagt ctagcaaaag ttcaccaagt cctaaattgc ttatccttac ttcactaagt 6481 catgaaatca ttttaatgaa aagaacatca cctaggtttt gtggtttctt tttttcttat 6541 tcatggctga gtgaaaacaa caatctctgt ttctccctag catctgtgga ctatttaatg 6601 taccattatt ccacactcta tggtccttac taaatacaaa attgaacaaa aagcagtaaa 6661 acaactgact cttcacccat attataaaat ataatccaag ccagattagt caacatccat 6721 aagatgaatc caagctgaac tgggcctaga ttattgagtt caggttggat cacatcccta 6781 tttattaata aacttaggaa agaaggcctt acagaccatc agttagctgg agctaataga 6841 acctacactt ctaaagttcg gcctagaatc aatgtggcct taaaagctga aaagaagcag 6901 gaaagaacag ttttcttcaa taatttgtcc accctgtcac tggagaaaat ttaagaattt 6961 gggggtgttg gtagtaagtt aaacacagca gctgttcatg gcagaaatta ttcaatacat 7021 accttctctg aatatcctat aaccaaagca aagaaaaaca ccaaggggtt tgttctcctc 7081 cttggagttg acctcattcc aaggcagagc tcaggtcaca ggcacagggg ctgcgcccaa 7141 gcttgtccgc agccttatgc agctgtggag tctggaagac tgttgcagga ctgctggcct 7201 agtcccagaa tgtcagcctc attttcgatt tactggctct tgttgctgta tgtcatgctg 7261 accttattgt taaacacagg tttgtttgct ttttttccac tcatggagac atgggagagg 7321 cattattttt aagctggttg aaagctttaa ccgataaagc atttttagag aaatgtgaat 7381 caggcagcta agaaagcata ctctgtccat tacggtaaag aaaatgcaca gattattaac 7441 tctgcagtgt ggcattagtg tcctggtcaa tattcggata gatatgaata aaatatttaa 7501 atggtattgt aaatagtttt caggacatat gctatagctt atttttatta tcttttgaaa 7561 ttgctcttaa tacatcaaat cctgatgtat tcaatttatc agatataaat tattctaaat 7621 gaagcccagt taaatgtttt tgtcttgtca gttatatgtt aagtttctga tctctttgtc 7681 tatgacgttt actaatctgc atttttactg ttatgaatta ttttagacag cagtggtttc 7741 aagctttttg ccactaaaaa taccttttat tttctcctcc cccagaaaag tctatacctt 7801 gaagtatcta tccaccaaac tgtacttcta ttaagaaata gttattgtgt tttcttaatg 7861 ttttgttatt caaagacata tcaatgaaag ctgctgagca gcatgaataa caattatatc 7921 cacacagatt tgatatattt tgtgcagcct taacttgata gtataaaatg tcattgcttt 7981 ttaaataata gttagtcaat ggacttctat catagctttc ctaaactagg ttaagatcca 8041 gagctttggg gtcataatat attacataca attaagttat ctttttctaa gggctttaaa 8101 attcatgaga ataaccaaaa aaggtatgtg gagagttaat acaaacatac catattcttg 8161 ttgaaacaga gatgtggctc tgcttgttct ccataaggta gaaatacttt ccagaatttg 8221 cctaaactag taagccctga atttgctatg attagggata ggaagagatt ttcacatggc 8281 agactttaga attcttcact ttagccagta aagtatctcc ttttgatctt agtattctgt 8341 gtattttaac ttttctgagt tgtgcatgtt tataagaaaa atcagcacaa agggtttaag 8401 ttaaagcctt tttactgaaa tttgaaagaa acagaagaaa atatcaaagt tctttgtatt 8461 ttgagaggat taaatatgat ttacaaaagt tacatggagg gctctctaaa acattaaatt 8521 aattattttt tgttgaaaag tcttacttta ggcatcattt tattcctcag caactagctg 8581 tgaagccttt actgtgctgt atgccagtca ctctgctaga ttgtggagat taccagtgtt 8641 cccgtcttct ccgagcttag agttggatgg ggaataaaga caggtaaaca gatagctaca 8701 atattgtact gtgaatgctt atgctggagg aagtacaggg aactattgga gcacctaaga 8761 ggagcaccta ccttgaattt aggggttagc agaggcatcc tgaaaaaagt caaagctaag 8821 ccacaatcta taagcagttt aggaattagc agaacgtgcg tggtgaggag atgccaaagg 8881 caagaagaga agagtattcc aaacaggagg gattccaaag agagaagagt atcccaaaca 8941 acatttgcac aaacctgatg gggagagaga atgtggggtg gggatggatg atgagactga 9001 agaagaaagc caggtctaga taatcagtgg ccttgtacac catgttaaag agtgtagact 9061 tgattctgtt gtaaacagga aagcagcaca attcatatga atattttaga agactcccac 9121 tggaatatgg agaataaagt tggagatgac taatcctgga agcagggaga acatttttga 9181 ggaagttgca ctattttggt gaaaatgatg atcataaaca tgaagaattg taggtgatca 9241 tgacctcctc tctaattttc cagaagggtt ttggaagata taacatagga acattgacag 9301 gactgacgaa aggagatgaa atacaccata taaattgtca aacacaaggc cagatgtcta 9361 attattttgc ttatgtgttg aaattacaaa tttttcatca ggaaaccaaa aactacaaaa 9421 cttagttttc ccaagtccca gaattctatc tgtccaaaca atctgtacca ctccacctat 9481 atccctacct ttgcatgtct gtccaacctc aaagtccagg tctatacaca cgggtaagac 9541 tagagcagtt caagtttcag aaaatgagaa agaggaactg agttgtgctg aacccataca 9601 aaataaacac attctttgta tagattcttg gaacctcgag aggaattcac ctaactcata 9661 ggtatttgat ggtatgaatc catggctggg ctcggctttt aaaaagcctt atctgggatt 9721 ccttctatgg aaccaagttc catcaaagcc catttaaaag cctacattaa aaacaaaatt 9781 cttgctgcat tgtatacaaa taatgatgtc atgatcaaat aatcagatgc cattatcaag 9841 tggaattaca aaatggtata cccactccaa aaaaaaaaaa aaagctaaat tctcagtaga 9901 acattgtgac ttcatgagcc ctccacagcc ttggagctga ggagggagca ctggtgagca 9961 gtaggttgaa gagaaaactt ggcgcttaat aatctatcca tgttttttca tctaaaagag 10021 ccttcttttt ggattacctt attcaatttc catcaaggaa attgttagtt ccactaacca 10081 gacagcagct gggaaggcag aagcttactg tatgtacatg gtagctgtgg gaaggaggtt 10141 tctttctcca ggtcctcact ggccatacac cagtcccttg ttagttatgc ctggtcatag 10201 acccccgttg ctatcatctc atatttaagt ctttggcttg tgaatttatc tattctttca 10261 gcttcagcac tgcagagtgc tgggactttg ctaacttcca tttcttgctg gcttagcaca 10321 ttcctcatag gcccagctct tttctcatct ggccctgctg tggagtcacc ttgccccttc 10381 aggagagcca tggcttacca ctgcctgcta agcctccact cagctgccac cacactaaat 10441 ccaagcttct ctaagatgtt gcagacttta caggcaagca taaaaggctt gatcttcctg 10501 gacttccctt tacttgtctg aatctcacct ccttcaactt tcagtctcag aatgtaggca 10561 tttgtcctct ttgccctaca tcttccttct tctgaatcat gaaagcctct cacttcctct 10621 tgctatgtgc tggaggcttc tgtcaggttt tagaatgagt tctcatctag tcctagtagc 10681 ttttgatgct taagtccacc ttttaaggat acctttgaga tttagaccat gtttttcgct 10741 tgagaaagcc ctaatctcca gacttgcctt tctgtggatt tcaaagacca actgaggaag 10801 tcaaaagctg aatgttgact ttctttgaac atttccgcta taacaattcc aattctcctc 10861 agagcaatat gcctgcctcc aactgaccag gagaaaggtc cagtgccaaa gagaaaaaca 10921 caaagattaa ttatttcagt tgagcacata ctttcaaagt ggtttgggta ttcatatgag 10981 gttttctgtc aagagggtga gactcttcat ctatccatgt gtgcctgaca gttctcctgg 11041 cactggctgg taacagatgc aaaactgtaa aaattaagtg atcatgtatt ttaacgatat 11101 catcacatac ttattttcta tgtaatgttt taaatttccc ctaacatact ttgactgttt 11161 tgcacatggt agatattcac atttttttgt gttgaagttg atgcaatctt caaagttatc 11221 taccccgttg cttattagta aaactagtgt taatacttgg caagagatgc agggaatctt 11281 tctcatgact cacgccctat ttagttatta atgctactac cctattttga gtaagtagta 11341 ggtccctaag tacattgtcc agagttatac ttttaaagat atttagcccc atatacttct 11401 tgaatctaaa gtcatacacc ttgctcctca tttctgagtg ggaaagacat ttgagagtat 11461 gttgacaatt gttctgaagg tttttgccaa gaaggtgaaa ctgtcctttc atctgtgtat 11521 gcctggggct gggtccctgg cagtgatggg gtgacaatgc aaagctgtaa aaactaggtg 11581 ctagtgggca cctaatatca tcatcatata cttattttca agctaatatg caaaatccca 11641 tctctgtttt taaactaagt gtagatttca gagaaaatat tttgtggttc acataagaaa 11701 acagtctact cagcttgaca agtgttttat gttaaattgg ctggtggttt gaaatgaatc 11761 atcttcacat aatgttttct ttaaaaatat tgtgaattta actctaattc ttgttattct 11821 gtgtgataat aaagaataaa ctaatttcta (SEQ ID NO: 128) .

[0314] An exemplary nucleic acid sequence encoding PGR (NM_001271162.1 transcript variant 7) comprises or consists of:

1 atttgagtga aatctacaac ccgaggcggc tagtgctccc gcactactgg gatctgagat 61 cttcggagat gactgtcgcc cgcagtacgg agccagcaga agtccgaccc ttcctgggaa 121 tgggctgtac cgagaggtcc gactagcccc agggttttag tgagggggca gtggaactca 181 gcgagggact gagagcttca cagcatgcac gagtttgatg ccagagaaaa agtcgggaga 241 taaaggagcc gcgtgtcact aaattgccgt cgcagccgca gccactcaag tgccggactt 301 gccggattca gaagccagcc agagcccaca atacagcttc gagtcattac ctcagaagat 361 ttgtttaatc tgtggggatg aagcatcagg ctgtcattat ggtgtcctta cctgtgggag 421 ctgtaaggtc ttctttaaga gggcaatgga agggcagcac aactacttat gtgctggaag 481 aaatgactgc atcgttgata aaatccgcag aaaaaactgc ccagcatgtc gccttagaaa 541 gtgctgtcag gctggcatgg tccttggagg tcgaaaattt aaaaagttca ataaagtcag 601 agttgtgaga gcactggatg ctgttgctct cccacagcca gtgggcgttc caaatgaaag 661 ccaagcccta agccagagat tcactttttc accaggtcaa gacatacagt tgattccacc 721 actgatcaac ctgttaatga gcattgaacc agatgtgatc tatgcaggac atgacaacac 781 aaaacctgac acctccagtt ctttgctgac aagtcttaat caactaggcg agaggcaact 841 tctttcagta gtcaagtggt ctaaatcatt gccaggtttt cgaaacttac atattgatga 901 ccagataact ctcattcagt attcttggat gagcttaatg gtgtttggtc taggatggag 961 atcctacaaa cacgtcagtg ggcagatgct gtattttgca cctgatctaa tactaaatga 1021 acagcggatg aaagaatcat cattctattc attatgcctt accatgtggc agatcccaca 1081 ggagtttgtc aagcttcaag ttagccaaga agagttcctc tgtatgaaag tattgttact 1141 tcttaataca attcctttgg aagggctacg aagtcaaacc cagtttgagg agatgaggtc 1201 aagctacatt agagagctca tcaaggcaat tggtttgagg caaaaaggag ttgtgtcgag 1261 ctcacagcgt ttctatcaac ttacaaaact tcttgataac ttgcatgatc ttgtcaaaca 1321 acttcatctg tactgcttga atacatttat ccagtcccgg gcactgagtg ttgaatttcc 1381 agaaatgatg tctgaagtta ttgctgcaca attacccaag atattggcag ggatggtgaa 1441 accccttctc tttcataaaa agtgaatgtc atctttttct tttaaagaat taaattttgt 1501 ggtatgtctt tttgttttgg tcaggattat gaggtcttga gtttttataa tgttcttctg 1561 aaagccttac atttataaca tcatagtgtg taaatttaaa agaaaaattg tgaggttcta 1621 attattttct tttataaagt ataattagaa tgtttaactg ttttgtttac ccatattttc 1681 ttgaagaatt tacaagattg aaaaagtact aaaattgtta aagtaaacta tcttatccat 1741 attatttcat accatgtagg tgaggatttt taacttttgc atctaacaaa tcatcgactt 1801 aagagaaaaa atcttacatg taataacaca aagctattat atgttatttc taggtaactc 1861 cctttgtgtc aattatattt ccaaaaatga acctttaaaa tggtatgcaa aattttgtct 1921 atatatattt gtgtgaggag gaaattcata actttcctca gattttcaaa agtattttta 1981 atgcaaaaaa tgtagaaaga gtttaaaacc actaaaatag attgatgttc ttcaaactag 2041 gcaaaacaac tcatatgtta agaccatttt ccagattgga aacacaaatc tcttaggaag 2101 ttaataagta gattcatatc attatgcaaa tagtattgtg ggttttgtag gtttttaaaa 2161 taaccttttt tggggagaga attgtcctct aatgaggtat tgcgagtgga cataagaaat 2221 cagaagatta tggcctaact gtactcctta ccaactgtgg catgctgaaa gttagtcact 2281 cttactgatt ctcaattctc tcacctttga aagtagtaaa atatctttcc tgccaattgc 2341 tcctttgggt cagagcttat taacatcttt tcaaatcaaa ggaaagaaga aagggagagg 2401 aggaggaggg aggtatcaat tcacatacct ttctcctctt tatcctccac tatcatgaat 2461 tcatattatg tttcagccat gcaaatcttt ttaccatgaa atttcttcca gaattttccc 2521 cctttgacac aaattccatg catgtttcaa ccttcgagac tcagccaaat gtcatttctg 2581 taaaatcttc cctgagtctt ccaagcagta atttgccttc tcctagagtt tacctgccat 2641 tttgtgcaca tttgagttac agtagcatgt tattttacaa ttgtgactct cctgggagtc 2701 tgggagccat ataaagtggt caatagtgtt tgctgactga gagttgaatg acattttctc 2761 tctgtcttgg tattactgta gatttcgatc attctttggt tacatttctg catatttctg 2821 tacccatgac tttatcactt tcttctccca tgctttatct ccatcaatta tcttcattac 2881 ttttaaattt tccacctttg cttcctactt tgtgagatct ctccctttac tgactataac 2941 atagaagaat agaagtgtat tttatgtgtc ttaaggacaa tactttagat tccttgttct 3001 aagtttttaa actgaatgaa tggaatatta tttctctccc taagcaaaat tccacaaaac 3061 aattatttct tatgtttatg tagccttaaa ttgttttgta ctgtaaacct cagcataaaa 3121 actttcttca tttctaattt cattcaacaa atattgattg aatacctggt attagcacaa 3181 gaaaaatgtg ctaataagcc ttatgagaat ttggagctga agaaagacat ataactcagg 3241 aaagttacag tccagtagta ggtataaatt acagtgcctg ataaataggc attttaatat 3301 ttgtacactc aacgtatact aggtaggtgc aaaacattta catataattt tactgatacc 3361 catgcagcac aaaggtacta actttaaata ttaaataaca cctttatgtg tcagtaattc 3421 atttgcatta aatcttattg aaaaggcttt caatatattt tccccacaaa tgtcatccca 3481 agaaaaaagt atttttaaca tctcccaaat ataatagtta caggaaatct acctctgtga 3541 gagtgacacc tctcagaatg aactgtgtga cacaagaaaa tgaatgtagg tctatccaaa 3601 aaaaacccca agaaacaaaa acaatattat tagcccttta tgcttaagtg atggactcag 3661 ggaacagttg atgttgtgat cattttatta tctgattctt gttactttga attaaaccaa 3721 tattttgatg atataaatca tttccaccag catatattta atttccataa taactttaaa 3781 attttctaat ttcactcaac tatgagggaa tagaatgtgg tggccacagg tttggctttt 3841 gttaaaatgt ttgatatctt cgatgttgat ctctgtctgc aatgtagatg tctaaacact 3901 aggatttaat atttaaggct aagctttaaa aataaagtac ctttttaaaa agaatatggc 3961 ttcaccaaat ggaaaatacc taatttctaa atctttttct ctacaaagtc ctatctacta 4021 atgtctccat tactatttag tcatcataac cattatcttc attttacatg tcgtgttctt 4081 tctggtagct ctaaaatgac actaaatcat aagaagacag gttacatatc aggaaatact 4141 tgaaggttac tgaaatagat tcttgagtta atgaaaatat tttctgtaaa aaggtttgaa 4201 aagccatttg agtctaaagc attatacctc cattatcagt agttatgtga caattgtgtg 4261 tgtgtttaat gtttaaagat gtggcacttt ttaataaggc aatgctatgc tattttttcc 4321 catttaacat taagataatt tattgctata cagatgatat ggaaatatga tgaacaatat 4381 tttttttgcc aaaactatgc cttgtaagta gccatggaat gtcaacctgt aacttaaatt 4441 atccacagat agtcatgtgt ttgatgatgg gcactgtgga gataactgac ataggactgt 4501 gccccccttc tctgccactt actagctgga tgagattaag caagtcattt aactgctctg 4561 attaaacctg cctttcccaa gtgctttgta atgaatagaa atggaaacca aaaaaaacgt 4621 atacaggcct tcagaaatag taattgctac tattttgttt tcattaagcc atagttctgg 4681 ctataatttt atcaaactca ccagctatat tctacagtga aagcaggatt ctagaaagtc 4741 tcactgtttt atttatgtca ccatgtgcta tgatatattt ggttgaattc atttgaaatt 4801 agggctggaa gtattcaagt aatttcttct gctgaaaaaa tacagtgttt tgagtttagg 4861 gcctgtttta tcaaagttct aaagagccta tcactcttcc attgtagaca ttttaaaata 4921 atgacactga ttttaacatt tttaagtgtc tttttagaac agagagcctg actagaacac 4981 agcccctcca aaaacccatg ctcaaattat ttttactatg gcagcaattc cacaaaaggg 5041 aacaatgggt ttagaaatta caatgaagtc atcaacccaa aaaacatccc tatccctaag 5101 aaggttatga tataaaatgc ccacaagaaa tctatgtctg ctttaatctg tcttttattg 5161 ctttggaagg atggctatta catttttagt ttttgctgtg aatacctgag cagtttctct 5221 catccatact tatccttcac acatcagaag tcaggataga atatgaatca ttttaaaaac 5281 ttttacaact ccagagccat gtgcataaga agcattcaaa acttgccaaa acatacattt 5341 tttttcaaat ttaaagatac tctatttttg tattcaatag ctcaacaact gtggtcccca 5401 ctgataaagt gaagtggaca aggagacaag taatggcata agtttgtttt tcccaaagta 5461 tgcctgttca atagccattg gatgtgggaa atttctacat ctcttaaaat tttacagaaa 5521 atacatagcc agatagtcta gcaaaagttc accaagtcct aaattgctta tccttacttc 5581 actaagtcat gaaatcattt taatgaaaag aacatcacct aggttttgtg gtttcttttt 5641 ttcttattca tggctgagtg aaaacaacaa tctctgtttc tccctagcat ctgtggacta 5701 tttaatgtac cattattcca cactctatgg tccttactaa atacaaaatt gaacaaaaag 5761 cagtaaaaca actgactctt cacccatatt ataaaatata atccaagcca gattagtcaa 5821 catccataag atgaatccaa gctgaactgg gcctagatta ttgagttcag gttggatcac 5881 atccctattt attaataaac ttaggaaaga aggccttaca gaccatcagt tagctggagc 5941 taatagaacc tacacttcta aagttcggcc tagaatcaat gtggccttaa aagctgaaaa 6001 gaagcaggaa agaacagttt tcttcaataa tttgtccacc ctgtcactgg agaaaattta 6061 agaatttggg ggtgttggta gtaagttaaa cacagcagct gttcatggca gaaattattc 6121 aatacatacc ttctctgaat atcctataac caaagcaaag aaaaacacca aggggtttgt 6181 tctcctcctt ggagttgacc tcattccaag gcagagctca ggtcacaggc acaggggctg 6241 cgcccaagct tgtccgcagc cttatgcagc tgtggagtct ggaagactgt tgcaggactg 6301 ctggcctagt cccagaatgt cagcctcatt ttcgatttac tggctcttgt tgctgtatgt 6361 catgctgacc ttattgttaa acacaggttt gtttgctttt tttccactca tggagacatg 6421 ggagaggcat tatttttaag ctggttgaaa gctttaaccg ataaagcatt tttagagaaa 6481 tgtgaatcag gcagctaaga aagcatactc tgtccattac ggtaaagaaa atgcacagat 6541 tattaactct gcagtgtggc attagtgtcc tggtcaatat tcggatagat atgaataaaa 6601 tatttaaatg gtattgtaaa tagttttcag gacatatgct atagcttatt tttattatct 6661 tttgaaattg ctcttaatac atcaaatcct gatgtattca atttatcaga tataaattat 6721 tctaaatgaa gcccagttaa atgtttttgt cttgtcagtt atatgttaag tttctgatct 6781 ctttgtctat gacgtttact aatctgcatt tttactgtta tgaattattt tagacagcag 6841 tggtttcaag ctttttgcca ctaaaaatac cttttatttt ctcctccccc agaaaagtct 6901 ataccttgaa gtatctatcc accaaactgt acttctatta agaaatagtt attgtgtttt 6961 cttaatgttt tgttattcaa agacatatca atgaaagctg ctgagcagca tgaataacaa 7021 ttatatccac acagatttga tatattttgt gcagccttaa cttgatagta taaaatgtca 7081 ttgcttttta aataatagtt agtcaatgga cttctatcat agctttccta aactaggtta 7141 agatccagag ctttggggtc ataatatatt acatacaatt aagttatctt tttctaaggg 7201 ctttaaaatt catgagaata accaaaaaag gtatgtggag agttaataca aacataccat 7261 attcttgttg aaacagagat gtggctctgc ttgttctcca taaggtagaa atactttcca 7321 gaatttgcct aaactagtaa gccctgaatt tgctatgatt agggatagga agagattttc 7381 acatggcaga ctttagaatt cttcacttta gccagtaaag tatctccttt tgatcttagt 7441 attctgtgta ttttaacttt tctgagttgt gcatgtttat aagaaaaatc agcacaaagg 7501 gtttaagtta aagccttttt actgaaattt gaaagaaaca gaagaaaata tcaaagttct 7561 ttgtattttg agaggattaa atatgattta caaaagttac atggagggct ctctaaaaca 7621 ttaaattaat tattttttgt tgaaaagtct tactttaggc atcattttat tcctcagcaa 7681 ctagctgtga agcctttact gtgctgtatg ccagtcactc tgctagattg tggagattac 7741 cagtgttccc gtcttctccg agcttagagt tggatgggga ataaagacag gtaaacagat 7801 agctacaata ttgtactgtg aatgcttatg ctggaggaag tacagggaac tattggagca 7861 cctaagagga gcacctacct tgaatttagg ggttagcaga ggcatcctga aaaaagtcaa 7921 agctaagcca caatctataa gcagtttagg aattagcaga acgtgcgtgg tgaggagatg 7981 ccaaaggcaa gaagagaaga gtattccaaa caggagggat tccaaagaga gaagagtatc 8041 ccaaacaaca tttgcacaaa cctgatgggg agagagaatg tggggtgggg atggatgatg 8101 agactgaaga agaaagccag gtctagataa tcagtggcct tgtacaccat gttaaagagt 8161 gtagacttga ttctgttgta aacaggaaag cagcacaatt catatgaata ttttagaaga 8221 ctcccactgg aatatggaga ataaagttgg agatgactaa tcctggaagc agggagaaca 8281 tttttgagga agttgcacta ttttggtgaa aatgatgatc ataaacatga agaattgtag 8341 gtgatcatga cctcctctct aattttccag aagggttttg gaagatataa cataggaaca 8401 ttgacaggac tgacgaaagg agatgaaata caccatataa attgtcaaac acaaggccag 8461 atgtctaatt attttgctta tgtgttgaaa ttacaaattt ttcatcagga aaccaaaaac 8521 tacaaaactt agttttccca agtcccagaa ttctatctgt ccaaacaatc tgtaccactc 8581 cacctatatc cctacctttg catgtctgtc caacctcaaa gtccaggtct atacacacgg 8641 gtaagactag agcagttcaa gtttcagaaa atgagaaaga ggaactgagt tgtgctgaac 8701 ccatacaaaa taaacacatt ctttgtatag attcttggaa cctcgagagg aattcaccta 8761 actcataggt atttgatggt atgaatccat ggctgggctc ggcttttaaa aagccttatc 8821 tgggattcct tctatggaac caagttccat caaagcccat ttaaaagcct acattaaaaa 8881 caaaattctt gctgcattgt atacaaataa tgatgtcatg atcaaataat cagatgccat 8941 tatcaagtgg aattacaaaa tggtataccc actccaaaaa aaaaaaaaaa gctaaattct 9001 cagtagaaca ttgtgacttc atgagccctc cacagccttg gagctgagga gggagcactg 9061 gtgagcagta ggttgaagag aaaacttggc gcttaataat ctatccatgt tttttcatct 9121 aaaagagcct tctttttgga ttaccttatt caatttccat caaggaaatt gttagttcca 9181 ctaaccagac agcagctggg aaggcagaag cttactgtat gtacatggta gctgtgggaa 9241 ggaggtttct ttctccaggt cctcactggc catacaccag tcccttgtta gttatgcctg 9301 gtcatagacc cccgttgcta tcatctcata tttaagtctt tggcttgtga atttatctat 9361 tctttcagct tcagcactgc agagtgctgg gactttgcta acttccattt cttgctggct 9421 tagcacattc ctcataggcc cagctctttt ctcatctggc cctgctgtgg agtcaccttg 9481 ccccttcagg agagccatgg cttaccactg cctgctaagc ctccactcag ctgccaccac 9541 actaaatcca agcttctcta agatgttgca gactttacag gcaagcataa aaggcttgat 9601 cttcctggac ttccctttac ttgtctgaat ctcacctcct tcaactttca gtctcagaat 9661 gtaggcattt gtcctctttg ccctacatct tccttcttct gaatcatgaa agcctctcac 9721 ttcctcttgc tatgtgctgg aggcttctgt caggttttag aatgagttct catctagtcc 9781 tagtagcttt tgatgcttaa gtccaccttt taaggatacc tttgagattt agaccatgtt 9841 tttcgcttga gaaagcccta atctccagac ttgcctttct gtggatttca aagaccaact 9901 gaggaagtca aaagctgaat gttgactttc tttgaacatt tccgctataa caattccaat 9961 tctcctcaga gcaatatgcc tgcctccaac tgaccaggag aaaggtccag tgccaaagag 10021 aaaaacacaa agattaatta tttcagttga gcacatactt tcaaagtggt ttgggtattc 10081 atatgaggtt ttctgtcaag agggtgagac tcttcatcta tccatgtgtg cctgacagtt 10141 ctcctggcac tggctggtaa cagatgcaaa actgtaaaaa ttaagtgatc atgtatttta 10201 acgatatcat cacatactta ttttctatgt aatgttttaa atttccccta acatactttg 10261 actgttttgc acatggtaga tattcacatt tttttgtgtt gaagttgatg caatcttcaa 10321 agttatctac cccgttgctt attagtaaaa ctagtgttaa tacttggcaa gagatgcagg 10381 gaatctttct catgactcac gccctattta gttattaatg ctactaccct attttgagta 10441 agtagtaggt ccctaagtac attgtccaga gttatacttt taaagatatt tagccccata 10501 tacttcttga atctaaagtc atacaccttg ctcctcattt ctgagtggga aagacatttg 10561 agagtatgtt gacaattgtt ctgaaggttt ttgccaagaa ggtgaaactg tcctttcatc 10621 tgtgtatgcc tggggctggg tccctggcag tgatggggtg acaatgcaaa gctgtaaaaa 10681 ctaggtgcta gtgggcacct aatatcatca tcatatactt attttcaagc taatatgcaa 10741 aatcccatct ctgtttttaa actaagtgta gatttcagag aaaatatttt gtggttcaca 10801 taagaaaaca gtctactcag cttgacaagt gttttatgtt aaattggctg gtggtttgaa 10861 atgaatcatc ttcacataat gttttcttta aaaatattgt gaatttaact ctaattcttg 10921 ttattctgtg tgataataaa gaataaacta atttcta (SEQ ID NO: 129) .

[0315] An exemplary amino acid sequence encoding PGR (NP 001258091.1 , isoform D) comprises or consists of:

MEGQHNYLCAGRNDCIVDKIRRKNCPACRLRKCCQAGMVLGGRKFKKFNKVRWRALDAVALPQPVGVPNESQAL SQRFTFSPGQDIQLIPPLINLLMSIEPDVIYAGHDNTKPDTSSSLLTSLNQLGERQLLSWKWSKSLPGFRNLHI DDQITLIQYSWMSLMVFGLGWRSYKHVSGQMLYFAPDLILNEQRMKESSFYSLCLTMWQIPQEFVKLQVSQEEFL CMKVLLLLNTIPLEGLRSQTQFEEMRSSYIRELIKAIGLRQKGWSSSQRFYQLTKLLDNLHDLVKQLHLYCLNT FIQSRALSVEFPEMMSEVIAAQLPKILAGMVKPLLFHKK (SEQ ID NO: 130) .

[0316] An exemplary nucleic acid sequence encoding PSEN1 (NM_000021.3 transcript variant 1) comprises or consists of:

1 aaatgacgac aacggtgagg gttctcgggc ggggcctggg acaggcagct ccggggtccg 61 cggtttcaca tcggaaacaa aacagcggct ggtctggaag gaacctgagc tacgagccgc 121 ggcggcagcg gggcggcggg gaagcgtata cctaatctgg gagcctgcaa gtgacaacag 181 cctttgcggt ccttagacag cttggcctgg aggagaacac atgaaagaaa gaacctcaag 241 aggctttgtt ttctgtgaaa cagtatttct atacagttgc tccaatgaca gagttacctg 301 caccgttgtc ctacttccag aatgcacaga tgtctgagga caaccacctg agcaatactg 361 tacgtagcca gaatgacaat agagaacggc aggagcacaa cgacagacgg agccttggcc 421 accctgagcc attatctaat ggacgacccc agggtaactc ccggcaggtg gtggagcaag 481 atgaggaaga agatgaggag ctgacattga aatatggcgc caagcatgtg atcatgctct 541 ttgtccctgt gactctctgc atggtggtgg tcgtggctac cattaagtca gtcagctttt 601 atacccggaa ggatgggcag ctaatctata ccccattcac agaagatacc gagactgtgg 661 gccagagagc cctgcactca attctgaatg ctgccatcat gatcagtgtc attgttgtca 721 tgactatcct cctggtggtt ctgtataaat acaggtgcta taaggtcatc catgcctggc 781 ttattatatc atctctattg ttgctgttct ttttttcatt catttacttg ggggaagtgt 841 ttaaaaccta taacgttgct gtggactaca ttactgttgc actcctgatc tggaattttg 901 gtgtggtggg aatgatttcc attcactgga aaggtccact tcgactccag caggcatatc 961 tcattatgat tagtgccctc atggccctgg tgtttatcaa gtacctccct gaatggactg 1021 cgtggctcat cttggctgtg atttcagtat atgatttagt ggctgttttg tgtccgaaag 1081 gtccacttcg tatgctggtt gaaacagctc aggagagaaa tgaaacgctt tttccagctc 1141 tcatttactc ctcaacaatg gtgtggttgg tgaatatggc agaaggagac ccggaagctc 1201 aaaggagagt atccaaaaat tccaagtata atgcagaaag cacagaaagg gagtcacaag 1261 acactgttgc agagaatgat gatggcgggt tcagtgagga atgggaagcc cagagggaca 1321 gtcatctagg gcctcatcgc tctacacctg agtcacgagc tgctgtccag gaactttcca 1381 gcagtatcct cgctggtgaa gacccagagg aaaggggagt aaaacttgga ttgggagatt 1441 tcattttcta cagtgttctg gttggtaaag cctcagcaac agccagtgga gactggaaca 1501 caaccatagc ctgtttcgta gccatattaa ttggtttgtg ccttacatta ttactccttg 1561 ccattttcaa gaaagcattg ccagctcttc caatctccat cacctttggg cttgttttct 1621 actttgccac agattatctt gtacagcctt ttatggacca attagcattc catcaatttt 1681 atatctagca tatttgcggt tagaatccca tggatgtttc ttctttgact ataacaaaat 1741 ctggggagga caaaggtgat tttcctgtgt ccacatctaa caaagtcaag attcccggct 1801 ggacttttgc agcttccttc caagtcttcc tgaccacctt gcactattgg actttggaag 1861 gaggtgccta tagaaaacga ttttgaacat acttcatcgc agtggactgt gtccctcggt 1921 gcagaaacta ccagatttga gggacgaggt caaggagata tgataggccc ggaagttgct 1981 gtgccccatc agcagcttga cgcgtggtca caggacgatt tcactgacac tgcgaactct 2041 caggactacc gttaccaaga ggttaggtga agtggtttaa accaaacgga actcttcatc 2101 ttaaactaca cgttgaaaat caacccaata attctgtatt aactgaattc tgaacttttc 2161 aggaggtact gtgaggaaga gcaggcacca gcagcagaat ggggaatgga gaggtgggca 2221 ggggttccag cttccctttg attttttgct gcagactcat cctttttaaa tgagacttgt 2281 tttcccctct ctttgagtca agtcaaatat gtagattgcc tttggcaatt cttcttctca 2341 agcactgaca ctcattaccg tctgtgattg ccatttcttc ccaaggccag tctgaacctg 2401 aggttgcttt atcctaaaag ttttaacctc aggttccaaa ttcagtaaat tttggaaaca 2461 gtacagctat ttctcatcaa ttctctatca tgttgaagtc aaatttggat tttccaccaa 2521 attctgaatt tgtagacata cttgtacgct cacttgcccc agatgcctcc tctgtcctca 2581 ttcttctctc ccacacaagc agtctttttc tacagccagt aaggcagctc tgtcgtggta 2641 gcagatggtc ccattattct agggtcttac tctttgtatg atgaaaagaa tgtgttatga 2701 atcggtgctg tcagccctgc tgtcagacct tcttccacag caaatgagat gtatgcccaa 2761 agacggtaga attaaagaag agtaaaatgg ctgttgaagc actttctgtc ctggtatttt 2821 gtttttgctt ttgccacaca gtagctcaga atttgaacaa atagccaaaa gctggtggtt 2881 gatgaattat gaactagttg tatcaacaca aagcaagagt tggggaaagc catatttaac 2941 ttggtgagct gtgggagaac ctggtggcag aaggagaacc aactgccaag gggaaagaga 3001 aggggcctcc agcagcgaag gggatacagt gagctaatga tgtcaaggag gagtttcagg 3061 ttattctcgt cagctccaca aatgggtgct ttgtggtctc tgcccgcgtt acctttcctc 3121 tcaatgtacc tttgtgtgaa ctgggcagtg gaggtgcctg ctgcagttac catggagttc 3181 aggctctggg cagctcagtc aggcaaaaca cacaaacagc catcagcctg tgtgggctca 3241 gggcacctct ggacaaaggc ttgtggggca taaccttctt taccacagag agcccttagc 3301 tatgctgatc agaccgtaag cgtttatgag aaacttagtt tcctcctgtg gctgaggagg 3361 ggccagcttt ttcttctttt gcctgctgtt ttctctccca atctatgata tgatatgacc 3421 tggtttgggg ctgtctttgg tgtttagaat atttgttttc tgtcccagga tatttcttat 3481 aagaacctaa cttcaagagt agtgtgcgag tactgatctg aatttaaatt aaaattggct 3541 tatattaggc agtcacagac aggaaaaata agagctatgc aaagaaaggg ggatttaaag 3601 tagtaggttc tatcatctca attcattttt ttccatgaaa tcccttcttc caagattcat 3661 tccctctctc agacatgtgc tagcatgggt attatcattg agaaagcaca gctacagcaa 3721 agccacctga atagcaattt gtgattggaa gcattcttga gggatcccta atctagagta 3781 atttatttgt gtaaggatcc caaatgtgtt gcacctttca tgatacattt cttctctgaa 3841 gagggtacgt ggggtgtgtg tatttaaatc catcctatgt attactgatt gtcctgtgta 3901 gaaagatggc aattattctg tctctttctc caagtttgag ccacatctca gccacattgt 3961 tagacagtgt acagagaacc tatctttcct tttttttttt ttaaaggaca ggattttgct 4021 gtgttgccca ggctagactt gaactcctgg gctcaagtaa tccacctcag cctgagtagc 4081 tgagactaca gcccatctta tttctttaaa tcattcatct caggcagaga acttttccct 4141 caaacattct ttttagaatt agttcagtca ttcctaaaac atccaaatgc tagtcttcca 4201 ccatgaaaaa tagattgtca ctggaaagaa cagtagcaat ttccataagg atgtgccttc 4261 actcacacgg gacaggcggt ggttatagag tcgggcaaaa ccagcagtag agtatgacca 4321 gccaagccaa tctgcttaat aaaaagatgg aagacagtaa ggaaggaaag tagccactaa 4381 gagtctgagt ctgactgggc tacagaataa agggtattta tggacagaat gtcattacat 4441 gcctatggga ataccaatca tatttggaag atttgcagat tttttttcag agaggaaaga 4501 ctcaccttcc tgtttttggt tctcagtagg ttcgtgtgtg ttcctagaat cacagctctg 4561 actccaaatg actcaatttc tcaattagaa aaagtagaag ctttctaagc aacttggaag 4621 aaaacagtca taagtaagca atttgttgat tttactacag aagcaacaac tgaagaggca 4681 gtgtttttac tttcagactc cgggattccc attctgtagt ctctctgctt ttaaaaaccc 4741 tccttttgca atagatgccc aaacagatga tgtttattac ttgttattta cgtggcctca 4801 gacagtgtat gtattctcga tataacttgt agagtgtgaa atataagttt aactaccaaa 4861 taaggtctcc cagggttaga tgactgcggg aagcctttga tcccaacccc caaggctttg 4921 tatatttgat catttgtgat ctaaccctgg aagaaaaaga gctcagaaac cactatgaaa 4981 aaatttgttc agtgttttct gtgttcccgt aggttctgga gtctgaggat gcaaagatga 5041 ataagataaa ttctcagaat gtagttataa tctcttgttt tctggtatat gccatctttc 5101 tttaacttct ctaaaatatt gggtatttgt caaataacca cttttaacag ttaccattac 5161 tgagggctta tacattggtg ttataaaagt gacttgattc agaaatcaat ccattcagta 5221 aagtactcct tctctaaatt tgctgttatg tctataagga acagtttgac ctgcccttct 5281 cctcacctcc tcacctgcct tccaacattg aatttggaag gagacgtgaa aattggacat 5341 ttggttttgc ccttgggctg gaaactatca tataatcata agtttgagcc tagaagtgat 5401 ccttgtgatc ttctcacctc tttaaattcc cacaacacaa gagattaaaa acagaggttt 5461 cagctcttca tagtgcgttg tgaaatggct ggccagagtg taccaacaaa gctgtcatcg 5521 ggctcacagc tcagagacat ctgcatgtga tcatctgcat agtcctctcc tctaacggga 5581 aacacctcag atttgcatat aaaaaagcac cctggtgctg aaatgaaccc ctttcttgaa 5641 catcaaagct gtctcccaca gccttgggca gcagggtgcc tcttagtgga tgtgctgggt 5701 ccaccctgag ccctgacatg tggtggcagc attgccagtt ggtctgtgtg tctgtgtagc 5761 agggacgatt tcccagaaag caattttcct tttgaaatac gtaattgttg agactaggca 5821 gtttcaaagt cagctgcata tagtagcaag tacaggactg tcttgttttt ggtgtccttg 5881 gaggtgctgg ggtgagggtt tcagtgggat catttactct cacatgttgt ctgccttctg 5941 cttctgtgga cactgctttg tacttaattc agacagactg tgaatacacc ttttttataa 6001 atacctttca aattcttggt aagatataat tttgatagct gattgcagat tttctgtatt 6061 tgtcagatta ataaagactg catgaatcca aaaaaaaaaa aaaaaaa (SEQ ID NO:

131)

[0317] An exemplary amino acid sequence encoding PSEN1 (NP_000012.1, isoform 1-467) comprises or consists of:

MTELPAPLSYFQNAQMSEDNHLSNTVRSQNDNRERQEHNDRRSLGHPEPLSNGRPQGNSRQWEQDEEEDEELTL KYGAKHVIMLFVPVTLCMWWATIKSVSFYTRKDGQLIYTPFTEDTETVGQRALHSILNAAIMISVIWMTILL WLYKYRCYKVIHAWLIISSLLLLFFFSFIYLGEVFKTYNVAVDYITVALLIWNFGWGMISIHWKGPLRLQQAY LIMISALMALVFIKYLPEWTAWLILAVISVYDLVAVLCPKGPLRMLVETAQERNETLFPALIYSSTMVWLVNMAE GDPEAQRRVSKNSKYNAESTERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAAVQELSSSILAGEDPE ERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCLTLLLLAIFKKALPALPISITFGLVFYFATD YLVQPFMDQLAFHQFYI (SEQ ID NO: 132) .

[0318] An exemplary nucleic acid sequence encoding PSEN1 (NM_007318.2 transcript variant 2) comprises or consists of: 1 aaatgacgac aacggtgagg gttctcgggc ggggcctggg acaggcagct ccggggtccg 61 cggtttcaca tcggaaacaa aacagcggct ggtctggaag gaacctgagc tacgagccgc 121 ggcggcagcg gggcggcggg gaagcgtata cctaatctgg gagcctgcaa gtgacaacag 181 cctttgcggt ccttagacag cttggcctgg aggagaacac atgaaagaaa gaacctcaag 241 aggctttgtt ttctgtgaaa cagtatttct atacagttgc tccaatgaca gagttacctg 301 caccgttgtc ctacttccag aatgcacaga tgtctgagga caaccacctg agcaatacta 361 atgacaatag agaacggcag gagcacaacg acagacggag ccttggccac cctgagccat 421 tatctaatgg acgaccccag ggtaactccc ggcaggtggt ggagcaagat gaggaagaag 481 atgaggagct gacattgaaa tatggcgcca agcatgtgat catgctcttt gtccctgtga 541 ctctctgcat ggtggtggtc gtggctacca ttaagtcagt cagcttttat acccggaagg 601 atgggcagct aatctatacc ccattcacag aagataccga gactgtgggc cagagagccc 661 tgcactcaat tctgaatgct gccatcatga tcagtgtcat tgttgtcatg actatcctcc 721 tggtggttct gtataaatac aggtgctata aggtcatcca tgcctggctt attatatcat 781 ctctattgtt gctgttcttt ttttcattca tttacttggg ggaagtgttt aaaacctata 841 acgttgctgt ggactacatt actgttgcac tcctgatctg gaattttggt gtggtgggaa 901 tgatttccat tcactggaaa ggtccacttc gactccagca ggcatatctc attatgatta 961 gtgccctcat ggccctggtg tttatcaagt acctccctga atggactgcg tggctcatct 1021 tggctgtgat ttcagtatat gatttagtgg ctgttttgtg tccgaaaggt ccacttcgta 1081 tgctggttga aacagctcag gagagaaatg aaacgctttt tccagctctc atttactcct 1141 caacaatggt gtggttggtg aatatggcag aaggagaccc ggaagctcaa aggagagtat 1201 ccaaaaattc caagtataat gcagaaagca cagaaaggga gtcacaagac actgttgcag 1261 agaatgatga tggcgggttc agtgaggaat gggaagccca gagggacagt catctagggc 1321 ctcatcgctc tacacctgag tcacgagctg ctgtccagga actttccagc agtatcctcg 1381 ctggtgaaga cccagaggaa aggggagtaa aacttggatt gggagatttc attttctaca 1441 gtgttctggt tggtaaagcc tcagcaacag ccagtggaga ctggaacaca accatagcct 1501 gtttcgtagc catattaatt ggtttgtgcc ttacattatt actccttgcc attttcaaga 1561 aagcattgcc agctcttcca atctccatca cctttgggct tgttttctac tttgccacag 1621 attatcttgt acagcctttt atggaccaat tagcattcca tcaattttat atctagcata 1681 tttgcggtta gaatcccatg gatgtttctt ctttgactat aacaaaatct ggggaggaca 1741 aaggtgattt tcctgtgtcc acatctaaca aagtcaagat tcccggctgg acttttgcag 1801 cttccttcca agtcttcctg accaccttgc actattggac tttggaagga ggtgcctata 1861 gaaaacgatt ttgaacatac ttcatcgcag tggactgtgt ccctcggtgc agaaactacc 1921 agatttgagg gacgaggtca aggagatatg ataggcccgg aagttgctgt gccccatcag 1981 cagcttgacg cgtggtcaca ggacgatttc actgacactg cgaactctca ggactaccgt 2041 taccaagagg ttaggtgaag tggtttaaac caaacggaac tcttcatctt aaactacacg 2101 ttgaaaatca acccaataat tctgtattaa ctgaattctg aacttttcag gaggtactgt 2161 gaggaagagc aggcaccagc agcagaatgg ggaatggaga ggtgggcagg ggttccagct 2221 tccctttgat tttttgctgc agactcatcc tttttaaatg agacttgttt tcccctctct 2281 ttgagtcaag tcaaatatgt agattgcctt tggcaattct tcttctcaag cactgacact 2341 cattaccgtc tgtgattgcc atttcttccc aaggccagtc tgaacctgag gttgctttat 2401 cctaaaagtt ttaacctcag gttccaaatt cagtaaattt tggaaacagt acagctattt 2461 ctcatcaatt ctctatcatg ttgaagtcaa atttggattt tccaccaaat tctgaatttg 2521 tagacatact tgtacgctca cttgccccag atgcctcctc tgtcctcatt cttctctccc 2581 acacaagcag tctttttcta cagccagtaa ggcagctctg tcgtggtagc agatggtccc 2641 attattctag ggtcttactc tttgtatgat gaaaagaatg tgttatgaat cggtgctgtc 2701 agccctgctg tcagaccttc ttccacagca aatgagatgt atgcccaaag acggtagaat 2761 taaagaagag taaaatggct gttgaagcac tttctgtcct ggtattttgt ttttgctttt 2821 gccacacagt agctcagaat ttgaacaaat agccaaaagc tggtggttga tgaattatga 2881 actagttgta tcaacacaaa gcaagagttg gggaaagcca tatttaactt ggtgagctgt 2941 gggagaacct ggtggcagaa ggagaaccaa ctgccaaggg gaaagagaag gggcctccag 3001 cagcgaaggg gatacagtga gctaatgatg tcaaggagga gtttcaggtt attctcgtca 3061 gctccacaaa tgggtgcttt gtggtctctg cccgcgttac ctttcctctc aatgtacctt 3121 tgtgtgaact gggcagtgga ggtgcctgct gcagttacca tggagttcag gctctgggca 3181 gctcagtcag gcaaaacaca caaacagcca tcagcctgtg tgggctcagg gcacctctgg 3241 acaaaggctt gtggggcata accttcttta ccacagagag cccttagcta tgctgatcag 3301 accgtaagcg tttatgagaa acttagtttc ctcctgtggc tgaggagggg ccagcttttt 3361 cttcttttgc ctgctgtttt ctctcccaat ctatgatatg atatgacctg gtttggggct 3421 gtctttggtg tttagaatat ttgttttctg tcccaggata tttcttataa gaacctaact 3481 tcaagagtag tgtgcgagta ctgatctgaa tttaaattaa aattggctta tattaggcag 3541 tcacagacag gaaaaataag agctatgcaa agaaaggggg atttaaagta gtaggttcta 3601 tcatctcaat tcattttttt ccatgaaatc ccttcttcca agattcattc cctctctcag 3661 acatgtgcta gcatgggtat tatcattgag aaagcacagc tacagcaaag ccacctgaat 3721 agcaatttgt gattggaagc attcttgagg gatccctaat ctagagtaat ttatttgtgt 3781 aaggatccca aatgtgttgc acctttcatg atacatttct tctctgaaga gggtacgtgg 3841 ggtgtgtgta tttaaatcca tcctatgtat tactgattgt cctgtgtaga aagatggcaa 3901 ttattctgtc tctttctcca agtttgagcc acatctcagc cacattgtta gacagtgtac 3961 agagaaccta tctttccttt tttttttttt aaaggacagg attttgctgt gttgcccagg 4021 ctagacttga actcctgggc tcaagtaatc cacctcagcc tgagtagctg agactacagc 4081 ccatcttatt tctttaaatc attcatctca ggcagagaac ttttccctca aacattcttt 4141 ttagaattag ttcagtcatt cctaaaacat ccaaatgcta gtcttccacc atgaaaaata 4201 gattgtcact ggaaagaaca gtagcaattt ccataaggat gtgccttcac tcacacggga 4261 caggcggtgg ttatagagtc gggcaaaacc agcagtagag tatgaccagc caagccaatc 4321 tgcttaataa aaagatggaa gacagtaagg aaggaaagta gccactaaga gtctgagtct 4381 gactgggcta cagaataaag ggtatttatg gacagaatgt cattacatgc ctatgggaat 4441 accaatcata tttggaagat ttgcagattt tttttcagag aggaaagact caccttcctg 4501 tttttggttc tcagtaggtt cgtgtgtgtt cctagaatca cagctctgac tccaaatgac 4561 tcaatttctc aattagaaaa agtagaagct ttctaagcaa cttggaagaa aacagtcata 4621 agtaagcaat ttgttgattt tactacagaa gcaacaactg aagaggcagt gtttttactt 4681 tcagactccg ggattcccat tctgtagtct ctctgctttt aaaaaccctc cttttgcaat 4741 agatgcccaa acagatgatg tttattactt gttatttacg tggcctcaga cagtgtatgt 4801 attctcgata taacttgtag agtgtgaaat ataagtttaa ctaccaaata aggtctccca 4861 gggttagatg actgcgggaa gcctttgatc ccaaccccca aggctttgta tatttgatca 4921 tttgtgatct aaccctggaa gaaaaagagc tcagaaacca ctatgaaaaa atttgttcag 4981 tgttttctgt gttcccgtag gttctggagt ctgaggatgc aaagatgaat aagataaatt 5041 ctcagaatgt agttataatc tcttgttttc tggtatatgc catctttctt taacttctct 5101 aaaatattgg gtatttgtca aataaccact tttaacagtt accattactg agggcttata 5161 cattggtgtt ataaaagtga cttgattcag aaatcaatcc attcagtaaa gtactccttc 5221 tctaaatttg ctgttatgtc tataaggaac agtttgacct gcccttctcc tcacctcctc 5281 acctgccttc caacattgaa tttggaagga gacgtgaaaa ttggacattt ggttttgccc 5341 ttgggctgga aactatcata taatcataag tttgagccta gaagtgatcc ttgtgatctt 5401 ctcacctctt taaattccca caacacaaga gattaaaaac agaggtttca gctcttcata 5461 gtgcgttgtg aaatggctgg ccagagtgta ccaacaaagc tgtcatcggg ctcacagctc 5521 agagacatct gcatgtgatc atctgcatag tcctctcctc taacgggaaa cacctcagat 5581 ttgcatataa aaaagcaccc tggtgctgaa atgaacccct ttcttgaaca tcaaagctgt 5641 ctcccacagc cttgggcagc agggtgcctc ttagtggatg tgctgggtcc accctgagcc 5701 ctgacatgtg gtggcagcat tgccagttgg tctgtgtgtc tgtgtagcag ggacgatttc 5761 ccagaaagca attttccttt tgaaatacgt aattgttgag actaggcagt ttcaaagtca 5821 gctgcatata gtagcaagta caggactgtc ttgtttttgg tgtccttgga ggtgctgggg 5881 tgagggtttc agtgggatca tttactctca catgttgtct gccttctgct tctgtggaca 5941 ctgctttgta cttaattcag acagactgtg aatacacctt ttttataaat acctttcaaa 6001 ttcttggtaa gatataattt tgatagctga ttgcagattt tctgtatttg tcagattaat 6061 aaagactgca tgaatccaaa aaaaaaaaaa aaaaa (SEQ ID NO: 133)

[0319] An exemplary amino acid sequence encoding PSEN1 (NP_015557.2, isoform 1-463) comprises or consists of:

MTELPAPLSYFQNAQMSEDNHLSNTNDNRERQEHNDRRSLGHPEPLSNGRPQGNSRQWEQDEEEDEELTLKYGA KHVIMLFVPVTLCMWWATIKSVSFYTRKDGQLIYTPFTEDTETVGQRALHSILNAAIMISVIWMTILLWLY KYRCYKVIHAWLIISSLLLLFFFSFIYLGEVFKTYNVAVDYITVALLIWNFGWGMISIHWKGPLRLQQAYLIMI SALMALVFIKYLPEWTAWLILAVISVYDLVAVLCPKGPLRMLVETAQERNETLFPALIYSSTMVWLVNMAEGDPE AQRRVSKNSKYNAESTERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAAVQELSSSILAGEDPEERGV KLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCLTLLLLAIFKKALPALPISITFGLVFYFATDYLVQ PFMDQLAFHQFYI (SEQ ID NO: 134) .

[0320] An exemplary nucleic acid sequence encoding PSEN1 (AF205592.1 , 5 ' regulatory region and partial sequence) comprises or consists of: 1 gaattccgac cacacagttc agtacttcag ctgtgtgtaa tgaaaagggt tgggatgagt 61 tagggagagc tagtgtgggg agcagcttct agggctgttt ttaaagaatg gaaagaggag 121 tggggaaagg atttaggatc tatggggtca gctaggtttc cttttgtgag tttatataat 181 ggtttagtca ggataggaaa accaggtatc caaaggcgaa agtatctaac catgcctagg 241 aaggaaagga gttgttgctt tgtagaaggg attggggtta gggagattag ctggacacga 301 ttagcaggga gagcacgtgt gtttttatga agaattaagc cgagataggt aatggatgaa 361 gaagaaattt gggctttgga gggggataca cgatattcct ttgagaacag atgttggagg 421 agcaggagga tgtcctgttg ggaagatttg taggaggggc tctaaagtag aaggtcgtca 481 gaatattgaa taaggtgaga agcagatgga cagaaagaaa gtaaatcatg agaaagggct 541 tgactgaagt aatgggggct gtccttgaag ccttgtggca gtgcagccca gataagttgc 601 tgaggctaat gggtgtcagg gtcagtccaa ttgaaagcga agagaggccg ggatgaaggg 661 tgcaaaggaa tagtaaagga agcatgtttg agatccagaa cagaataatg ggttgtggag 721 ggaggtattg agcataggag agtatatggg cttggcacca ttgggtggat aggcaagaca 781 atttggttga taaggcgaag atcttggaac agcctgtaag acttgtctgg tttttggaca 841 ggtaggatag gagagttgta aggagagttt atagacttta agaggccatg ttgtaacagg 901 caggtgataa caggctttaa cttttttaaa gcctgctgtg ggatgggata ttggcgttga 961 gcagggtaag ggtgattagg ttttaatggg atggaaaggg gtgcatgatt ggtcactgag 1021 gaggaagcag aggtatccca tacttgtgga ttaaggtagg gagacacaag gggaggatgc 1081 gaaggaggct ttgaactggg gaaaagggtg gcaatgaggt gtggctgtag cccaggaata 1141 gtcagggaag cagataattt attaaaatgt ctcaacctaa taagggagct gggcaggtgg 1201 ggataactaa aaaggagtgc ataaaagaat gttgtccaag ttggcaccag agtgggggag 1261 ttttaagggg tctagcagcc tggctgtcaa tacccacaac agttatggag gcaagggaaa 1321 caggcccttg aaaaaaaggt aatgtggagt gggtagcctc cgtattgatg aagaagggga 1381 tggacttacc ctccactgta agagttacct aaagcatctg tgatggtcca ggaggcttct 1441 gaggcgatcg ggcagcgtca gtcttcagcc actaagctga gtgggtctgg gaaggagtcg 1501 gccaaggaac attgggtttg agctccagga cctttaggag cagtggcgat gtgagtcgga 1561 cagtctgacc tccagtgggg gcccgcacag acagggcatg gcttaggagg aatctcgggc 1621 tgtgggcatt ccaaggccca gtggccaggc ttttggcatt tgaagcaagg tccacgagga 1681 ggttttgaag gagcccctgg gagctgtggc ttggatgtta tgaagttttt gtatgctgga 1741 gacgtggttg tgggttgtct tacagcagag gcaagtagct gtaactcaga gatgcgttgt 1801 cacttggctg cctcttctct attattgtac accttgaagg cgaggttaat taagtcctgt 1861 tgtgaggttg agggctggaa tccaattttt tggagttttt tttttaatgt tgggagcaga 1921 taaaatgcat attgagaata agatggcctt agggctgggc gcggtggctt acacctgtaa 1981 tcccagcact ttgggaggcc aaggcgggca gatcacctga ggtcaggagt tcgagaccag 2041 cctgaccaac atggagaaac cccgtctcta ctaaaaatac aaaactagcc tggcgtggtg 2101 gtgcatggct gtaaccccag cttctcggga ggctgaggca ggagaatcgc ttgaacccgg 2161 gaggcggagg ttgcagtgag ctgagatcgg gccattgcac cccaatctgg gcaaaaagag 2221 tgaaactcca tctcaaaaaa aaaaaaaaaa aaaaagaata agatggcctt ctggcccttc 2281 tgggtctagg gcagtaaagc atctaagagt tgttgccaaa tgggccatga actgggctgg 2341 gtttttatat ttgatgaaaa ggagcctaag cactaactga tttgggagag gtcagataaa 2401 gaaaaaggag cattaacctt gactgtgcct tcagctccag ccacctcttt aggaggaaat 2461 tgttgggcag gtgggggagg gctagtcacg aaacaaaact gtaagccaga ccaggtatga 2521 ggaggggagg tgatagaagg attatagggt gggggagtgg aggccgagga agaattggga 2581 cctggctcgg cctggtgagg agcagcctgg ggagaagggg agaggtcaga tgggtccgta 2641 gaaaaggagg atttaaagga ctcagagctt ggggtggaga ctgaaggaac acacaggaga 2701 gaaagaagaa agatttggaa cgagttgcat tgggagcaga gactagggag ggaccaatgt 2761 gtgaaagaat gcctggatgt caggcacctc agaccatttg cccatttttc gacaaaaatt 2821 atctagatct tgtaggatgg agaaatcaaa agtgccgttt tctggctatt tgggaccatt 2881 gtcgaatttg tactggggcc aagcagggtt gtagaagaaa ataaggtgtt ttggtcttag 2941 gtcaagtgta agttgaagag gttttaagtt cttgagaaca caggctaagg gagaaagggg 3001 aatggagggt ggaagtttgc ccatagtgaa ggaggcaagc ccagagaaaa gagagggtag 3061 agacttggag tgggtggtgg tacttgccac ccaggggagg aggtacttgc caccaagggg 3121 aggtggtact tgccaccaag gtgaaggatc aaggcaggca tccccgtggt gatcagacac 3181 ctctgaaatg tgagtgaata atcaagcagg cgttcctgca gtgattggac accaagggaa 3241 aactgtcttc ccgagtctgt gaccaatgcc agagttttgg gtgcacagat aaaatgtgtc 3301 tcctttgtct ctactagaga ggaaaaaact ggaattggaa ggacagggag attaaagggt 3361 agtgagaagg ctggagaaga gagtgaaaag gccgcttacc caattttaaa ttggtgagat 3421 gttccttggg ctgattgatg ggaggacgcg aggtcatagg tggatctcct catgcagtga 3481 gggtgaggac aggggaccag tttcccgaag gagtcctcct gtcctgggtc ttcagcacca 3541 aatgacacac acgtccgtgt gaagagagtc caccaacagg ctttgtgtga gcaacaaggc 3601 tgtttatttc acttgggtgc aagtgggttg agtccgaaaa gagagtcagc aaagggaaat 3661 gggggtgggg cagttttata ggatttgggt aggtagtgga aaattacagt taaagggggt 3721 tgtgctcttg tgggcagggg cgggggtcac aaggtgtttg gtggggagct ccagagacat 3781 tatccaggag aaggaatgtc acaaggtaat gtcatcagtt aaggcaggaa ctggccattt 3841 tcacttcttt tgtggtcctt cagttgcctc aggccatccg gatgtatacg tgaaggcttg 3901 ggctcagagg cctaacagta ggacataaag aaaatgagaa gaaaattatc tgaaggctgg 3961 ttattcaatg ttagggtttg ctattttttt aaaatcttac tgcctttttg ttgcaggact 4021 tttttttttt tttgggaaaa acagagtctc actgtgtctc ccaggctgga gtgcagtggt 4081 gcaaactcgg ctcactgcaa actttccttc tcagattcaa gcctcagcca cctgagtagc 4141 tgagattaca ggcccacacc accatgccgg gctaattttt gtatttttaa tagagacggg 4201 gtttcaccat gttgtccagg ctggtcttgt actcccaacc tcaagtgatc ctcctgcctt 4261 ggcctcccaa agtgctggga ttacaggcat gagccaccgt gaccaggcgt tcatgaaaaa 4321 ttttcatgac attctgtgag gtgggtggac cataatttat tgtaccacat ttatttattt 4381 atttatttat ttatttattt atttatttat ttatttttat tttttgagac atagtttcgc 4441 tcttgttgcc caggctggaa tgcaatggcg caatctcggt tcactgcaac ctctgccttc 4501 caggctcaag caattctgcc tcagcctccc aagtagctgg gattacaggc atgcgccacc 4561 acgcctggct aacttttttt gtatttttag tagagacggg gtttctccat gttgatcagg 4621 ctggtctcga actcctgacc tcagatgagc cgcccacctt ggcctcccaa agtgctggaa 4681 ttacaggcgt gagccaccgc accctgccta ttgtaccata tttagtttcc caattttttg 4741 ctatataata ttccatgaat atctttgccc aaaatttttg tagattgttt ctaagaatag 4801 ttcatcagca ttttaagaca tcctattaat attagcggac tgcaatcaga ttgaagtagt 4861 tcacaaatag atgggtttta gcctgtattt gttcaatact gaactattgt atgtatcagg 4921 cactgttatg tatcaggcac tgttctcagc acttgtaaaa tgtatatgtg ctgctgacaa 4981 gcatgagcac ttgtaaatga acaaactaaa atccctactc ttgttaaagt gggggaggtg 5041 aagaatttta aaaacatctt ttttcgttca accttctccc acaacttatc tttcattctg 5101 ctaatggaaa atattacttt tgttcttaaa tatgaagctt ttgtgtgtaa aaagtattag 5161 aatctcatgt ttttgaacaa ggttggcagt gggttgggag gagggattgg agattgatgc 5221 gataggaatg tgaagggata gcttggggtg gattttattt tttaatttta atttttattt 5281 tttgagatgg agtcttgctc tgtctcccag gctggagtgc agtggtgtga tctcagctca 5341 cgggttcaag cgattctcct gctgcagcct cccgagtagc tgggattaca ggagcgcgcc 5401 accacacccg gctaattttt ttgtattttt agtagagacg gggtttcacc atgttggtta 5461 ggctggtcta gaactcccaa cctcatgatc cgcctgcttc ggcctcccaa agtgccggaa 5521 ttacaggcgt gagcgactgc acccggccgc ttgggggtgg atttttaaag aaactttaga 5581 agaatgtaac ttgcccagat accatgtacc gttaatttca ttttcggttt tttgaatacc 5641 catgtttgac atttctccgt tcaccttgat taaataaggt agtattcatt ttttagtttt 5701 agcttttgga tatatgtgta agtgtggtat gctgtctaat gaattagaca ttggtactgt 5761 ctttaccaaa actggacaaa gagcaggcag atgcaaaaat caagtgaccc agcaaaccag 5821 acacattttc tgctctcagc tagcttgcca cctagaaaga ctggttgtca aagttggagt 5881 ccaagaatcg cggaggatgt ttaaaatgca gtttctcagg ttctcgccac ccaccagaag 5941 ttttgattca ttgagtggtg ggagagggca gagatatttg cgattttaac agcattctct 6001 tgattgtgat gcagctggtt cgcaaatagg taccctaaag aaatgacagg tgttaaattt 6061 aggatggcca tcgcttgtat gccgggagaa gcacacgctg ggcccaattt atataggggc 6121 tttcgtcctc agctcgagca gcctcagaac cccgacaacc cacgccagcg ctctgggcgg 6181 attccgtcag gtggggaagg ccaggtggag ctctgggttc tccccgcaat cgtttctcca 6241 ggccggaggc cccgccccct tcctcctggc tcctcccctc ctccgtgggc cggccgccaa 6301 cgacgccaga gccggaaatg acgacaacgg tgagggttct cgggcggggc ctgggacagg 6361 cagctccggg gtccgcggtt tcacatcgga aacaaaacag cggctggtct ggaaggaacc 6421 tgagctacga gccgcggcgg cagcggggcg gcggggaagc gtatgtgcgt gatggggagt 6481 ccgggcaagc caggaaggca ccgcggacat gggcggccgc gggcagggcc cggccctttg 6541 tggccgcccg ggccgcgaag ccggtgtcct aaaagatgag gggcggggcg cggccggttg 6601 gggctgggga accccgtgtg ggaaaccagg aggggcggcc cgtttctcgg gcttcgggcg 6661 cggccgggtg gagagagatt ccggggagcc ttggtccgga aatgctgttt gctcgaagac 6721 gtctcagggc gcaggtgcct tgggccggga ttagtagccg tctgaactgg agtggagtag 6781 gagaaagagg aagcgtcttg ggctgggtct gcttgagcaa ctggtgaaac tccgcgcctc 6841 acgccccggg tgtgtccttg tccaggggcg acgagcattc tgggcgaagt ccgcacgcct 6901 cttgttcgag gcggaagacg gggtctgatg ctttctcctt ggtcgggact gtctcgaggc 6961 atgcatgtcc agtgactctt gtgtttgctg ctgcttccct ctcagattct tctcaccgtt 7021 gtggtcagct ctgctttagg catattaatc catagtggag gctgggatgg gtgagagaat 7081 tgaggtgact tttccataat tcaggtgaga tgtgattaga gttcgatctg cggtggtggc 7141 agaggcttac aagaaacact aacgggacat gggaaccaat tgaggatcag ggaataaagt 7201 gtgaagttga ctaggaggtt ttcagtttag aacatggcag agacattctc agaaataagg 7261 aagttaggaa gaaagacctg gtttagagag gagggcgagg aagtggtttg gaagtgtcac 7321 tttggaagtg ccagcaggtg aaaatgccct gtgaacagga ctggagctga aaacaggaat 7381 caattccata gatttccagt tgatgttgga gcagtggaga agtctaagct aaggaagggg 7441 aagaggaggc caaggcaaac acttaggaac acttgcaacg agggggtgga agaagagcaa 7501 ggagccagct gaggagaatg agtgtggttg gagaaccacc acagcgcagg gtcgccagag 7561 ctgaggaagg ggagggaagc ttcaggaagg aaaaggttgg cagggatttt gagtgttagg 7621 cctggtgtag cagaaggaac agaagattta gagcagcgct agccaataga aataaaatgt 7681 gaggcccggg gcggtggctc acgcctgtaa tcccagcact ttgggaggcc gcggggcgga 7741 tccttgagct gaggagttcg agaccagaca acacggcgaa accccggctc tacaaaaaat 7801 tagctgggcg tgggggcgcg cgcctgtagt cccagctgct cccaagcgag gctgaggcag 7861 gagaatcact tgaacccggg agaaggaggt tgcagtaagc caagattatg ccactgcact 7921 gcagcctggg caaaagagtg agactgtctc aaaaaaaaaa aaaacctgtt ttgtttttct 7981 tttggagaaa aggcatacaa atttattagc atgcagactg ggagaaccac aaggtgatta 8041 tccctatttt aaattttcta ataaacatac tattatttat ttatttattt atttatttat 8101 ttatttattt tttgagacgg agtctggctc tgtcgcccag gctggagtgc agtggcgcga 8161 tctcagctca ctgcaagctc cgcctcccgg gttcacgcca ttctcctgcc tcatcctccc 8221 cagcagctgg gactacaggc gtccgccacc acgcccggct aatttttttg tatttttagt 8281 agacacgggg tttcaccgtg ttagccagta tggtctcgat ctcctgacct ggtgatccgc 8341 ccgcctcggc ctcccagagt gctgcgatta caggngtgag ccactctgcc cggccggcta 8401 tttatttttt tagagatggg agcctcacta tgttgcccag gctggtcttg aactcctgga 8461 gtcaagtgat cctcccgcct tggcctccca gagtggtggg atacaggcac aagccactgt 8521 gcctagccat aaacacattt ttaaaggtaa aaaaaggccg agcgcggtgg ctcacccctg 8581 taatcccagc actttgggag gccgtggcgg gcggatcatg aggtcaggag atcgagacat 8641 cctggctaac acggtgaaac cccatctcta ctaaaaaata caaaaaaaaa aaaattagcc 8701 gggcgtgatg gcgggcgcct gtagtcccag ctactcggga ggctgaggca ggagaatggc 8761 gtgaacccgg gaggcggagc ttgcagtgag cggagatcgc gccactgcac tccagcctgg 8821 gcgacagagc cagactctgt caagaaaaaa agaaaaaaaa tgtaaaaaga ggctgggtgg 8881 ccgggcgcag cggctcacgc ctgtaaaccc agcactttgg gaggccgagg cgggtggata 8941 accagatcag gagatggaga ccatcctggc tcacgcggtg aaaccccgtc tctactaaaa 9001 gtacaaaaaa ttagccagac atggtgccag gcacttgtag tcccagctac tcgggaggct 9061 gaggcaggac aatggcgtga acccaggagg cggagcttgc agtgagccga gatcgcgcca 9121 ctgcactcca gcctgggcaa cagagtgaga cttcgttttt tttttaaaaa aaggctgggc 9181 acagtggctc acacctgtaa tctgccagca ctttgggagg ccgaggcagg tagatcacct 9241 gaggtcagga gttcgagacc agcctcgcca aaatggtgag accctgtgtc tactaaaaat 9301 acaaaaaatt agccgggtgt gttggcgtgt acctgttatc ccagctactc gggaggtgag 9361 gcaggagaat cgcttgaacc cagaaggtgg aggttgcagt gagccgagat catgccactg 9421 cactccagac tgggctacag agcgagactc cataagaaaa aaagaaaaaa aaggggggca 9481 aaaagaaaca gatgaaacca atgtgaataa tttattttaa cacaatatac ctaacatatt 9541 tttatttcaa tatctaacca gtataaaaat ttacttgttt tgccctctag agatagtaag 9601 ctccttaagt aaacagaagt aatacctgat taattagaat tc (SEQ ID NO: 135) .

[0321] An exemplary nucleic acid sequence encoding PTK2B (NM_173174.2 transcript variant 1) comprises or consists of:

1 gcagttcccg cctcctcagg tccgggcggg tccctggccg gggtagcacg gaagggtctc 61 ccaggcggcg tagtagggct tccgtgttac tggaaaccta cttccggctg caaatgggaa 121 aaggagcctc taccttaacc aatccccggg aacctcaggc ccgcggatgg gagaaaccag 181 agatgccaac ttcctgcttc cgaagtagtg gctgggtctt aaagcaccga tgtttctgca 241 ttgaatagcc ctggaagaca gaattcttgt ctctccaaag atctggcaga cttattccca 301 attataagag atccttgcaa aggaggtgtc ttgcttcacc ttcaccttcc actgtgattg 361 taagttttct gaggcctcgc cagccatgcg gaactgaata ggactagcaa cttcatagac 421 ggttgtgaag acaagctaga cggcagatga aagttcttgg cacagagtga acacttgata 481 aactatatgg cagggagggc tggaacgggg cttgtttgaa gagcaatatg agccagggtt 541 atagacctga gtttggggta agagtggaac atccaaatgg aagagtccag cagctgaaag 601 gacatttgtt caaaggcctt tttcattaca gttttctcct tcttctgatc cagccacagc 661 ctccggagcc gttgcacacc tacctgcccg gccgacttac ctgtacttgc cgccgtcccg 721 gctcacctgg cggtgcccga ggagtagtcg ctggagtccg cgcctccctg ggactgcaat 781 gtgccgatct tagctgctgc ctgagaggat gtctggggtg tccgagcccc tgagtcgagt 841 aaagttgggc acgttacgcc ggcctgaagg ccctgcagag cccatggtgg tggtaccagt 901 agatgtggaa aaggaggacg tgcgtatcct caaggtctgc ttctatagca acagcttcaa 961 tcctgggaaa aacttcaaac tggtcaaatg cactgtccag acggagatcc gggagatcat 1021 cacctccatc ctgctgagcg ggcggatcgg gcccaacatc cggttggctg agtgctatgg 1081 gctgaggctg aagcacatga agtccgatga gatccactgg ctgcacccac agatgacggt 1141 gggtgaggtg caggacaagt atgagtgtct gcacgtggaa gccgagtgga ggtatgacct 1201 tcaaatccgc tacttgccag aagacttcat ggagagcctg aaggaggaca ggaccacgct 1261 gctctatttt taccaacagc tccggaacga ctacatgcag cgctacgcca gcaaggtcag 1321 cgagggcatg gccctgcagc tgggctgcct ggagctcagg cggttcttca aggatatgcc 1381 ccacaatgca cttgacaaga agtccaactt cgagctccta gaaaaggaag tggggctgga 1441 cttgtttttc ccaaagcaga tgcaggagaa cttaaagccc aaacagttcc ggaagatgat 1501 ccagcagacc ttccagcagt acgcctcgct cagggaggag gagtgcgtca tgaagttctt 1561 caacactctc gccggcttcg ccaacatcga ccaggagacc taccgctgtg aactcattca 1621 aggatggaac attactgtgg acctggtcat tggccctaaa gggatccgcc agctgactag 1681 tcaggacgca aagcccacct gcctggccga gttcaagcag atcaggtcca tcaggtgcct 1741 cccgctggag gagggccagg cagtacttca gctgggcatt gaaggtgccc cccaggcctt 1801 gtccatcaaa acctcatccc tagcagaggc tgagaacatg gctgacctca tagacggcta 1861 ctgccggctg cagggtgagc accaaggctc tctcatcatc catcctagga aagatggtga 1921 gaagcggaac agcctgcccc agatccccat gctaaacctg gaggcccggc ggtcccacct 1981 ctcagagagc tgcagcatag agtcagacat ctacgcagag attcccgacg aaaccctgcg 2041 aaggcccgga ggtccacagt atggcattgc ccgtgaagat gtggtcctga atcgtattct 2101 tggggaaggc ttttttgggg aggtctatga aggtgtctac acaaatcaca aaggggagaa 2161 aatcaatgta gctgtcaaga cctgcaagaa agactgcact ctggacaaca aggagaagtt 2221 catgagcgag gcagtgatca tgaagaacct cgaccacccg cacatcgtga agctgatcgg 2281 catcattgaa gaggagccca cctggatcat catggaattg tatccctatg gggagctggg 2341 ccactacctg gagcggaaca agaactccct gaaggtgctc accctcgtgc tgtactcact 2401 gcagatatgc aaagccatgg cctacctgga gagcatcaac tgcgtgcaca gggacattgc 2461 tgtccggaac atcctggtgg cctcccctga gtgtgtgaag ctgggggact ttggtctttc 2521 ccggtacatt gaggacgagg actattacaa agcctctgtg actcgtctcc ccatcaaatg 2581 gatgtcccca gagtccatta acttccgacg cttcacgaca gccagtgacg tctggatgtt 2641 cgccgtgtgc atgtgggaga tcctgagctt tgggaagcag cccttcttct ggctggagaa 2701 caaggatgtc atcggggtgc tggagaaagg agaccggctg cccaagcctg atctctgtcc 2761 accggtcctt tataccctca tgacccgctg ctgggactac gaccccagtg accggccccg 2821 cttcaccgag ctggtgtgca gcctcagtga cgtttatcag atggagaagg acattgccat 2881 ggagcaagag aggaatgctc gctaccgaac ccccaaaatc ttggagccca cagccttcca 2941 ggaaccccca cccaagccca gccgacctaa gtacagaccc cctccgcaaa ccaacctcct 3001 ggctccaaag ctgcagttcc aggttcctga gggtctgtgt gccagctctc ctacgctcac 3061 cagccctatg gagtatccat ctcccgttaa ctcactgcac accccacctc tccaccggca 3121 caatgtcttc aaacgccaca gcatgcggga ggaggacttc atccaaccca gcagccgaga 3181 agaggcccag cagctgtggg aggctgaaaa ggtcaaaatg cggcaaatcc tggacaaaca 3241 gcagaagcag atggtggagg actaccagtg gctcaggcag gaggagaagt ccctggaccc 3301 catggtttat atgaatgata agtccccatt gacgccagag aaggaggtcg gctacctgga 3361 gttcacaggg cccccacaga agcccccgag gctgggcgca cagtccatcc agcccacagc 3421 taacctggac cggactgatg acctggtgta cctcaatgtc atggagctgg tgcgggccgt 3481 gctggagctc aagaatgagc tctgtcagct gccccccgag ggctacgtgg tggtggtgaa 3541 gaatgtgggg ctgaccctgc ggaagctcat cgggagcgtg gatgatctcc tgccttcctt 3601 gccgtcatct tcacggacag agatcgaggg cacccagaaa ctgctcaaca aagacctggc 3661 agagctcatc aacaagatgc ggctggcaca gcagaacgcc gtgacctccc taagtgagga 3721 gtgcaagagg cagatgctga cggcttcaca caccctggct gtggacgcca agaacctgct 3781 cgacgctgtg gaccaggcca aggttctggc caatctggcc cacccacctg cagagtgacg 3841 gagggtgggg gccacctgcc tgcgtcttcc gcccctgcct gccatgtacc tcccctgcct 3901 tgctgttggt catgtgggtc ttccaggggg aaggccaagg ggagtcacct tcccttgcca 3961 ctttgcacga cgccctctcc ccacccctac ccctggctgt actgctcagg ctgcagctgg 4021 acagagggga ctctgggcta tggacacagg gtgacggtga caaagatggc tcagaggggg 4081 actgctgctg cctggccact gctccctaag ccagcctggt ccatgcaggg ggctcctggg 4141 ggtggggagg tgtcacatgg tgcccctagc tttatatatg gacatggcag gccgatttgg 4201 gaaccaagct attcctttcc cttcctcttc ggccctcaga tgtcccttga tgcacagaga 4261 agctggggag gagctttgtt ttgggggtca ggcagccagt gagatgaggg atgggcctgg 4321 cattcttgta cagtgtatat tgaaatttat ttaatgtgag tttggtctgg actgacagca 4381 tgtgccctcc tgagggagga cctggggcac agtccaggaa caagctaatt gggagtccag 4441 gcacaggatg ctgtgttgtc aacaaaccaa gcatcagggg gaagaagcag agagatgcgg 4501 ccaagatagg accttgggcc aaatccgctc tcttcctgcc cctctttctc tttcttcctt 4561 tactttccct tgcttttccc tcttttctta ctcctcctct ttctctcccc aacccccatt 4621 ctcatctgca cccttctttt ctcatgtgtt tgcataaaca ttcttttaac ttctttctat 4681 ttgacttgtg gttgaattaa aattgtccca tttgctttgc aaaaaaaaaa aaaaaaaaaa 4741 aaaaaaaa (SEQ ID NO: 136) .

[0322] An exemplary nucleic acid sequence encoding PTK2B (NM_004103.4 transcript variant 2) comprises or consists of:

1 gaataggact agcaacttca tagacggttg tgaagacaag ctagacggca gatgaaagtt 61 cttggcacag agtgaacact tgataaacta tatggcagcc acagcctccg gagccgttgc 121 acacctacct gcccggccga cttacctgta cttgccgccg tcccggctca cctggcggtg 181 cccgaggagt agtcgctgga gtccgcgcct ccctgggact gcaatgtgcc gatcttagct 241 gctgcctgag aggatgtctg gggtgtccga gcccctgagt cgagtaaagt tgggcacgtt 301 acgccggcct gaaggccctg cagagcccat ggtggtggta ccagtagatg tggaaaagga 361 ggacgtgcgt atcctcaagg tctgcttcta tagcaacagc ttcaatcctg ggaaaaactt 421 caaactggtc aaatgcactg tccagacgga gatccgggag atcatcacct ccatcctgct 481 gagcgggcgg atcgggccca acatccggtt ggctgagtgc tatgggctga ggctgaagca 541 catgaagtcc gatgagatcc actggctgca cccacagatg acggtgggtg aggtgcagga 601 caagtatgag tgtctgcacg tggaagccga gtggaggtat gaccttcaaa tccgctactt 661 gccagaagac ttcatggaga gcctgaagga ggacaggacc acgctgctct atttttacca 721 acagctccgg aacgactaca tgcagcgcta cgccagcaag gtcagcgagg gcatggccct 781 gcagctgggc tgcctggagc tcaggcggtt cttcaaggat atgccccaca atgcacttga 841 caagaagtcc aacttcgagc tcctagaaaa ggaagtgggg ctggacttgt ttttcccaaa 901 gcagatgcag gagaacttaa agcccaaaca gttccggaag atgatccagc agaccttcca 961 gcagtacgcc tcgctcaggg aggaggagtg cgtcatgaag ttcttcaaca ctctcgccgg 1021 cttcgccaac atcgaccagg agacctaccg ctgtgaactc attcaaggat ggaacattac 1081 tgtggacctg gtcattggcc ctaaagggat ccgccagctg actagtcagg acgcaaagcc 1141 cacctgcctg gccgagttca agcagatcag gtccatcagg tgcctcccgc tggaggaggg 1201 ccaggcagta cttcagctgg gcattgaagg tgccccccag gccttgtcca tcaaaacctc 1261 atccctagca gaggctgaga acatggctga cctcatagac ggctactgcc ggctgcaggg 1321 tgagcaccaa ggctctctca tcatccatcc taggaaagat ggtgagaagc ggaacagcct 1381 gccccagatc cccatgctaa acctggaggc ccggcggtcc cacctctcag agagctgcag 1441 catagagtca gacatctacg cagagattcc cgacgaaacc ctgcgaaggc ccggaggtcc 1501 acagtatggc attgcccgtg aagatgtggt cctgaatcgt attcttgggg aaggcttttt 1561 tggggaggtc tatgaaggtg tctacacaaa tcacaaaggg gagaaaatca atgtagctgt 1621 caagacctgc aagaaagact gcactctgga caacaaggag aagttcatga gcgaggcagt 1681 gatcatgaag aacctcgacc acccgcacat cgtgaagctg atcggcatca ttgaagagga 1741 gcccacctgg atcatcatgg aattgtatcc ctatggggag ctgggccact acctggagcg 1801 gaacaagaac tccctgaagg tgctcaccct cgtgctgtac tcactgcaga tatgcaaagc 1861 catggcctac ctggagagca tcaactgcgt gcacagggac attgctgtcc ggaacatcct 1921 ggtggcctcc cctgagtgtg tgaagctggg ggactttggt ctttcccggt acattgagga 1981 cgaggactat tacaaagcct ctgtgactcg tctccccatc aaatggatgt ccccagagtc 2041 cattaacttc cgacgcttca cgacagccag tgacgtctgg atgttcgccg tgtgcatgtg 2101 ggagatcctg agctttggga agcagccctt cttctggctg gagaacaagg atgtcatcgg 2161 ggtgctggag aaaggagacc ggctgcccaa gcctgatctc tgtccaccgg tcctttatac 2221 cctcatgacc cgctgctggg actacgaccc cagtgaccgg ccccgcttca ccgagctggt 2281 gtgcagcctc agtgacgttt atcagatgga gaaggacatt gccatggagc aagagaggaa 2341 tgctcgctac cgaaccccca aaatcttgga gcccacagcc ttccaggaac ccccacccaa 2401 gcccagccga cctaagtaca gaccccctcc gcaaaccaac ctcctggctc caaagctgca 2461 gttccaggtt cctgagggtc tgtgtgccag ctctcctacg ctcaccagcc ctatggagta 2521 tccatctccc gttaactcac tgcacacccc acctctccac cggcacaatg tcttcaaacg 2581 ccacagcatg cgggaggagg acttcatcca acccagcagc cgagaagagg cccagcagct 2641 gtgggaggct gaaaaggtca aaatgcggca aatcctggac aaacagcaga agcagatggt 2701 ggaggactac cagtggctca ggcaggagga gaagtccctg gaccccatgg tttatatgaa 2761 tgataagtcc ccattgacgc cagagaagga ggtcggctac ctggagttca cagggccccc 2821 acagaagccc ccgaggctgg gcgcacagtc catccagccc acagctaacc tggaccggac 2881 tgatgacctg gtgtacctca atgtcatgga gctggtgcgg gccgtgctgg agctcaagaa 2941 tgagctctgt cagctgcccc ccgagggcta cgtggtggtg gtgaagaatg tggggctgac 3001 cctgcggaag ctcatcggga gcgtggatga tctcctgcct tccttgccgt catcttcacg 3061 gacagagatc gagggcaccc agaaactgct caacaaagac ctggcagagc tcatcaacaa 3121 gatgcggctg gcacagcaga acgccgtgac ctccctaagt gaggagtgca agaggcagat 3181 gctgacggct tcacacaccc tggctgtgga cgccaagaac ctgctcgacg ctgtggacca 3241 ggccaaggtt ctggccaatc tggcccaccc acctgcagag tgacggaggg tgggggccac 3301 ctgcctgcgt cttccgcccc tgcctgccat gtacctcccc tgccttgctg ttggtcatgt

3361 gggtcttcca gggggaaggc caaggggagt caccttccct tgccactttg cacgacgccc

3421 tctccccacc cctacccctg gctgtactgc tcaggctgca gctggacaga ggggactctg

3481 ggctatggac acagggtgac ggtgacaaag atggctcaga gggggactgc tgctgcctgg

3541 ccactgctcc ctaagccagc ctggtccatg cagggggctc ctgggggtgg ggaggtgtca

3601 catggtgccc ctagctttat atatggacat ggcaggccga tttgggaacc aagctattcc

3661 tttcccttcc tcttcggccc tcagatgtcc cttgatgcac agagaagctg gggaggagct

3721 ttgttttggg ggtcaggcag ccagtgagat gagggatggg cctggcattc ttgtacagtg

3781 tatattgaaa tttatttaat gtgagtttgg tctggactga cagcatgtgc cctcctgagg

3841 gaggacctgg ggcacagtcc aggaacaagc taattgggag tccaggcaca ggatgctgtg

3901 ttgtcaacaa accaagcatc agggggaaga agcagagaga tgcggccaag ataggacctt

3961 gggccaaatc cgctctcttc ctgcccctct ttctctttct tcctttactt tcccttgctt

4021 ttccctcttt tcttactcct cctctttctc tccccaaccc ccattctcat ctgcaccctt

4081 cttttctcat gtgtttgcat aaacattctt ttaacttctt tctatttgac ttgtggttga

4141 attaaaattg tcccatttgc tttgcaaaaa aaaaaaaaaa aaaaaaaaaa aaa (SEQ

NO: 137) .

[0323] An exemplary nucleic acid sequence encoding PTK2B (NM l 73176.2 transcript variant 3) comprises or consists of:

1 aaggaagtgg ggaggagagc agcaggggtg tggttaacaa ctcagaggag gagggagaat 61 ctaacctgtc agccctttta ctcagccaca gcctccggag ccgttgcaca cctacctgcc 121 cggccgactt acctgtactt gccgccgtcc cggctcacct ggcggtgccc gaggagtagt 181 cgctggagtc cgcgcctccc tgggactgca atgtgccgat cttagctgct gcctgagagg 241 atgtctgggg tgtccgagcc cctgagtcga gtaaagttgg gcacgttacg ccggcctgaa 301 ggccctgcag agcccatggt ggtggtacca gtagatgtgg aaaaggagga cgtgcgtatc 361 ctcaaggtct gcttctatag caacagcttc aatcctggga aaaacttcaa actggtcaaa 421 tgcactgtcc agacggagat ccgggagatc atcacctcca tcctgctgag cgggcggatc 481 gggcccaaca tccggttggc tgagtgctat gggctgaggc tgaagcacat gaagtccgat 541 gagatccact ggctgcaccc acagatgacg gtgggtgagg tgcaggacaa gtatgagtgt 601 ctgcacgtgg aagccgagtg gaggtatgac cttcaaatcc gctacttgcc agaagacttc 661 atggagagcc tgaaggagga caggaccacg ctgctctatt tttaccaaca gctccggaac 721 gactacatgc agcgctacgc cagcaaggtc agcgagggca tggccctgca gctgggctgc 781 ctggagctca ggcggttctt caaggatatg ccccacaatg cacttgacaa gaagtccaac 841 ttcgagctcc tagaaaagga agtggggctg gacttgtttt tcccaaagca gatgcaggag 901 aacttaaagc ccaaacagtt ccggaagatg atccagcaga ccttccagca gtacgcctcg 961 ctcagggagg aggagtgcgt catgaagttc ttcaacactc tcgccggctt cgccaacatc 1021 gaccaggaga cctaccgctg tgaactcatt caaggatgga acattactgt ggacctggtc 1081 attggcccta aagggatccg ccagctgact agtcaggacg caaagcccac ctgcctggcc 1141 gagttcaagc agatcaggtc catcaggtgc ctcccgctgg aggagggcca ggcagtactt 1201 cagctgggca ttgaaggtgc cccccaggcc ttgtccatca aaacctcatc cctagcagag 1261 gctgagaaca tggctgacct catagacggc tactgccggc tgcagggtga gcaccaaggc 1321 tctctcatca tccatcctag gaaagatggt gagaagcgga acagcctgcc ccagatcccc 1381 atgctaaacc tggaggcccg gcggtcccac ctctcagaga gctgcagcat agagtcagac 1441 atctacgcag agattcccga cgaaaccctg cgaaggcccg gaggtccaca gtatggcatt 1501 gcccgtgaag atgtggtcct gaatcgtatt cttggggaag gcttttttgg ggaggtctat 1561 gaaggtgtct acacaaatca caaaggggag aaaatcaatg tagctgtcaa gacctgcaag 1621 aaagactgca ctctggacaa caaggagaag ttcatgagcg aggcagtgat catgaagaac 1681 ctcgaccacc cgcacatcgt gaagctgatc ggcatcattg aagaggagcc cacctggatc 1741 atcatggaat tgtatcccta tggggagctg ggccactacc tggagcggaa caagaactcc 1801 ctgaaggtgc tcaccctcgt gctgtactca ctgcagatat gcaaagccat ggcctacctg 1861 gagagcatca actgcgtgca cagggacatt gctgtccgga acatcctggt ggcctcccct 1921 gagtgtgtga agctggggga ctttggtctt tcccggtaca ttgaggacga ggactattac 1981 aaagcctctg tgactcgtct ccccatcaaa tggatgtccc cagagtccat taacttccga 2041 cgcttcacga cagccagtga cgtctggatg ttcgccgtgt gcatgtggga gatcctgagc 2101 tttgggaagc agcccttctt ctggctggag aacaaggatg tcatcggggt gctggagaaa 2161 ggagaccggc tgcccaagcc tgatctctgt ccaccggtcc tttataccct catgacccgc 2221 tgctgggact acgaccccag tgaccggccc cgcttcaccg agctggtgtg cagcctcagt 2281 gacgtttatc agatggagaa ggacattgcc atggagcaag agaggaatgc tcgctaccga 2341 acccccaaaa tcttggagcc cacagccttc caggaacccc cacccaagcc cagccgacct 2401 aagtacagac cccctccgca aaccaacctc ctggctccaa agctgcagtt ccaggttcct 2461 gagggtctgt gtgccagctc tcctacgctc accagcccta tggagtatcc atctcccgtt 2521 aactcactgc acaccccacc tctccaccgg cacaatgtct tcaaacgcca cagcatgcgg 2581 gaggaggact tcatccaacc cagcagccga gaagaggccc agcagctgtg ggaggctgaa 2641 aaggtcaaaa tgcggcaaat cctggacaaa cagcagaagc agatggtgga ggactaccag 2701 tggctcaggc aggaggagaa gtccctggac cccatggttt atatgaatga taagtcccca 2761 ttgacgccag agaaggaggt cggctacctg gagttcacag ggcccccaca gaagcccccg 2821 aggctgggcg cacagtccat ccagcccaca gctaacctgg accggactga tgacctggtg 2881 tacctcaatg tcatggagct ggtgcgggcc gtgctggagc tcaagaatga gctctgtcag 2941 ctgccccccg agggctacgt ggtggtggtg aagaatgtgg ggctgaccct gcggaagctc 3001 atcgggagcg tggatgatct cctgccttcc ttgccgtcat cttcacggac agagatcgag 3061 ggcacccaga aactgctcaa caaagacctg gcagagctca tcaacaagat gcggctggca 3121 cagcagaacg ccgtgacctc cctaagtgag gagtgcaaga ggcagatgct gacggcttca 3181 cacaccctgg ctgtggacgc caagaacctg ctcgacgctg tggaccaggc caaggttctg 3241 gccaatctgg cccacccacc tgcagagtga cggagggtgg gggccacctg cctgcgtctt 3301 ccgcccctgc ctgccatgta cctcccctgc cttgctgttg gtcatgtggg tcttccaggg 3361 ggaaggccaa ggggagtcac cttcccttgc cactttgcac gacgccctct ccccacccct 3421 acccctggct gtactgctca ggctgcagct ggacagaggg gactctgggc tatggacaca 3481 gggtgacggt gacaaagatg gctcagaggg ggactgctgc tgcctggcca ctgctcccta 3541 agccagcctg gtccatgcag ggggctcctg ggggtgggga ggtgtcacat ggtgccccta 3601 gctttatata tggacatggc aggccgattt gggaaccaag ctattccttt cccttcctct 3661 tcggccctca gatgtccctt gatgcacaga gaagctgggg aggagctttg ttttgggggt 3721 caggcagcca gtgagatgag ggatgggcct ggcattcttg tacagtgtat attgaaattt 3781 atttaatgtg agtttggtct ggactgacag catgtgccct cctgagggag gacctggggc 3841 acagtccagg aacaagctaa ttgggagtcc aggcacagga tgctgtgttg tcaacaaacc 3901 aagcatcagg gggaagaagc agagagatgc ggccaagata ggaccttggg ccaaatccgc 3961 tctcttcctg cccctctttc tctttcttcc tttactttcc cttgcttttc cctcttttct 4021 tactcctcct ctttctctcc ccaaccccca ttctcatctg cacccttctt ttctcatgtg 4081 tttgcataaa cattctttta acttctttct atttgacttg tggttgaatt aaaattgtcc 4141 catttgcttt gcaaaaaaaa aaaaaaaaaa aaaaaaaaaa (SEQ ID NO 138) .

[0324] An exemplary amino acid sequence encoding PTK2B (NP 775266.1, isoform a, corresponding to transcript variants 1, 2, and 3) comprises or consists of:

MSGVSEPLSRVKLGTLRRPEGPAEPMVWPVDVEKEDVRILKVCFYSNSFNPGKNFKLVKCTVQTEIREIITSIL LSGRIGPNIRLAECYGLRLKHMKSDEIHWLHPQMTVGEVQDKYECLHVEAEWRYDLQIRYLPEDFMESLKEDRTT LLYFYQQLRNDYMQRYASKVSEGMALQLGCLELRRFFKDMPHNALDKKSNFELLEKEVGLDLFFPKQMQENLKPK QFRKMIQQTFQQYASLREEECVMKFFNTLAGFANIDQETYRCELIQGWNITVDLVIGPKGIRQLTSQDAKPTCLA EFKQIRSIRCLPLEEGQAVLQLGIEGAPQALSIKTSSLAEAENMADLIDGYCRLQGEHQGSLIIHPRKDGEKRNS LPQIPMLNLEARRSHLSESCSIESDIYAEIPDETLRRPGGPQYGIAREDWLNRILGEGFFGEVYEGVYTNHKGE KINVAVKTCKKDCTLDNKEKFMSEAVIMKNLDHPHIVKLIGIIEEEPTWIIMELYPYGELGHYLERNKNSLKVLT LVLYSLQICKAMAYLESINCVHRDIAVRNILVASPECVKLGDFGLSRYIEDEDYYKASVTRLPIKWMSPESINFR RFTTASDVWMFAVCMWEILSFGKQPFFWLENKDVIGVLEKGDRLPKPDLCPPVLYTLMTRCWDYDPSDRPRFTEL VCSLSDVYQMEKDIAMEQERNARYRTPKILEPTAFQEPPPKPSRPKYRPPPQTNLLAPKLQFQVPEGLCASSPTL TSPMEYPSPVNSLHTPPLHRHNVFKRHSMREEDFIQPSSREEAQQLWEAEKVKMRQILDKQQKQMVEDYQWLRQE EKSLDPMVYMNDKSPLTPEKEVGYLEFTGPPQKPPRLGAQSIQPTANLDRTDDLVYLNVMELVRAVLELKNELCQ LPPEGYWWKNVGLTLRKLIGSVDDLLPSLPSSSRTEIEGTQKLLNKDLAELINKMRLAQQNAVTSLSEECKRQ MLTASHTLAVDAKNLLDAVDQAKVLANLAHPPAE (SEQ ID NO: 139) .

[0325] An exemplary nucleic acid sequence encoding PTK2B (NM 173175.2 transcript variant 4) comprises or consists of: 1 ccacagcctc cggagccgtt gcacacctac ctgcccggcc gacttacctg tacttgccgc 61 cgtcccggct cacctggcgg tgcccgagga gtagtcgctg gagtccgcgc ctccctggga 121 ctgcaatgtg ccgatcttag ctgctgcctg agaggatgtc tggggtgtcc gagcccctga 181 gtcgagtaaa gttgggcacg ttacgccggc ctgaaggccc tgcagagccc atggtggtgg 241 taccagtaga tgtggaaaag gaggacgtgc gtatcctcaa ggtctgcttc tatagcaaca 301 gcttcaatcc tgggaaaaac ttcaaactgg tcaaatgcac tgtccagacg gagatccggg 361 agatcatcac ctccatcctg ctgagcgggc ggatcgggcc caacatccgg ttggctgagt 421 gctatgggct gaggctgaag cacatgaagt ccgatgagat ccactggctg cacccacaga 481 tgacggtggg tgaggtgcag gacaagtatg agtgtctgca cgtggaagcc gagtggaggt 541 atgaccttca aatccgctac ttgccagaag acttcatgga gagcctgaag gaggacagga 601 ccacgctgct ctatttttac caacagctcc ggaacgacta catgcagcgc tacgccagca 661 aggtcagcga gggcatggcc ctgcagctgg gctgcctgga gctcaggcgg ttcttcaagg 721 atatgcccca caatgcactt gacaagaagt ccaacttcga gctcctagaa aaggaagtgg 781 ggctggactt gtttttccca aagcagatgc aggagaactt aaagcccaaa cagttccgga 841 agatgatcca gcagaccttc cagcagtacg cctcgctcag ggaggaggag tgcgtcatga 901 agttcttcaa cactctcgcc ggcttcgcca acatcgacca ggagacctac cgctgtgaac 961 tcattcaagg atggaacatt actgtggacc tggtcattgg ccctaaaggg atccgccagc 1021 tgactagtca ggacgcaaag cccacctgcc tggccgagtt caagcagatc aggtccatca 1081 ggtgcctccc gctggaggag ggccaggcag tacttcagct gggcattgaa ggtgcccccc 1141 aggccttgtc catcaaaacc tcatccctag cagaggctga gaacatggct gacctcatag 1201 acggctactg ccggctgcag ggtgagcacc aaggctctct catcatccat cctaggaaag 1261 atggtgagaa gcggaacagc ctgccccaga tccccatgct aaacctggag gcccggcggt 1321 cccacctctc agagagctgc agcatagagt cagacatcta cgcagagatt cccgacgaaa 1381 ccctgcgaag gcccggaggt ccacagtatg gcattgcccg tgaagatgtg gtcctgaatc 1441 gtattcttgg ggaaggcttt tttggggagg tctatgaagg tgtctacaca aatcacaaag 1501 gggagaaaat caatgtagct gtcaagacct gcaagaaaga ctgcactctg gacaacaagg 1561 agaagttcat gagcgaggca gtgatcatga agaacctcga ccacccgcac atcgtgaagc 1621 tgatcggcat cattgaagag gagcccacct ggatcatcat ggaattgtat ccctatgggg 1681 agctgggcca ctacctggag cggaacaaga actccctgaa ggtgctcacc ctcgtgctgt 1741 actcactgca gatatgcaaa gccatggcct acctggagag catcaactgc gtgcacaggg 1801 acattgctgt ccggaacatc ctggtggcct cccctgagtg tgtgaagctg ggggactttg 1861 gtctttcccg gtacattgag gacgaggact attacaaagc ctctgtgact cgtctcccca 1921 tcaaatggat gtccccagag tccattaact tccgacgctt cacgacagcc agtgacgtct 1981 ggatgttcgc cgtgtgcatg tgggagatcc tgagctttgg gaagcagccc ttcttctggc 2041 tggagaacaa ggatgtcatc ggggtgctgg agaaaggaga ccggctgccc aagcctgatc 2101 tctgtccacc ggtcctttat accctcatga cccgctgctg ggactacgac cccagtgacc 2161 ggccccgctt caccgagctg gtgtgcagcc tcagtgacgt ttatcagatg gagaaggaca 2221 ttgccatgga gcaagagagg aatgctcgct accgaacccc caaaatcttg gagcccacag 2281 ccttccagga acccccaccc aagcccagcc gacctaagta cagaccccct ccgcaaacca 2341 acctcctggc tccaaagctg cagttccagg aggaggactt catccaaccc agcagccgag 2401 aagaggccca gcagctgtgg gaggctgaaa aggtcaaaat gcggcaaatc ctggacaaac 2461 agcagaagca gatggtggag gactaccagt ggctcaggca ggaggagaag tccctggacc 2521 ccatggttta tatgaatgat aagtccccat tgacgccaga gaaggaggtc ggctacctgg 2581 agttcacagg gcccccacag aagcccccga ggctgggcgc acagtccatc cagcccacag 2641 ctaacctgga ccggactgat gacctggtgt acctcaatgt catggagctg gtgcgggccg 2701 tgctggagct caagaatgag ctctgtcagc tgccccccga gggctacgtg gtggtggtga 2761 agaatgtggg gctgaccctg cggaagctca tcgggagcgt ggatgatctc ctgccttcct 2821 tgccgtcatc ttcacggaca gagatcgagg gcacccagaa actgctcaac aaagacctgg 2881 cagagctcat caacaagatg cggctggcac agcagaacgc cgtgacctcc ctaagtgagg 2941 agtgcaagag gcagatgctg acggcttcac acaccctggc tgtggacgcc aagaacctgc 3001 tcgacgctgt ggaccaggcc aaggttctgg ccaatctggc ccacccacct gcagagtgac 3061 ggagggtggg ggccacctgc ctgcgtcttc cgcccctgcc tgccatgtac ctcccctgcc 3121 ttgctgttgg tcatgtgggt cttccagggg gaaggccaag gggagtcacc ttcccttgcc 3181 actttgcacg acgccctctc cccaccccta cccctggctg tactgctcag gctgcagctg 3241 gacagagggg actctgggct atggacacag ggtgacggtg acaaagatgg ctcagagggg 3301 gactgctgct gcctggccac tgctccctaa gccagcctgg tccatgcagg gggctcctgg 3361 gggtggggag gtgtcacatg gtgcccctag ctttatatat ggacatggca ggccgatttg 3421 ggaaccaagc tattcctttc ccttcctctt cggccctcag atgtcccttg atgcacagag 3481 aagctgggga ggagctttgt tttgggggtc aggcagccag tgagatgagg gatgggcctg 3541 gcattcttgt acagtgtata ttgaaattta tttaatgtga gtttggtctg gactgacagc 3601 atgtgccctc ctgagggagg acctggggca cagtccagga acaagctaat tgggagtcca 3661 ggcacaggat gctgtgttgt caacaaacca agcatcaggg ggaagaagca gagagatgcg 3721 gccaagatag gaccttgggc caaatccgct ctcttcctgc ccctctttct ctttcttcct 3781 ttactttccc ttgcttttcc ctcttttctt actcctcctc tttctctccc caacccccat 3841 tctcatctgc acccttcttt tctcatgtgt ttgcataaac attcttttaa cttctttcta 3901 tttgacttgt ggttgaatta aaattgtccc atttgctttg caaaaaaaaa aaaaaaaaaa 3961 aaaaaaaaa (SEQ ID NO: 140) .

[0326] An exemplary amino acid sequence encoding PTK2B (NP_775267.1, isoform b) comprises or consists of:

MSGVSEPLSRVKLGTLRRPEGPAEPMVWPVDVEKEDVRILKVCFYSNSFNPGKNFKLVKCTVQTEIREIITSIL LSGRIGPNIRLAECYGLRLKHMKSDEIHWLHPQMTVGEVQDKYECLHVEAEWRYDLQIRYLPEDFMESLKEDRTT LLYFYQQLRNDYMQRYASKVSEGMALQLGCLELRRFFKDMPHNALDKKSNFELLEKEVGLDLFFPKQMQENLKPK QFRKMIQQTFQQYASLREEECVMKFFNTLAGFANIDQETYRCELIQGWNITVDLVIGPKGIRQLTSQDAKPTCLA EFKQIRSIRCLPLEEGQAVLQLGIEGAPQALSIKTSSLAEAENMADLIDGYCRLQGEHQGSLIIHPRKDGEKRNS LPQIPMLNLEARRSHLSESCSIESDIYAEIPDETLRRPGGPQYGIAREDWLNRILGEGFFGEVYEGVYTNHKGE KINVAVKTCKKDCTLDNKEKFMSEAVIMKNLDHPHIVKLIGIIEEEPTWIIMELYPYGELGHYLERNKNSLKVLT LVLYSLQICKAMAYLESINCVHRDIAVRNILVASPECVKLGDFGLSRYIEDEDYYKASVTRLPIKWMSPESINFR RFTTASDVWMFAVCMWEILSFGKQPFFWLENKDVIGVLEKGDRLPKPDLCPPVLYTLMTRCWDYDPSDRPRFTEL VCSLSDVYQMEKDIAMEQERNARYRTPKILEPTAFQEPPPKPSRPKYRPPPQTNLLAPKLQFQEEDFIQPSSREE AQQLWEAEKVKMRQILDKQQKQMVEDYQWLRQEEKSLDPMVYMNDKSPLTPEKEVGYLEFTGPPQKPPRLGAQSI QPTANLDRTDDLVYLNVMELVRAVLELKNELCQLPPEGYWWKNVGLTLRKLIGSVDDLLPSLPSSSRTEIEGT QKLLNKDLAELINKMRLAQQNAVTSLSEECKRQMLTASHTLAVDAKNLLDAVDQAKVLANLAHPPAE (SEQ ID NO: 141) .

[0327] An exemplary nucleic acid sequence encoding RPS6KB 1 (NM_001272060.1 transcript variant 1 ) comprises or consists of:

1 gtttggcttc acggaaccct gtacgcatgc tcctacgctg aactttagga gccagtctaa 61 ggcctaggcg cagacgcact gagcctaagc agccggtgat ggcggcagcg gctgtggtgg 121 ctgcggcggg tccgggccca tgaggcgacg aaggaggcgg gacggctttt acccagcccc 181 ggacttccga gacagggaag ctgaggacat ggcaggagtg tttgacatag acctggacca 241 gccagaggac gcgggctctg aggatgagct ggaggagggg ggtcagttaa atgaaagcat 301 ggaccatggg ggagttggac catatgaact tggcatggaa cattgtgaga aatttgaaat 361 ctcagaaact agtgtgaaca gagggccaga aaaaatcaga ccagaatgtt ttgagctact 421 tcgggtactt ggtaaagggg gctatggaaa ggtttttcaa gtacgaaaag taacaggagc 481 aaatactggg aaaatatttg ccatgaaggt gcttaaaaag gcaatgatag taagaaatgc 541 taaagataca gctcatacaa aagcagaacg gaatattctg gaggaagtaa agcatccctt 601 catcgtggat ttaatttatg cctttcagac tggtggaaaa ctctacctca tccttgagta 661 tctcagtgga ggagaactat ttatgcagtt agaaagagag ggaatattta tggaagacac 721 tgcctgcttt tacttggcag aaatctccat ggctttgggg catttacatc aaaaggggat 781 catctacaga gacctgaagc cggagaatat catgcttaat caccaaggtc atgtgaaact 841 aacagacttt ggactatgca aagaatctat tcatgatgga acagtcacac acacattttg 901 tggaacaata gaatacatgg cccctgaaat cttgatgaga agtggccaca atcgtgctgt 961 ggattggtgg agtttgggag cattaatgta tgacatgctg actggagcac ccccattcac 1021 tggggagaat agaaagaaaa caattgacaa aatcctcaaa tgtaaactca atttgcctcc 1081 ctacctcaca caagaagcca gagatctgct taaaaagctg ctgaaaagaa atgctgcttc 1141 tcgtctggga gctggtcctg gggacgctgg agaagttcaa gctcatccat tctttagaca 1201 cattaactgg gaagaacttc tggctcgaaa ggtggagccc ccctttaaac ctctgttgca 1261 atctgaagag gatgtaagtc agtttgattc caagtttaca cgtcagacac ctgtcgacag 1321 cccagatgac tcaactctca gtgaaagtgc caatcaggtc tttctgggtt ttacatatgt 1381 ggctccatct gtacttgaaa gtgtgaaaga aaagttttcc tttgaaccaa aaatccgatc 1441 acctcgaaga tttattggca gcccacgaac acctgtcagc ccagtcaaat tttctcctgg 1501 ggatttctgg ggaagaggtg cttcggccag cacagcaaat cctcagacac ctgtggaata 1561 cccaatggaa acaagtggca tagagcagat ggatgtgaca atgagtgggg aagcatcggc 1621 accacttcca atacgacagc cgaactctgg gccatacaaa aaacaagctt ttcccatgat 1681 ctccaaacgg ccagagcacc tgcgtatgaa tctatgacag agcaatgctt ttaatgaatt 1741 taaggcaaaa aaggtggaga gggagatgtg tgagcatcct gcaaggtgaa acgactcaaa 1801 atgacagttt cagagagtca atgtcattac atagaacact tcagacacag gaaaaataaa 1861 cgtggatttt aaaaaatcaa tcaatggtgc aaaaaaaaac ttaaagcaaa atagtattgc 1921 tgaactctta ggcacatcaa ttaattgatt cctcgcgaca tcttctcaac cttatcaagg 1981 attttcatgt tgatgactcg aaactgacag tattaagggt aggatgttgc ttctgaatca 2041 ctgttgagtt ctgattgtgt tgaagaaggg ttatcctttc attaggcaaa gtacaaaatt 2101 gcctataata cttgcaacta aggacaaatt agcatgcaag cttggtcaaa ctttttccag 2161 caaaatggaa gcaaagacaa aagaaactta ccaattgatg ttttacgtgc aaacaacctg 2221 aatctttttt ttatataaat atatattttt caaatagatt tttgattcag ctcattatga 2281 aaaacatccc aaactttaaa atgcgaaatt attggttggt gtgaagaaag ccagacaact 2341 tctgtttctt ctcttggtga aataataaaa tgcaaatgaa tcattgttaa ccacagctgt 2401 ggctcgtttg agggattggg gtggacctgg ggtttatttt cagtaaccca gctgcaatac 2461 ctgtctgtaa tatgagaaaa aaaaaatgaa tctatttaat catttctact tgcagtactg 2521 ctatgtgcta agcttaactg gaagccttgg aatgggcata agttgtatgt cctacatttc 2581 atcattgtcc cgggcctgca ttgcactgga aaaaaaaatc gccacctgtt cttacaccag 2641 tatttggttc aagacaccaa atgtcttcag cccatggctg aagaacaaca gaagagagtc 2701 aggataaaaa atacatactg tggtcggcaa ggtgagggag atagggatat ccaggggaag 2761 agggtgttgc tgtggcccac tctctgtcta atctctttac agcaaattgg taagattttc 2821 agttttactt ctttctactg tttctgctgt ctaccttcct tatatttttt tcctcaacag 2881 ttttaaaaag aaaaaaaggt ctattttttt ttctcctata cttgggctac attttttgat 2941 tgtaaaaata tttgatggcc ttttgatgaa tgtcttccac agtaaagaaa acttagtggc 3001 ttaatttagg aaacatgtta acaggacact atgtttttga aattgtaaca aaatctacat 3061 aaatgattta caggttaaaa gaataaaaat aaaggtaact ttacctttct taaatatttc 3121 ctgccttaaa gagagcattt ccatgacttt agctggtgaa agggtttaat atctgcagag 3181 ctttataaaa atatatttca gtgcatactg gtataataga tgatcatgca gttgcagttg 3241 agttgtatca ccttttttgt ttgtctttta taatgtcttc agtctgagtg tgcaaagtca 3301 atttgtaata ttttgcaacc ctaggatttt tttaaataga tgctgcttgc tatgttttca 3361 aacctttttg agccatagga tccaagccat aaaattcttt atgcatgttg aattcagtca 3421 gaaaagagca aggctttgct ttttgaaatt gcaactcaaa tgagatggga tgaaatccta 3481 tgacagtaag caaaaacaga accatgaaaa atgattggac atacaccttt tcaattgtgg 3541 caataattga aagaatcgat aaaagttcat ctttggacag aaagccttta aaaaaaaaat 3601 cactccctct tccccctcct cccttattgc agcagcctac tgagaacttt gactgttgct 3661 ggtaaattag aagctacaat aataattaag ggcagaaatt atacttaaaa agtgcagatc 3721 cttgttcttt gacaatttgt gatgtctgaa aaaacagaac ccgaaaagct atggtgatat 3781 gtacaggcat tatttcagac tgtaaatggc ttgtgatact cttgatactt gttttcaaat 3841 atgtttacta actgtagtgt tgactgcctg accaaattcc agtgaaactt atacaccaaa 3901 atattcttcc taggtcctat ttgctagtaa catgagcact gtgattggct ggctataacc 3961 accccagtta aaccattttc ataattagta gtgccagcaa tagtggcaaa cactgcaact 4021 tttctgcata aaaagcatta attgcacagc taccatccac acaaatacat agtttttctg 4081 acttcacatt tattaagtga aatttatttc ccatgctgtg gaaagtttat tgagaacttg 4141 tttcataaat ggatatccct actatgactg tgaaaacatg tcaagtgtca cattagtgtc 4201 acagacagaa agcacacacc tatgcaatat ggcttatcta tatttatttg taaaaatcca 4261 agcatagttt aaaatatgat gtcgatatta ctagtcttga gtttctaaga gggttcttta 4321 tgttatacca ggtaagtgta taaaagagat taagtgcttt tttttcatca cttgattatt 4381 ttctttaaaa tcagctatta caggatattt ttttatttta tacatgctgt tttttaatta 4441 aaatataatc actgaagttt actaatttga ttttataagg tttgtagcat tacagaataa 4501 ctaaactggg atttataaac cagctgtgat taacaatgta aagtattaat tattgaactt 4561 tgaaccagat ttttaggaaa attatgttct ttttccccct ttatggtctt aactaatttg 4621 aatccttcaa gaaggatttt tccatactat tttttaagat agaagataat ttgtgggcag 4681 gggtggagga tgcatgtatg atactccata aattcaacat tctttactat aggtaatgaa 4741 tgattataaa caagatgcat cttagatagt attaatatac tgagccttgg attatatatt 4801 taatatagga cctattttga atattcagtt aatcatatgg ttcctagctt acaagggcta 4861 gatctaagat tattcccatg agaaatgttg aatttatgaa gaatagattt taaggctttg 4921 aaaatggtta atttctcaaa aacatcaatg tccaaacatc tacctttttt cataggagta 4981 gacactagca agctggacaa actatcacaa aagtatttgt cacacataac ctgtggtctg 5041 ttgctgatta atacagtact ttttcttgtg tgattcttaa cattatagca caagtattat 5101 ctcagtggat tatccggaat aacatctgaa agatgggttc atctatgttt gtgtttgctc 5161 tttaaactat tgtttctcct atcccaagtt cgctttgcat ctatcagtaa ataaaattct 5221 tcagctgcct tattaggagt gctatgaggg taacacctgt tctgcttttc atcttgtatt 5281 tagttgactg tattatttga tttcggattg aatgaatgta aatagaaatt aaatgcaaat 5341 ttgaatgaac ataaaaaaaa aaaaaaaa (SEQ ID NO: 142).

[0328] An exemplary amino acid sequence encoding RPS6KB1 (NP 001258989.1, isoforom e) comprises or consists of:

MAGVFDIDLDQPEDAGSEDELEEGGQLNESMDHGGVGPYELGMEHCEKFEISETSVNRGPEKIRPECFELLRVLG KGGYGKVFQVRKVTGANTGKIFAMKVLKKAMIVRNAKDTAHTKAERNILEEVKHPFIVDLIYAFQTGGKLYLILE YLSGGELFMQLEREGIFMEDTACFYLAEISMALGHLHQKGI IYRDLKPENIMLNHQGHVKLTDFGLCKESIHDGT VTHTFCGTIEYMAPEILMRSGHNRAVDWWSLGALMYDMLTGAPPFTGENRKKTIDKILKCKLNLPPYLTQEARDL LKKLLKRNAASRLGAGPGDAGEVQAHPFFRHINWEELLARKVEPPFKPLLQSEEDVSQFDSKFTRQTPVDSPDDS TLSESANQVFLGFTYVAPSVLESVKEKFSFEPKIRSPRRFIGSPRTPVSPVKFSPGDFWGRGASASTANPQTPVE YPMETSGIEQMDVTMSGEASAPLPIRQPNSGPYKKQAFPMISKRPEHLRMNL (SEQ ID NO: 143) .

[0329] An exemplary nucleic acid sequence encoding RPS6KB1 (NM_001272042.1 transcript variant 2) comprises or consists of:

1 gtttggcttc acggaaccct gtacgcatgc tcctacgctg aactttagga gccagtctaa 61 ggcctaggcg cagacgcact gagcctaagc agccggtgat ggcggcagcg gctgtggtgg 121 ctgcggcggg tccgggccca tgaggcgacg aaggaggcgg gacggctttt acccagcccc 181 ggacttccga gacagggaag ctgaggacat ggcaggagtg tttgacatag acctggacca 241 gccagaggac gcgggctctg aggatgagct ggaggagggg ggtcagttaa atgaaagcat 301 ggaccatggg ggagttggac catatgaact tggcatggaa cattgtgaga aatttgaaat 361 ctcagaaact agtgtgaaca gagggccaga aaaaatcaga ccagaatgtt ttgagctact 421 tcgggtactt ggtaaagggg gctatggaaa ggcaatgata gtaagaaatg ctaaagatac 481 agctcataca aaagcagaac ggaatattct ggaggaagta aagcatccct tcatcgtgga 541 tttaatttat gcctttcaga ctggtggaaa actctacctc atccttgagt atctcagtgg 601 aggagaacta tttatgcagt tagaaagaga gggaatattt atggaagaca ctgcctgctt 661 ttacttggca gaaatctcca tggctttggg gcatttacat caaaagggga tcatctacag 721 agacctgaag ccggagaata tcatgcttaa tcaccaaggt catgtgaaac taacagactt 781 tggactatgc aaagaatcta ttcatgatgg aacagtcaca cacacatttt gtggaacaat 841 agaatacatg gcccctgaaa tcttgatgag aagtggccac aatcgtgctg tggattggtg 901 gagtttggga gcattaatgt atgacatgct gactggagca cccccattca ctggggagaa 961 tagaaagaaa acaattgaca aaatcctcaa atgtaaactc aatttgcctc cctacctcac 1021 acaagaagcc agagatctgc ttaaaaagct gctgaaaaga aatgctgctt ctcgtctggg 1081 agctggtcct ggggacgctg gagaagttca agctcatcca ttctttagac acattaactg 1141 ggaagaactt ctggctcgaa aggtggagcc cccctttaaa cctctgttgc aatctgaaga 1201 ggatgtaagt cagtttgatt ccaagtttac acgtcagaca cctgtcgaca gcccagatga 1261 ctcaactctc agtgaaagtg ccaatcaggt ctttctgggt tttacatatg tggctccatc 1321 tgtacttgaa agtgtgaaag aaaagttttc ctttgaacca aaaatccgat cacctcgaag 1381 atttattggc agcccacgaa cacctgtcag cccagtcaaa ttttctcctg gggatttctg 1441 gggaagaggt gcttcggcca gcacagcaaa tcctcagaca cctgtggaat acccaatgga 1501 aacaagtggc atagagcaga tggatgtgac aatgagtggg gaagcatcgg caccacttcc 1561 aatacgacag ccgaactctg ggccatacaa aaaacaagct tttcccatga tctccaaacg 1621 gccagagcac ctgcgtatga atctatgaca gagcaatgct tttaatgaat ttaaggcaaa 1681 aaaggtggag agggagatgt gtgagcatcc tgcaaggtga aacgactcaa aatgacagtt 1741 tcagagagtc aatgtcatta catagaacac ttcagacaca ggaaaaataa acgtggattt 1801 taaaaaatca atcaatggtg caaaaaaaaa cttaaagcaa aatagtattg ctgaactctt 1861 aggcacatca attaattgat tcctcgcgac atcttctcaa ccttatcaag gattttcatg 1921 ttgatgactc gaaactgaca gtattaaggg taggatgttg cttctgaatc actgttgagt 1981 tctgattgtg ttgaagaagg gttatccttt cattaggcaa agtacaaaat tgcctataat 2041 acttgcaact aaggacaaat tagcatgcaa gcttggtcaa actttttcca gcaaaatgga 2101 agcaaagaca aaagaaactt accaattgat gttttacgtg caaacaacct gaatcttttt 2161 tttatataaa tatatatttt tcaaatagat ttttgattca gctcattatg aaaaacatcc 2221 caaactttaa aatgcgaaat tattggttgg tgtgaagaaa gccagacaac ttctgtttct 2281 tctcttggtg aaataataaa atgcaaatga atcattgtta accacagctg tggctcgttt 2341 gagggattgg ggtggacctg gggtttattt tcagtaaccc agctgcaata cctgtctgta 2401 atatgagaaa aaaaaaatga atctatttaa tcatttctac ttgcagtact gctatgtgct 2461 aagcttaact ggaagccttg gaatgggcat aagttgtatg tcctacattt catcattgtc 2521 ccgggcctgc attgcactgg aaaaaaaaat cgccacctgt tcttacacca gtatttggtt 2581 caagacacca aatgtcttca gcccatggct gaagaacaac agaagagagt caggataaaa 2641 aatacatact gtggtcggca aggtgaggga gatagggata tccaggggaa gagggtgttg 2701 ctgtggccca ctctctgtct aatctcttta cagcaaattg gtaagatttt cagttttact 2761 tctttctact gtttctgctg tctaccttcc ttatattttt ttcctcaaca gttttaaaaa 2821 gaaaaaaagg tctatttttt tttctcctat acttgggcta cattttttga ttgtaaaaat 2881 atttgatggc cttttgatga atgtcttcca cagtaaagaa aacttagtgg cttaatttag 2941 gaaacatgtt aacaggacac tatgtttttg aaattgtaac aaaatctaca taaatgattt 3001 acaggttaaa agaataaaaa taaaggtaac tttacctttc ttaaatattt cctgccttaa 3061 agagagcatt tccatgactt tagctggtga aagggtttaa tatctgcaga gctttataaa 3121 aatatatttc agtgcatact ggtataatag atgatcatgc agttgcagtt gagttgtatc 3181 accttttttg tttgtctttt ataatgtctt cagtctgagt gtgcaaagtc aatttgtaat 3241 attttgcaac cctaggattt ttttaaatag atgctgcttg ctatgttttc aaaccttttt 3301 gagccatagg atccaagcca taaaattctt tatgcatgtt gaattcagtc agaaaagagc 3361 aaggctttgc tttttgaaat tgcaactcaa atgagatggg atgaaatcct atgacagtaa 3421 gcaaaaacag aaccatgaaa aatgattgga catacacctt ttcaattgtg gcaataattg 3481 aaagaatcga taaaagttca tctttggaca gaaagccttt aaaaaaaaaa tcactccctc 3541 ttccccctcc tcccttattg cagcagccta ctgagaactt tgactgttgc tggtaaatta 3601 gaagctacaa taataattaa gggcagaaat tatacttaaa aagtgcagat ccttgttctt 3661 tgacaatttg tgatgtctga aaaaacagaa cccgaaaagc tatggtgata tgtacaggca 3721 ttatttcaga ctgtaaatgg cttgtgatac tcttgatact tgttttcaaa tatgtttact 3781 aactgtagtg ttgactgcct gaccaaattc cagtgaaact tatacaccaa aatattcttc 3841 ctaggtccta tttgctagta acatgagcac tgtgattggc tggctataac caccccagtt 3901 aaaccatttt cataattagt agtgccagca atagtggcaa acactgcaac ttttctgcat 3961 aaaaagcatt aattgcacag ctaccatcca cacaaataca tagtttttct gacttcacat 4021 ttattaagtg aaatttattt cccatgctgt ggaaagttta ttgagaactt gtttcataaa 4081 tggatatccc tactatgact gtgaaaacat gtcaagtgtc acattagtgt cacagacaga 4141 aagcacacac ctatgcaata tggcttatct atatttattt gtaaaaatcc aagcatagtt 4201 taaaatatga tgtcgatatt actagtcttg agtttctaag agggttcttt atgttatacc 4261 aggtaagtgt ataaaagaga ttaagtgctt ttttttcatc acttgattat tttctttaaa 4321 atcagctatt acaggatatt tttttatttt atacatgctg ttttttaatt aaaatataat 4381 cactgaagtt tactaatttg attttataag gtttgtagca ttacagaata actaaactgg 4441 gatttataaa ccagctgtga ttaacaatgt aaagtattaa ttattgaact ttgaaccaga 4501 tttttaggaa aattatgttc tttttccccc tttatggtct taactaattt gaatccttca 4561 agaaggattt ttccatacta ttttttaaga tagaagataa tttgtgggca ggggtggagg 4621 atgcatgtat gatactccat aaattcaaca ttctttacta taggtaatga atgattataa 4681 acaagatgca tcttagatag tattaatata ctgagccttg gattatatat ttaatatagg 4741 acctattttg aatattcagt taatcatatg gttcctagct tacaagggct agatctaaga 4801 ttattcccat gagaaatgtt gaatttatga agaatagatt ttaaggcttt gaaaatggtt 4861 aatttctcaa aaacatcaat gtccaaacat ctaccttttt tcataggagt agacactagc 4921 aagctggaca aactatcaca aaagtatttg tcacacataa cctgtggtct gttgctgatt 4981 aatacagtac tttttcttgt gtgattctta acattatagc acaagtatta tctcagtgga 5041 ttatccggaa taacatctga aagatgggtt catctatgtt tgtgtttgct ctttaaacta 5101 ttgtttctcc tatcccaagt tcgctttgca tctatcagta aataaaattc ttcagctgcc 5161 ttattaggag tgctatgagg gtaacacctg ttctgctttt catcttgtat ttagttgact 5221 gtattatttg atttcggatt gaatgaatgt aaatagaaat taaatgcaaa tttgaatgaa 5281 cataaaaaaa aaaaaaaaa (SEQ ID NO: 144) .

[0330] An exemplary amino acid sequence encoding RPS6KB1 (NP 001258971.1, isoform b) comprises or consists of:

MRRRRRRDGFYPAPDFRDREAEDMAGVFDIDLDQPEDAGSEDELEEGGQLNESMDHGGVGPYELGMEHCEKFEIS ETSVNRGPEKIRPECFELLRVLGKGGYGKAMIVRNAKDTAHTKAERNILEEVKHPFIVDLIYAFQTGGKLYLILE YLSGGELFMQLEREGIFMEDTACFYLAEISMALGHLHQKGI IYRDLKPENIMLNHQGHVKLTDFGLCKESIHDGT VTHTFCGTIEYMAPEILMRSGHNRAVDWWSLGALMYDMLTGAPPFTGENRKKTIDKILKCKLNLPPYLTQEARDL LKKLLKRNAASRLGAGPGDAGEVQAHPFFRHINWEELLARKVEPPFKPLLQSEEDVSQFDSKFTRQTPVDSPDDS TLSESANQVFLGFTYVAPSVLESVKEKFSFEPKIRSPRRFIGSPRTPVSPVKFSPGDFWGRGASASTANPQTPVE YPMETSGIEQMDVTMSGEASAPLPIRQPNSGPYKKQAFPMISKRPEHLRMNL (SEQ ID NO: 145) .

[0331] An exemplary nucleic acid sequence encoding RPS6KB1 (NM_001272043.1 transcript variant 3) comprises or consists of:

1 gtttggcttc acggaaccct gtacgcatgc tcctacgctg aactttagga gccagtctaa 61 ggcctaggcg cagacgcact gagcctaagc agccggtgat ggcggcagcg gctgtggtgg 121 ctgcggcggg tccgggccca tgaggcgacg aaggaggcgg gacggctttt acccagcccc 181 ggacttccga gacagggaag ctgaggacat ggcaggagtg tttgacatag acctggacca 241 gccagaggac gcgggctctg aggatgagct ggaggagggg ggtcagttaa atgaaagcat 301 ggaccatggg ggagttggac catatgaact tggcatggaa cattgtgaga aatttgaaat 361 ctcagaaact agtgtgaaca gagggccaga aaaaatcaga ccagaatgtt ttgagctact 421 tcgggtactt ggtaaagggg gctatggaaa ggtttttcaa gtacgaaaag taacaggagc 481 aaatactggg aaaatatttg ccatgaaggt gcttaaaaag gcaatgatag taagaaatgc 541 taaagataca gctcatacaa aagcagaacg gaatattctg gaggaagtaa agcatccctt 601 catcgtggat ttaatttatg cctttcagac tggtggaaaa ctctacctca tccttgagta 661 tctcagtgga ggagaactat ttatgcagtt agaaagagag ggaatattta tggaagacac 721 tgcctgcttt tacttggcag aaatctccat ggctttgggg catttacatc aaaaggggat 781 catctacaga gacctgaagc cggagaatat catgcttaat caccaaggtc atgtgaaact 841 aacagacttt ggactatgca aagaatctat tcatgatgga acagtcacac acacattttg 901 tggaacaata gaatacatgg cccctgaaat cttgatgaga agtggccaca atcgtgctgt 961 ggattggtgg agtttgggag cattaatgta tgacatgctg actggagcac ccccattcac 1021 tggggagaat agaaagaaaa caattgacaa aatcctcaaa tgtaaactca atttgcctcc 1081 ctacctcaca caagaagcca gagatctgct taaaaagctg ctgaaaagaa atgctgcttc 1141 tcgtctggga gctggtcctg gggacgctgg agaagttcaa gctcatccat tctttagaca 1201 cattaactgg gaagaacttc tggctcgaaa ggtggagccc ccctttaaac ctctgttgca 1261 atctgaagag gatgtaagtc agtttgattc caagtttaca cgtcagacac ctgtcgacag 1321 cccagatgac tcaactctca gtgaaagtgc caatcaggtc tttctgggtt ttacatatgt 1381 ggctccatct gtacttgaaa gtgtgaaaga aaagttttcc tttgaaccaa aaatccgatc 1441 acctcgaaga tttattggca gcccacgaac acctgtcagt actgctatgt gctaagctta 1501 actggaagcc ttggaatggg cataagttgt atgtcctaca tttcatcatt gtcccgggcc 1561 tgcattgcac tggaaaaaaa aatcgccacc tgttcttaca ccagtatttg gttcaagaca 1621 ccaaatgtct tcagcccatg gctgaagaac aacagaagag agtcaggata aaaaatacat 1681 actgtggtcg gcaaggtgag ggagataggg atatccaggg gaagagggtg ttgctgtggc 1741 ccactctctg tctaatctct ttacagcaaa ttggtaagat tttcagtttt acttctttct 1801 actgtttctg ctgtctacct tccttatatt tttttcctca acagttttaa aaagaaaaaa 1861 aggtctattt ttttttctcc tatacttggg ctacattttt tgattgtaaa aatatttgat 1921 ggccttttga tgaatgtctt ccacagtaaa gaaaacttag tggcttaatt taggaaacat 1981 gttaacagga cactatgttt ttgaaattgt aacaaaatct acataaatga tttacaggtt 2041 aaaagaataa aaataaaggt aactttacct ttcttaaata tttcctgcct taaagagagc 2101 atttccatga ctttagctgg tgaaagggtt taatatctgc agagctttat aaaaatatat 2161 ttcagtgcat actggtataa tagatgatca tgcagttgca gttgagttgt atcacctttt 2221 ttgtttgtct tttataatgt cttcagtctg agtgtgcaaa gtcaatttgt aatattttgc 2281 aaccctagga tttttttaaa tagatgctgc ttgctatgtt ttcaaacctt tttgagccat 2341 aggatccaag ccataaaatt ctttatgcat gttgaattca gtcagaaaag agcaaggctt 2401 tgctttttga aattgcaact caaatgagat gggatgaaat cctatgacag taagcaaaaa 2461 cagaaccatg aaaaatgatt ggacatacac cttttcaatt gtggcaataa ttgaaagaat 2521 cgataaaagt tcatctttgg acagaaagcc tttaaaaaaa aaatcactcc ctcttccccc 2581 tcctccctta ttgcagcagc ctactgagaa ctttgactgt tgctggtaaa ttagaagcta 2641 caataataat taagggcaga aattatactt aaaaagtgca gatccttgtt ctttgacaat 2701 ttgtgatgtc tgaaaaaaca gaacccgaaa agctatggtg atatgtacag gcattatttc 2761 agactgtaaa tggcttgtga tactcttgat acttgttttc aaatatgttt actaactgta 2821 gtgttgactg cctgaccaaa ttccagtgaa acttatacac caaaatattc ttcctaggtc 2881 ctatttgcta gtaacatgag cactgtgatt ggctggctat aaccacccca gttaaaccat 2941 tttcataatt agtagtgcca gcaatagtgg caaacactgc aacttttctg cataaaaagc 3001 attaattgca cagctaccat ccacacaaat acatagtttt tctgacttca catttattaa 3061 gtgaaattta tttcccatgc tgtggaaagt ttattgagaa cttgtttcat aaatggatat 3121 ccctactatg actgtgaaaa catgtcaagt gtcacattag tgtcacagac agaaagcaca 3181 cacctatgca atatggctta tctatattta tttgtaaaaa tccaagcata gtttaaaata 3241 tgatgtcgat attactagtc ttgagtttct aagagggttc tttatgttat accaggtaag 3301 tgtataaaag agattaagtg cttttttttc atcacttgat tattttcttt aaaatcagct 3361 attacaggat atttttttat tttatacatg ctgtttttta attaaaatat aatcactgaa 3421 gtttactaat ttgattttat aaggtttgta gcattacaga ataactaaac tgggatttat 3481 aaaccagctg tgattaacaa tgtaaagtat taattattga actttgaacc agatttttag 3541 gaaaattatg ttctttttcc ccctttatgg tcttaactaa tttgaatcct tcaagaagga 3601 tttttccata ctatttttta agatagaaga taatttgtgg gcaggggtgg aggatgcatg 3661 tatgatactc cataaattca acattcttta ctataggtaa tgaatgatta taaacaagat 3721 gcatcttaga tagtattaat atactgagcc ttggattata tatttaatat aggacctatt 3781 ttgaatattc agttaatcat atggttccta gcttacaagg gctagatcta agattattcc 3841 catgagaaat gttgaattta tgaagaatag attttaaggc tttgaaaatg gttaatttct 3901 caaaaacatc aatgtccaaa catctacctt ttttcatagg agtagacact agcaagctgg 3961 acaaactatc acaaaagtat ttgtcacaca taacctgtgg tctgttgctg attaatacag 4021 tactttttct tgtgtgattc ttaacattat agcacaagta ttatctcagt ggattatccg 4081 gaataacatc tgaaagatgg gttcatctat gtttgtgttt gctctttaaa ctattgtttc 4141 tcctatccca agttcgcttt gcatctatca gtaaataaaa ttcttcagct gccttattag 4201 gagtgctatg agggtaacac ctgttctgct tttcatcttg tatttagttg actgtattat 4261 ttgatttcgg attgaatgaa tgtaaataga aattaaatgc aaatttgaat gaacataaaa 4321 aaaaaaaaaa aa (SEQ ID NO: 146) .

[0332] An exemplary amino acid sequence encoding RPS6KB1 (NP 001258972.1, isoform c) comprises or consists of:

MRRRRRRDGFYPAPDFRDREAEDMAGVFDIDLDQPEDAGSEDELEEGGQLNESMDHGGVGPYELGMEHCEKFEIS ETSVNRGPEKIRPECFELLRVLGKGGYGKVFQVRKVTGANTGKIFAMKVLKKAMIVRNAKDTAHTKAERNILEEV KHPFIVDLIYAFQTGGKLYLILEYLSGGELFMQLEREGIFMEDTACFYLAEISMALGHLHQKGI IYRDLKPENIM LNHQGHVKLTDFGLCKESIHDGTVTHTFCGTIEYMAPEILMRSGHNRAVDWWSLGALMYDMLTGAPPFTGENRKK TIDKILKCKLNLPPYLTQEARDLLKKLLKRNAASRLGAGPGDAGEVQAHPFFRHINWEELLARKVEPPFKPLLQS EEDVSQFDSKFTRQTPVDSPDDSTLSESANQVFLGFTYVAPSVLESVKEKFSFEPKIRSPRRFIGSPRTPVSTAM

C (SEQ ID NO: 147) .

[0333] An exemplary nucleic acid sequence encoding RPS6KB1 (NM_001272044.1 transcript variant 4) comprises or consists of:

1 gtttggcttc acggaaccct gtacgcatgc tcctacgctg aactttagga gccagtctaa 61 ggcctaggcg cagacgcact gagcctaagc agccggtgat ggcggcagcg gctgtggtgg 121 ctgcggcggg tccgggccca tgaggcgacg aaggaggcgg gacggctttt acccagcccc 181 ggacttccga gacagggaag ctgaggacat ggcaggagtg tttgacatag acctggacca 241 gccagaggac gcgggctctg aggatgagct ggaggagggg gaagcgctca gctgttagaa 301 gtgacagctg aaaacttctg tcgggagtag cactgccgct gctgttacag ccaccaggag 361 ttttatttcg ggagcaaggg ggctctgctg catcttccaa tcttccaggg gtcagttaaa 421 tgaaagcatg gaccatgggg gagttggacc atatgaactt ggcatggaac attgtgagaa 481 atttgaaatc tcagaaacta gtgtgaacag agggccagaa aaaatcagac cagaatgttt 541 tgagctactt cgggtacttg gtaaaggggg ctatggaaag gtttttcaag tacgaaaagt 601 aacaggagca aatactggga aaatatttgc catgaaggtg cttaaaaagg caatgatagt 661 aagaaatgct aaagatacag ctcatacaaa agcagaacgg aatattctgg aggaagtaaa 721 gcatcccttc atcgtggatt taatttatgc ctttcagact ggtggaaaac tctacctcat 781 ccttgagtat ctcagtggag gagaactatt tatgcagtta gaaagagagg gaatatttat 841 ggaagacact gcctgctttt acttggcaga aatctccatg gctttggggc atttacatca 901 aaaggggatc atctacagag acctgaagcc ggagaatatc atgcttaatc accaaggtca 961 tgtgaaacta acagactttg gactatgcaa agaatctatt catgatggaa cagtcacaca 1021 cacattttgt ggaacaatag aatacatggc ccctgaaatc ttgatgagaa gtggccacaa 1081 tcgtgctgtg gattggtgga gtttgggagc attaatgtat gacatgctga ctggagcacc 1141 cccattcact ggggagaata gaaagaaaac aattgacaaa atcctcaaat gtaaactcaa 1201 tttgcctccc tacctcacac aagaagccag agatctgctt aaaaagctgc tgaaaagaaa 1261 tgctgcttct cgtctgggag ctggtcctgg ggacgctgga gaagttcaag ctcatccatt 1321 ctttagacac attaactggg aagaacttct ggctcgaaag gtggagcccc cctttaaacc 1381 tctgttgcaa tctgaagagg atgtaagtca gtttgattcc aagtttacac gtcagacacc 1441 tgtcgacagc ccagatgact caactctcag tgaaagtgcc aatcaggtct ttctgggttt 1501 tacatatgtg gctccatctg tacttgaaag tgtgaaagaa aagttttcct ttgaaccaaa 1561 aatccgatca cctcgaagat ttattggcag cccacgaaca cctgtcagcc cagtcaaatt 1621 ttctcctggg gatttctggg gaagaggtgc ttcggccagc acagcaaatc ctcagacacc 1681 tgtggaatac ccaatggaaa caagtggcat agagcagatg gatgtgacaa tgagtgggga 1741 agcatcggca ccacttccaa tacgacagcc gaactctggg ccatacaaaa aacaagcttt 1801 tcccatgatc tccaaacggc cagagcacct gcgtatgaat ctatgacaga gcaatgcttt 1861 taatgaattt aaggcaaaaa aggtggagag ggagatgtgt gagcatcctg caaggtgaaa 1921 cgactcaaaa tgacagtttc agagagtcaa tgtcattaca tagaacactt cagacacagg 1981 aaaaataaac gtggatttta aaaaatcaat caatggtgca aaaaaaaact taaagcaaaa 2041 tagtattgct gaactcttag gcacatcaat taattgattc ctcgcgacat cttctcaacc 2101 ttatcaagga ttttcatgtt gatgactcga aactgacagt attaagggta ggatgttgct 2161 tctgaatcac tgttgagttc tgattgtgtt gaagaagggt tatcctttca ttaggcaaag 2221 tacaaaattg cctataatac ttgcaactaa ggacaaatta gcatgcaagc ttggtcaaac 2281 tttttccagc aaaatggaag caaagacaaa agaaacttac caattgatgt tttacgtgca 2341 aacaacctga atcttttttt tatataaata tatatttttc aaatagattt ttgattcagc 2401 tcattatgaa aaacatccca aactttaaaa tgcgaaatta ttggttggtg tgaagaaagc 2461 cagacaactt ctgtttcttc tcttggtgaa ataataaaat gcaaatgaat cattgttaac 2521 cacagctgtg gctcgtttga gggattgggg tggacctggg gtttattttc agtaacccag 2581 ctgcaatacc tgtctgtaat atgagaaaaa aaaaatgaat ctatttaatc atttctactt 2641 gcagtactgc tatgtgctaa gcttaactgg aagccttgga atgggcataa gttgtatgtc 2701 ctacatttca tcattgtccc gggcctgcat tgcactggaa aaaaaaatcg ccacctgttc 2761 ttacaccagt atttggttca agacaccaaa tgtcttcagc ccatggctga agaacaacag 2821 aagagagtca ggataaaaaa tacatactgt ggtcggcaag gtgagggaga tagggatatc 2881 caggggaaga gggtgttgct gtggcccact ctctgtctaa tctctttaca gcaaattggt 2941 aagattttca gttttacttc tttctactgt ttctgctgtc taccttcctt atattttttt 3001 cctcaacagt tttaaaaaga aaaaaaggtc tatttttttt tctcctatac ttgggctaca 3061 ttttttgatt gtaaaaatat ttgatggcct tttgatgaat gtcttccaca gtaaagaaaa 3121 cttagtggct taatttagga aacatgttaa caggacacta tgtttttgaa attgtaacaa 3181 aatctacata aatgatttac aggttaaaag aataaaaata aaggtaactt tacctttctt 3241 aaatatttcc tgccttaaag agagcatttc catgacttta gctggtgaaa gggtttaata 3301 tctgcagagc tttataaaaa tatatttcag tgcatactgg tataatagat gatcatgcag 3361 ttgcagttga gttgtatcac cttttttgtt tgtcttttat aatgtcttca gtctgagtgt 3421 gcaaagtcaa tttgtaatat tttgcaaccc taggattttt ttaaatagat gctgcttgct 3481 atgttttcaa acctttttga gccataggat ccaagccata aaattcttta tgcatgttga 3541 attcagtcag aaaagagcaa ggctttgctt tttgaaattg caactcaaat gagatgggat 3601 gaaatcctat gacagtaagc aaaaacagaa ccatgaaaaa tgattggaca tacacctttt 3661 caattgtggc aataattgaa agaatcgata aaagttcatc tttggacaga aagcctttaa 3721 aaaaaaaatc actccctctt ccccctcctc ccttattgca gcagcctact gagaactttg 3781 actgttgctg gtaaattaga agctacaata ataattaagg gcagaaatta tacttaaaaa 3841 gtgcagatcc ttgttctttg acaatttgtg atgtctgaaa aaacagaacc cgaaaagcta 3901 tggtgatatg tacaggcatt atttcagact gtaaatggct tgtgatactc ttgatacttg 3961 ttttcaaata tgtttactaa ctgtagtgtt gactgcctga ccaaattcca gtgaaactta 4021 tacaccaaaa tattcttcct aggtcctatt tgctagtaac atgagcactg tgattggctg 4081 gctataacca ccccagttaa accattttca taattagtag tgccagcaat agtggcaaac 4141 actgcaactt ttctgcataa aaagcattaa ttgcacagct accatccaca caaatacata 4201 gtttttctga cttcacattt attaagtgaa atttatttcc catgctgtgg aaagtttatt 4261 gagaacttgt ttcataaatg gatatcccta ctatgactgt gaaaacatgt caagtgtcac 4321 attagtgtca cagacagaaa gcacacacct atgcaatatg gcttatctat atttatttgt 4381 aaaaatccaa gcatagttta aaatatgatg tcgatattac tagtcttgag tttctaagag 4441 ggttctttat gttataccag gtaagtgtat aaaagagatt aagtgctttt ttttcatcac 4501 ttgattattt tctttaaaat cagctattac aggatatttt tttattttat acatgctgtt 4561 ttttaattaa aatataatca ctgaagttta ctaatttgat tttataaggt ttgtagcatt 4621 acagaataac taaactggga tttataaacc agctgtgatt aacaatgtaa agtattaatt 4681 attgaacttt gaaccagatt tttaggaaaa ttatgttctt tttccccctt tatggtctta

4741 actaatttga atccttcaag aaggattttt ccatactatt ttttaagata gaagataatt

4801 tgtgggcagg ggtggaggat gcatgtatga tactccataa attcaacatt ctttactata

4861 ggtaatgaat gattataaac aagatgcatc ttagatagta ttaatatact gagccttgga

4921 ttatatattt aatataggac ctattttgaa tattcagtta atcatatggt tcctagctta

4981 caagggctag atctaagatt attcccatga gaaatgttga atttatgaag aatagatttt

5041 aaggctttga aaatggttaa tttctcaaaa acatcaatgt ccaaacatct accttttttc

5101 ataggagtag acactagcaa gctggacaaa ctatcacaaa agtatttgtc acacataacc

5161 tgtggtctgt tgctgattaa tacagtactt tttcttgtgt gattcttaac attatagcac

5221 aagtattatc tcagtggatt atccggaata acatctgaaa gatgggttca tctatgtttg

5281 tgtttgctct ttaaactatt gtttctccta tcccaagttc gctttgcatc tatcagtaaa

5341 taaaattctt cagctgcctt attaggagtg ctatgagggt aacacctgtt ctgcttttca

5401 tcttgtattt agttgactgt attatttgat ttcggattga atgaatgtaa atagaaatta

5461 aatgcaaatt tgaatgaaca taaaaaaaaa aaaaaaa (SEQ ID NO: 148).

[0334] An exemplary amino acid sequence encoding RPS6KB1 (NP 001258973.1 " isoform d) comprises or consists of:

MDHGGVGPYELGMEHCEKFEISETSVNRGPEKIRPECFELLRVLGKGGYGKVFQVRKVTGANTGKIFAMKVLKKA MIVRNAKDTAHTKAERNILEEVKHPFIVDLIYAFQTGGKLYLILEYLSGGELFMQLEREGIFMEDTACFYLAEIS MALGHLHQKGIIYRDLKPENIMLNHQGHVKLTDFGLCKESIHDGTVTHTFCGTIEYMAPEILMRSGHNRAVDWWS LGALMYDMLTGAPPFTGENRKKTIDKILKCKLNLPPYLTQEARDLLKKLLKRNAASRLGAGPGDAGEVQAHPFFR HINWEELLARKVEPPFKPLLQSEEDVSQFDSKFTRQTPVDSPDDSTLSESANQVFLGFTYVAPSVLESVKEKFSF EPKIRSPRRFIGSPRTPVSPVKFSPGDFWGRGASASTANPQTPVEYPMETSGIEQMDVTMSGEASAPLPIRQPNS

GPYKKQAFPMISKRPEHLRMNL (SEQ ID NO: 149)

[0335] An exemplary nucleic acid sequence encoding SLC16A1 (NM_003051.3 transcript variant 1) comprises or consists of:

1 agagggcgcg cgcggctgaa agcgtgtgga ggcgcgggct gcagttcgga tgtctgtgtg 61 gcggggaggg ggcggcggcc gggagagacg actccgcccc ctgcgcgcat gctccggccc 121 cggcgggtta taaggcagcc tcgctggccc ggccagacaa agtggtgagc tgcgacgtga 181 ctggctagct gcgtgggtac tggaacaagc aaacgaggca gcgagcgaag gacgggagcc 241 ggaccctggg ccccgtggaa ctccagcctg cgccaccacg tcacgcacac gctcggcgct 301 gcgatccgcg catataacga tatttggatt tgacctgcat tttggaattt atctacactt 361 aaaatgccac cagcagttgg aggtccagtt ggatacaccc ccccagatgg aggctggggc 421 tgggcagtgg taattggagc tttcatttcc atcggcttct cttatgcatt tcccaaatca 481 attactgtct tcttcaaaga gattgaaggt atattccatg ccaccaccag cgaagtgtca 541 tggatatcct ccataatgtt ggctgtcatg tatggtggag gtcctatcag cagtatcctg 601 gtgaataaat atggaagtcg tatagtcatg attgttggtg gctgcttgtc aggctgtggc 661 ttgattgcag cttctttctg taacaccgta cagcaactat acgtctgtat tggagtcatt 721 ggaggtcttg ggcttgcctt caacttgaat ccagctctga ccatgattgg caagtatttc 781 tacaagaggc gaccattggc caacggactg gccatggcag gcagccctgt gttcctctgt 841 actctggccc ccctcaatca ggttttcttc ggtatctttg gatggagagg aagctttcta 901 attcttgggg gcttgctact aaactgctgt gttgctggag ccctcatgcg accaatcggg 961 cccaagccaa ccaaggcagg gaaagataag tctaaagcat cccttgagaa agctggaaaa 1021 tctggtgtga aaaaagatct gcatgatgca aatacagatc ttattggaag acaccctaaa 1081 caagagaaac gatcagtctt ccaaacaatt aatcagttcc tggacttaac cctattcacc 1141 cacagaggct ttttgctata cctctctgga aatgtgatca tgttttttgg actctttgca 1201 cctttggtgt ttcttagtag ttatgggaag agtcagcatt attctagtga gaagtctgcc 1261 ttccttcttt ccattctggc ttttgttgac atggtagccc gaccatctat gggacttgta 1321 gccaacacaa agccaataag acctcgaatt cagtatttct ttgcggcttc cgttgttgca 1381 aatggagtgt gtcatatgct agcaccttta tccactacct atgttggatt ctgtgtctat 1441 gcgggattct ttggatttgc cttcgggtgg ctcagctccg tattgtttga aacattgatg 1501 gaccttgttg gaccccagag gttctccagc gctgtgggat tggtgaccat tgtggaatgc 1561 tgtcctgtcc tcctggggcc accactttta ggtcggctca atgacatgta tggagactac 1621 aaatacacat actgggcatg tggcgtcgtc ctaattattt caggtatcta tctcttcatt 1681 ggcatgggca tcaattatcg acttttggca aaagaacaga aagcaaacga gcagaaaaag 1741 gaaagtaaag aggaagagac cagtatagat gttgctggga agccaaatga agttaccaaa 1801 gcagcagaat ctccggacca gaaagacaca gatggagggc ccaaggagga ggaaagtcca 1861 gtctgaatcc atggggctga agggtaaatt gagcagttca tgacccagga tatctgaaaa 1921 tattctactg gcctgtaatc taccagtggt gctcaatgca aatagtagac atttgtgtgg 1981 aaatcatacc agttgttcat tgatgggatt tttgtttgac tccttaccaa tagcctgaat 2041 ttgaggaggg aatgattggt agcaaaggat gggggaaaga agtaggttct gttttgtttt 2101 gttttaatct tagcttttaa tagtgtcata aagattataa tatgtgcctt aagttttagt 2161 ctttagaact ctagagagcc ttaacttctt aaaccatttt tgctgaattc atctatttcg 2221 agtgttgtgt taaaaggaaa aataacaact aacttgtttg aggcaaatct aaaatttaaa 2281 attaatcttg cttcattgtt acatgtaata tatttcagac attttcactg gaagatttat 2341 gaacagaaat attggttgaa agttagagat tttacaaaat gctgacaaaa atattttcct 2401 agcatcagta gatttctggc atatgtttct gctagctata tatttaggaa attcaaagca 2461 taaaactttg gcaacatctt ggctgttcta gacacagtgt acttgtcaac ccctctcagg 2521 taccttttct tgggatgctt attagaagcc aagtaaagtg cttaaggttt gttttcatta 2581 aattagctat ttctgctccc ctgttcaaag atgcattttg agtgtttata gatcactgcc 2641 ctttttgaaa tcacctggta ttatttttct tactggaaaa gttagtatta aaatctacag 2701 aactacatat ttgtgcctcc ttggtaaata caacacatct aattaaatgt agacagatat 2761 ttcaaacatc agctgaattc acttaagttt ttccaaaacc tcagttaaac tgtgaagcta 2821 ttggaatttt tttttcctgg aatttttccc ctttgattca cagtggtccc atttatatct 2881 gcttctagct tagtgctatg tgtgagatat gtgtgtgttt ggtgtttttg tttttttgtt 2941 tttttttttt taaggtttgc aaattaaaaa gggccagaaa aatttggcac caggcaaacg 3001 aataaagata ggattgggaa agaagttgct aagtgtgctt agttttaata agtaattcct 3061 tctctttttt cagagaaggc cttacagaaa attgttgtgc ttagaattgc tggatgcatt 3121 tttaccctcc acacaaacct aaaaattttg tgaccccttt cacttacctg aaaagtagag 3181 aaatggattc agtataagga taaggaggga aggtggacca gaatgaaaac tgtaaatatt 3241 tttttaacct aatatcactt aaatcgaggc agaaagatac agacattcaa tgaattatat 3301 tcaatgcatt taaaatacca ctgtaattga cagagtaaaa gtatagatac aaaaccttgt 3361 gtaagaggct gacttttcca aataaacatt ttttaagaaa acatttcttc tcccaaatgt 3421 ctattttctt gaggaaaata ttgctgtgtc ttcattttca ttaccaggtt tcattttggg 3481 ccttgctaaa ttgattgaat taaatcctcc agcttttgaa ccttgatatt tgtgtatatg 3541 atttattttc atttgaattt ctcctttcct cttctttgct gtaaggcaag gaggagggga 3601 attttaaaac catcttattt gaactgagag catccagagc agttaacctt aaggaaacaa 3661 tgaaaaactc cctttgtatg cctgggcatc atggcagata gaggaagagt gttagaggag 3721 aaaactgctg ctgagagtat tggcaggctt ggcctcagtt tggactctgt aattttcttt 3781 ggacccaagt ctgtaacctc tgcgtacttc ttctctctta ccttctataa aaatgaggat 3841 tactgttggt gagggaataa ggaatgtaag taaaggaaat ctgaaaaaat aaaagtaaag 3901 caagtataaa aaaaaaaaaa aaaaaaa (SEQ ID NO: 150) .

[0336] An exemplary nucleic acid sequence encoding SLC16A1 (NM_001166496.1 transcript variant 2) comprises or consists of:

1 gctcggcgct gcgatccgcg catataacgg ttagttgggt aacagccggc ggcacgcggc 61 gcggacccca cggtgccctc gctgccctgg tggggtcgga ggggacctcc ggggttggga 121 gactttgtct ccggcggagg gaggcggccc agcagagggc atcgtggtca caggcagccg 181 cgtggcctcg gactgcagtg ctggtgaagg agaccttgag gcgctggggt cagcgcctct 241 cttagccgag ccgcgggccc cgtgctaaga tgccggtccc aggcctggcc gaggagttgg 301 gtcgtggtgc ccggtgacgg tggggaagtc ccttcccccc taagtcttca ataggctcct 361 cgagagatgc tttgatctgg aaaagggata acatgaggct gctgcatgtg gtacctccag 421 actctcctgg ccgcttctgc cccaagggaa gggactcggg gcagaagtta tttatgattc 481 gtgacattgt ccgccccaac cttcttggcc cgccgatcct tgccccacct ggtgacttgc 541 gagagtggtg cggagagccg cattccccac agccaaggcg tgactgcagg gttcgagtag 601 actttgcgga ggggacgggg cagcccgcag actcctggga gtggtgctga cgggggctct 661 ttgtcattca acctgtggct gccagcgtcc gccgcagcgc ccttctactc atggacttaa 721 ggcggccctg ttgagagaaa tctggaggat agcgttacac ttggtccgat gcaagttttt 781 tgttccaaat atttggattt gacctgcatt ttggaattta tctacactta aaatgccacc 841 agcagttgga ggtccagttg gatacacccc cccagatgga ggctggggct gggcagtggt 901 aattggagct ttcatttcca tcggcttctc ttatgcattt cccaaatcaa ttactgtctt 961 cttcaaagag attgaaggta tattccatgc caccaccagc gaagtgtcat ggatatcctc 1021 cataatgttg gctgtcatgt atggtggagg tcctatcagc agtatcctgg tgaataaata 1081 tggaagtcgt atagtcatga ttgttggtgg ctgcttgtca ggctgtggct tgattgcagc 1141 ttctttctgt aacaccgtac agcaactata cgtctgtatt ggagtcattg gaggtcttgg 1201 gcttgccttc aacttgaatc cagctctgac catgattggc aagtatttct acaagaggcg 1261 accattggcc aacggactgg ccatggcagg cagccctgtg ttcctctgta ctctggcccc 1321 cctcaatcag gttttcttcg gtatctttgg atggagagga agctttctaa ttcttggggg 1381 cttgctacta aactgctgtg ttgctggagc cctcatgcga ccaatcgggc ccaagccaac 1441 caaggcaggg aaagataagt ctaaagcatc ccttgagaaa gctggaaaat ctggtgtgaa 1501 aaaagatctg catgatgcaa atacagatct tattggaaga caccctaaac aagagaaacg 1561 atcagtcttc caaacaatta atcagttcct ggacttaacc ctattcaccc acagaggctt 1621 tttgctatac ctctctggaa atgtgatcat gttttttgga ctctttgcac ctttggtgtt 1681 tcttagtagt tatgggaaga gtcagcatta ttctagtgag aagtctgcct tccttctttc 1741 cattctggct tttgttgaca tggtagcccg accatctatg ggacttgtag ccaacacaaa 1801 gccaataaga cctcgaattc agtatttctt tgcggcttcc gttgttgcaa atggagtgtg 1861 tcatatgcta gcacctttat ccactaccta tgttggattc tgtgtctatg cgggattctt 1921 tggatttgcc ttcgggtggc tcagctccgt attgtttgaa acattgatgg accttgttgg 1981 accccagagg ttctccagcg ctgtgggatt ggtgaccatt gtggaatgct gtcctgtcct 2041 cctggggcca ccacttttag gtcggctcaa tgacatgtat ggagactaca aatacacata 2101 ctgggcatgt ggcgtcgtcc taattatttc aggtatctat ctcttcattg gcatgggcat 2161 caattatcga cttttggcaa aagaacagaa agcaaacgag cagaaaaagg aaagtaaaga 2221 ggaagagacc agtatagatg ttgctgggaa gccaaatgaa gttaccaaag cagcagaatc 2281 tccggaccag aaagacacag atggagggcc caaggaggag gaaagtccag tctgaatcca 2341 tggggctgaa gggtaaattg agcagttcat gacccaggat atctgaaaat attctactgg 2401 cctgtaatct accagtggtg ctcaatgcaa atagtagaca tttgtgtgga aatcatacca 2461 gttgttcatt gatgggattt ttgtttgact ccttaccaat agcctgaatt tgaggaggga 2521 atgattggta gcaaaggatg ggggaaagaa gtaggttctg ttttgttttg ttttaatctt 2581 agcttttaat agtgtcataa agattataat atgtgcctta agttttagtc tttagaactc 2641 tagagagcct taacttctta aaccattttt gctgaattca tctatttcga gtgttgtgtt 2701 aaaaggaaaa ataacaacta acttgtttga ggcaaatcta aaatttaaaa ttaatcttgc 2761 ttcattgtta catgtaatat atttcagaca ttttcactgg aagatttatg aacagaaata 2821 ttggttgaaa gttagagatt ttacaaaatg ctgacaaaaa tattttccta gcatcagtag 2881 atttctggca tatgtttctg ctagctatat atttaggaaa ttcaaagcat aaaactttgg 2941 caacatcttg gctgttctag acacagtgta cttgtcaacc cctctcaggt accttttctt 3001 gggatgctta ttagaagcca agtaaagtgc ttaaggtttg ttttcattaa attagctatt 3061 tctgctcccc tgttcaaaga tgcattttga gtgtttatag atcactgccc tttttgaaat 3121 cacctggtat tatttttctt actggaaaag ttagtattaa aatctacaga actacatatt 3181 tgtgcctcct tggtaaatac aacacatcta attaaatgta gacagatatt tcaaacatca 3241 gctgaattca cttaagtttt tccaaaacct cagttaaact gtgaagctat tggaattttt 3301 ttttcctgga atttttcccc tttgattcac agtggtccca tttatatctg cttctagctt 3361 agtgctatgt gtgagatatg tgtgtgtttg gtgtttttgt ttttttgttt tttttttttt 3421 aaggtttgca aattaaaaag ggccagaaaa atttggcacc aggcaaacga ataaagatag 3481 gattgggaaa gaagttgcta agtgtgctta gttttaataa gtaattcctt ctcttttttc 3541 agagaaggcc ttacagaaaa ttgttgtgct tagaattgct ggatgcattt ttaccctcca 3601 cacaaaccta aaaattttgt gacccctttc acttacctga aaagtagaga aatggattca 3661 gtataaggat aaggagggaa ggtggaccag aatgaaaact gtaaatattt ttttaaccta 3721 atatcactta aatcgaggca gaaagataca gacattcaat gaattatatt caatgcattt 3781 aaaataccac tgtaattgac agagtaaaag tatagataca aaaccttgtg taagaggctg 3841 acttttccaa ataaacattt tttaagaaaa catttcttct cccaaatgtc tattttcttg 3901 aggaaaatat tgctgtgtct tcattttcat taccaggttt cattttgggc cttgctaaat 3961 tgattgaatt aaatcctcca gcttttgaac cttgatattt gtgtatatga tttattttca 4021 tttgaatttc tcctttcctc ttctttgctg taaggcaagg aggaggggaa ttttaaaacc 4081 atcttatttg aactgagagc atccagagca gttaacctta aggaaacaat gaaaaactcc 4141 ctttgtatgc ctgggcatca tggcagatag aggaagagtg ttagaggaga aaactgctgc 4201 tgagagtatt ggcaggcttg gcctcagttt ggactctgta attttctttg gacccaagtc 4261 tgtaacctct gcgtacttct tctctcttac cttctataaa aatgaggatt actgttggtg 4321 agggaataag gaatgtaagt aaaggaaatc tgaaaaaata aaagtaaagc aagtataaaa 4381 aaaaaaaaaa (SEQ ID NO 151) . An exemplary amino acid sequence encoding SLC16A1 (NP_003042.3) comprises or consists of:

MPPAVGGPVGYTPPDGGWGWAWIGAFISIGFSYAFPKSITVFFKEIEGIFHATTSEVSWISSIMLAVMYGGGPI SSILVNKYGSRIVMIVGGCLSGCGLIAASFCNTVQQLYVCIGVIGGLGLAFNLNPALTMIGKYFYKRRPLANGLA MAGSPVFLCTLAPLNQVFFGIFGWRGSFLILGGLLLNCCVAGALMRPIGPKPTKAGKDKSKASLEKAGKSGVKKD LHDANTDLIGRHPKQEKRSVFQTINQFLDLTLFTHRGFLLYLSGNVIMFFGLFAPLVFLSSYGKSQHYSSEKSAF LLSILAFVDMVARPSMGLVANTKPIRPRIQYFFAASWANGVCHMLAPLSTTYVGFCVYAGFFGFAFGWLSSVLF ETLMDLVGPQRFSSAVGLVTIVECCPVLLGPPLLGRLNDMYGDYKYTYWACGVVLI ISGIYLFIGMGINYRLLAK EQKANEQKKESKEEETSIDVAGKPNEVTKAAESPDQKDTDGGPKEEESPV (SEQ ID NO: 152) .

[0338] An exemplary nucleic acid sequence encoding SLC16A1 (AJ438944.1, 5' flanking region) comprises or consists of:

1 ggatcctgtc tctctaactt aattctcctt accatctacc tgaatgctgc tgccacccta 61 gcactgctct tataagtcct agctgcccca atgacccgaa atgccttccc tttctccgtg 121 tttatcaaat gtaaaaagca attactgtat tactcactag tagtacttgg ccgtggatgc 181 cacactgtct tctaatatac tgaactgtta ttggaaagca catgggacct ctcaggatct 241 gatcctccaa tctctactct tcttcaatct caggttcttc atttgcaaaa cagaaaccat 301 aaggcctacc tcccagggtt gctgtgagaa ttgaggggga gggtaagtga gggggagggt 361 aagtgagggg gtgagtcctg gaagggagga agacacgagg ggaagggcag ggtcctggca 421 agcagcaagt gctcaacaga tgttggttaa tttgtgccta agtctccccc aaaaacttgc 481 aagctctttg aaggcagggg ccttgcctca tatttttcgg tatttctcaa aagtcctgga 541 catcaaagac actccatggt tatttgatca cttcaacaca cacgttggtt atgcggtcac 601 agcggctatt atgttaaaaa caggctctgg agtgtgactt caaatgctgg ccgctgacga 661 gctgggctgt ctggaaagtt acttcacctc tctgagcctc gggtccctta tttacaaaat 721 gttcagggca gtgcccactt cacagggctg aggattagag aggataatcc gggtgaggag 781 catcagcccc agcgccgcct gccacaattc tatccggccc cacatatgca tcgtccataa 841 gcgtccggcc tctgcattct cgcttttcca cgtggccgag gtgcacaccc caacccactg 901 ggccagtctc cccaccctct tacctgctct tctttcccga ctcgtcttta atacccacca 961 ggcgccaacc gccgcgggcc tggctctatg gtggcaagtt gcatgggttc tcccatcagg 1021 acctcccgat gagcctacga ggtcggttct actactgtcg ccacttcaga gggaggaaac 1081 aggcccggag ggttggggaa cttcccgagg tcactgaact ggtgtcaggc ccggattgga 1141 atccaaacac atcccagccc atgcccggct ctacagcgcc ggcccccagc gtcttcccgg 1201 gtgccagcgg cacccgcatc cattcaaatg ctgcccattc cccgctcctc agtcgcttcc 1261 cgctactccg cacgcgcatc tcccccaccc gtcagggtca ggcctctcgg tgacttttcc 1321 tttttctctg gcagaaactg aggggtgaga ccgatggttg tgtcccgaac gagggcagat 1381 tgcctagagc tcgtcagaca gggacccaag ggcgagtctg gcagggcgtg gtagctccgc 1441 gccgctcagc aggggcgcag cgcgcgggtc ggactgggac gccggtcacg tggcggggag 1501 ggggcgccgg cgcgcgcggg cgagctagag ggcgcgcgcg gctgaaagcg tgtggaggcg 1561 cgggctgcag ttcggatgtc tgtgtggcgg ggagggggcg gcggccggga gagacgactc 1621 cgccccctgc gcgcatgctc cggccccggc gggttataag gcagcctcgc tggcccggcc 1681 agacaaagtg gtgagctgcg acgtgactgg ctagctgcgt gggtactgga acaagcaaac 1741 gaggcagcga gcgaaggacg ggagccggac cctgggcccc gtggaactcc agcctgcgcc 1801 accacgtcac gcacacgctc ggcgctgcga tccgcgcata taacggttag ttgggtaaca 1861 gccggcggca cgcggcgcgg accccacggt gccctcgctg ccctggtggg gtcggagggg 1921 acctccgggg ttgggagact ttgtctccgg cggagggagg cggcccagca gagggcatcg 1981 tggtcacagg cagccgcgtg gcctcggact gcagtgctgg tgaaggagac cttgaggcgc 2041 tggggtcagc gcctctctta gccgagccgc gggccccgtg ctaagatgcc ggtcccaggc 2101 ctggccgagg agttgggtcg tggtgcccgg tgacggtggg gaagtccctt cccccctaag 2161 tcttcaatag gctcctcgag agatgctttg atctggaaaa gggataacat gaggctgctg 2221 catgtggtac ctccagactc tcctggccgc ttctgcccca agggaaggga ctcggggcag 2281 aagttattta tgattcgtga cattgtccgc cccaaccttc ttggcccgcc gatccttgcc 2341 ccacctggtg acttgcgaga gtggtgcgga gagccgcatt ccccacagcc aaggcgtgac 2401 tgcagggttc gagtagactt tgcggagggg acggggcagc ccgcagactc ctgggagtgg 2461 tgctgacggg ggctctttgt cattcaacct gtggctgcca gcgtccgccg cagcgccctt 2521 ctactcatgg acttaaggcg gccctgttga gagaaatctg gaggatagcg ttacacttgg 2581 tccgatgcaa gttttttgtt ccaagtacgt cttttttttt ttccagcatg cgttttaaca 2641 ttttattact ttgtcatgac atatttgatg gaacaagcag ttgccaaaac tagtttgtaa 2701 ttaatctaaa ccaggagaca aacttgttac tactttagtc tttctttggg tttccagtgg 2761 ctgattagaa actgggctgc tactgataac agtaaaatgt ttacacgcta ctttatttac 2821 tgtaacttac taagctactt tatttactgt aacttactat aacttgtttt gaattttttt 2881 ttcaaaaatt actctggttt caacaatttt tttatcccaa ccaccagccc agtgaggtga 2941 tgcaaagact atgtatcttc agttttttag ttaggtgtta aatagtaccc ataaattcaa 3001 gtcttacacc ctggggcacg actttgcctt cagattgcca tagaaatgac caacaattca 3061 agatatttag cacttaaaac acgtggtaag atttattatt tacacagaag ttgaatatat 3121 ttcagtaatt cattttggtc ttaggtagat gctgttgttt catcagattg cagttaccat 3181 tgttaaatat gcaagttaat gatctgagga gcattttgta agatttttat agctgaatag 3241 atttgaaggt ttagttgtaa gcttaacggg atagactgta atgtccttaa acagattaaa 3301 aaggaaaaaa gtcatatcac tataggatga aagcaaatga ttagtatttc actagtttac 3361 atgttttagc ctttaaatat tagggcatat attagccctg gaaaggatcc (SEQ ID

NO: 153) .

[0339] An exemplary nucleic acid sequence encoding SLC16A1 (AJ438942.2, 3 ' UTR) comprises or consists of:

1 aggtatctat ctcttcattg gcatgggcat caattatcga cttttggcaa aagaacagaa 61 agcaaacgag cagaaaaagg aaagtaaaga ggaagagacc agtatagatg ttgctgggaa 121 gccaaatgaa gttaccaaaa cagcagaatc tccggaccag aaagacacag aaggagggcc 181 caaggaggag gaaagtccag tctgaatcca tggggctgaa gggtaaattg agcagttcat 241 gacccaggat atctgaaaat attctactgg cctgtaatct accagtggtg ctcaatgcaa 301 atagtagaca tttgtgtgga aatcatacca gttgttcatt gatgggattt ttgtttgact 361 ccttaccaat agcctgaatt tgaggaggga atgattggta gcaaaggatg ggggaaagaa 421 gtaggttctg ttttgttttg ttttaatctt agcttttaat agtgtcataa agattataat 481 atgtgcctta agttttagtc tttagaactc tagagagcct taacttctta aaccattttt 541 gctgaattca tctatttcga gtgttgtgtt aaaaggaaaa ataacaacta acttgtttga 601 ggcaaatcta aaatttaaaa ttaatcttgc ttcattgtta catgtaatat atttcagaca 661 ttttcactgg aagatttatg aacagaaata ttggttgaaa gttagagatt ttacaaaatg 721 ctgacaaaaa tattttccta gcatcagtag atttctggca tatgtttctg ctagctatat 781 atttaggaaa ttcaaagcat aaaactttgg caacatcttg gctgttctag acacagtgta 841 cttgtcaacc cctctcaggt accttttctt gggatgctta ttagaagcca agtaaagtgc 901 ttaaggtttg ttttcattaa attagctatt tctgctcccc tgttcaaaga tgcattttga 961 gtgtttatag atcactgccc tttttgaaat cacctggtat tatttttctt actggaaaag 1021 ttagtattaa aatctacaga actacatatt tgtgcctcct tggtaaatac aacacatcta 1081 attaaatgta gacagatatt tcaaacatca gctgaattca cttaagtttt tccaaaacct 1141 cagttaaact gtgaagctat tggaattttt ttttcctgga atttttcccc tttgattcac 1201 agtggtccca tttatatctg cttctagctt agtgctatgt gtgagatatg tgtgtgtttg 1261 gtgtttttgt ttttttgttt tttttttttt aaggtttgca aattaaaaag ggccagaaaa 1321 atttggcacc aggcaaacga ataaagatag gattgggaaa gaagttgcta agtgtgctta 1381 gttttaataa gtaattcctt ctcttttttc agagaaggcc ttacagaaaa ttgttgtgct 1441 tagaattgct ggatgcattt ttaccctcca cacaaaccta aaaattttgt gacccctttc 1501 acttacctga aaagtagaga aatggattca gtataaggat aaggagggaa ggtggaccag 1561 aatgaaaact gtaaatattt ttttaaccta atatcactta aatcgaggca gaaagataca 1621 gacattcaat gaattatatt caatgcattt aaaataccac tgtaattgac agagtaaaag 1681 tatagataca aaaccttgtg taagaggctg acttttccaa ataaacattt tttaagaaaa 1741 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa (SEQ ID NO: 154) .

[0340] An exemplary nucleic acid sequence encoding SLC16A1 (AJ438943.2, 5 ' UTR) comprises or consists of:

1 gggctgcagt tcggatgtct gtgtggcggg gagggggcgg cggccgggag agacgactcc

61 gccccctgcg cgcatgctcc ggccccggcg ggttataagg cagcctcgct ggcccggcca

121 gacaaagtgg tgagctgcga cgtgactggc tagctgcgtg ggtactggaa caagcaaacg

181 aggcagcgag cgaaggacgg gagccggacc ctgggccccg tggaactcca gcctgcgcca

241 ccacgtcacg cacacgctcg gcgctgcgat ccgcgcatat aacgatattt ggatttgacc

301 tgcattttgg aatttatcta cacttaaaat gccaccagca gttggaggtc cagttggata 361 caccccccca gatggaggct ggggctgggc agtggtaatt ggagctttca tttccatcgg 421 cttctc (SEQ ID NO: 155) .

[0341] An exemplary nucleic acid sequence encoding SLC3A2 (NM_001012662.2 transcript variant 2) comprises or consists of:

1 agttccaggg aaggagggcg tagacaaagc gccacctgaa cttgcggcgc gaaaaaggcg 61 cgcatgcgtc ctacgggagc gtgctggctc accgaccgca ttgcggcttg gttttctcac 121 ccagtgcatg tggcaggagc ggtgagatca ctgcctcacg gcgatcctgg actgacggtc 181 acgactgcct accctctaac cctgttctga gctgcccctt gcccacacac cccaaacctg 241 tgtgcaggat ccgcctccat ggagctacag cctcctgaag cctcgatcgc cgtcgtgtcg 301 attccgcgcc agttgcctgg ctcacattcg gaggctggtg tccagggtct cagcgcgggg 361 gacgactcag agacggggtc tgactgtgtt acccaggctg gtcttcaact cttggcctca 421 agtgatcctc ctgccttagc ttccaagaat gctgaggtta cagtagaaac ggggtttcac 481 catgttagcc aggctgatat tgaattcctg acctcaattg atccgactgc ctcggcctcc 541 ggaagtgctg ggattacagg caccatgagc caggacaccg aggtggatat gaaggaggtg 601 gagctgaatg agttagagcc cgagaagcag ccgatgaacg cggcgtctgg ggcggccatg 661 tccctggcgg gagccgagaa gaatggtctg gtgaagatca aggtggcgga agacgaggcg 721 gaggcggcag ccgcggctaa gttcacgggc ctgtccaagg aggagctgct gaaggtggca 781 ggcagccccg gctgggtacg cacccgctgg gcactgctgc tgctcttctg gctcggctgg 841 ctcggcatgc ttgctggtgc cgtggtcata atcgtgcgag cgccgcgttg tcgcgagcta 901 ccggcgcaga agtggtggca cacgggcgcc ctctaccgca tcggcgacct tcaggccttc 961 cagggccacg gcgcgggcaa cctggcgggt ctgaaggggc gtctcgatta cctgagctct 1021 ctgaaggtga agggccttgt gctgggtcca attcacaaga accagaagga tgatgtcgct 1081 cagactgact tgctgcagat cgaccccaat tttggctcca aggaagattt tgacagtctc 1141 ttgcaatcgg ctaaaaaaaa gagcatccgt gtcattctgg accttactcc caactaccgg 1201 ggtgagaact cgtggttctc cactcaggtt gacactgtgg ccaccaaggt gaaggatgct 1261 ctggagtttt ggctgcaagc tggcgtggat gggttccagg ttcgggacat agagaatctg 1321 aaggatgcat cctcattctt ggctgagtgg caaaatatca ccaagggctt cagtgaagac 1381 aggctcttga ttgcggggac taactcctcc gaccttcagc agatcctgag cctactcgaa 1441 tccaacaaag acttgctgtt gactagctca tacctgtctg attctggttc tactggggag 1501 catacaaaat ccctagtcac acagtatttg aatgccactg gcaatcgctg gtgcagctgg 1561 agtttgtctc aggcaaggct cctgacttcc ttcttgccgg ctcaacttct ccgactctac 1621 cagctgatgc tcttcaccct gccagggacc cctgttttca gctacgggga tgagattggc 1681 ctggatgcag ctgcccttcc tggacagcct atggaggctc cagtcatgct gtgggatgag 1741 tccagcttcc ctgacatccc aggggctgta agtgccaaca tgactgtgaa gggccagagt 1801 gaagaccctg gctccctcct ttccttgttc cggcggctga gtgaccagcg gagtaaggag 1861 cgctccctac tgcatgggga cttccacgcg ttctccgctg ggcctggact cttctcctat 1921 atccgccact gggaccagaa tgagcgtttt ctggtagtgc ttaactttgg ggatgtgggc 1981 ctctcggctg gactgcaggc ctccgacctg cctgccagcg ccagcctgcc agccaaggct 2041 gacctcctgc tcagcaccca gccaggccgt gaggagggct cccctcttga gctggaacgc 2101 ctgaaactgg agcctcacga agggctgctg ctccgcttcc cctacgcggc ctgacttcag 2161 cctgacatgg acccactacc cttctccttt ccttcccagg ccctttggct tctgattttt 2221 ctctttttta aaaacaaaca aacaaactgt tgcagattat gagtgaaccc ccaaataggg 2281 tgttttctgc cttcaaataa aagtcacccc tgcatggtga agtcttccct ctgcttctct 2341 cataaaaaaa (SEQ ID NO 156) .

[0342] An exemplary amino acid sequence encoding SLC3A2 (NP_001012680.1, isoform b) comprises or consists of:

MELQPPEASIAWSIPRQLPGSHSEAGVQGLSAGDDSETGSDCVTQAGLQLLASSDPPALASKNAEVTVETGFHH VSQADIEFLTSIDPTASASGSAGITGTMSQDTEVDMKEVELNELEPEKQPMNAASGAAMSLAGAEKNGLVKIKVA EDEAEAAAAAKFTGLSKEELLKVAGSPG VRTRWALLLLFWLGWLGMLAGAWI IVRAPRCRELPAQKWWHTGAL YRIGDLQAFQGHGAGNLAGLKGRLDYLSSLKVKGLVLGPIHKNQKDDVAQTDLLQIDPNFGSKEDFDSLLQSAKK KSIRVILDLTPNYRGENSWFSTQVDTVATKVKDALEFWLQAGVDGFQVRDIENLKDASSFLAEWQNITKGFSEDR LLIAGTNSSDLQQILSLLESNKDLLLTSSYLSDSGSTGEHTKSLVTQYLNATGNRWCSWSLSQARLLTSFLPAQL LRLYQLMLFTLPGTPVFSYGDEIGLDAAALPGQPMEAPVMLWDESSFPDIPGAVSANMTVKGQSEDPGSLLSLFR RLSDQRSKERSLLHGDFHAFSAGPGLFSYIRHWDQNERFLWLNFGDVGLSAGLQASDLPASASLPAKADLLLST QPGREEGSPLELERLKLEPHEGLLLRFPYAA (SEQ ID NO: 157) .

[0343] An exemplary nucleic acid sequence encoding SLC3A2 (NM_002394.5 transcript variant 3) comprises or consists of:

1 agttccaggg aaggagggcg tagacaaagc gccacctgaa cttgcggcgc gaaaaaggcg 61 cgcatgcgtc ctacgggagc gtgctggctc accgaccgca ttgcggcttg gttttctcac 121 ccagtgcatg tggcaggagc ggtgagatca ctgcctcacg gcgatcctgg actgacggtc 181 acgactgcct accctctaac cctgttctga gctgcccctt gcccacacac cccaaacctg 241 tgtgcaggat ccgcctccat ggagctacag cctcctgaag cctcgatcgc cgtcgtgtcg 301 attccgcgcc agttgcctgg ctcacattcg gaggctggtg tccagggtct cagcgcgggg 361 gacgactcag agttggggtc tcactgtgtt gcccagactg gtctcgaact cttggcctca 421 ggtgatcctc ttccctcagc ttcccagaat gccgagatga tagagacggg gtctgactgt 481 gttacccagg ctggtcttca actcttggcc tcaagtgatc ctcctgcctt agcttccaag 541 aatgctgagg ttacaggcac catgagccag gacaccgagg tggatatgaa ggaggtggag 601 ctgaatgagt tagagcccga gaagcagccg atgaacgcgg cgtctggggc ggccatgtcc 661 ctggcgggag ccgagaagaa tggtctggtg aagatcaagg tggcggaaga cgaggcggag 721 gcggcagccg cggctaagtt cacgggcctg tccaaggagg agctgctgaa ggtggcaggc 781 agccccggct gggtacgcac ccgctgggca ctgctgctgc tcttctggct cggctggctc 841 ggcatgcttg ctggtgccgt ggtcataatc gtgcgagcgc cgcgttgtcg cgagctaccg 901 gcgcagaagt ggtggcacac gggcgccctc taccgcatcg gcgaccttca ggccttccag 961 ggccacggcg cgggcaacct ggcgggtctg aaggggcgtc tcgattacct gagctctctg 1021 aaggtgaagg gccttgtgct gggtccaatt cacaagaacc agaaggatga tgtcgctcag 1081 actgacttgc tgcagatcga ccccaatttt ggctccaagg aagattttga cagtctcttg 1141 caatcggcta aaaaaaagag catccgtgtc attctggacc ttactcccaa ctaccggggt 1201 gagaactcgt ggttctccac tcaggttgac actgtggcca ccaaggtgaa ggatgctctg 1261 gagttttggc tgcaagctgg cgtggatggg ttccaggttc gggacataga gaatctgaag 1321 gatgcatcct cattcttggc tgagtggcaa aatatcacca agggcttcag tgaagacagg 1381 ctcttgattg cggggactaa ctcctccgac cttcagcaga tcctgagcct actcgaatcc 1441 aacaaagact tgctgttgac tagctcatac ctgtctgatt ctggttctac tggggagcat 1501 acaaaatccc tagtcacaca gtatttgaat gccactggca atcgctggtg cagctggagt 1561 ttgtctcagg caaggctcct gacttccttc ttgccggctc aacttctccg actctaccag 1621 ctgatgctct tcaccctgcc agggacccct gttttcagct acggggatga gattggcctg 1681 gatgcagctg cccttcctgg acagcctatg gaggctccag tcatgctgtg ggatgagtcc 1741 agcttccctg acatcccagg ggctgtaagt gccaacatga ctgtgaaggg ccagagtgaa 1801 gaccctggct ccctcctttc cttgttccgg cggctgagtg accagcggag taaggagcgc 1861 tccctactgc atggggactt ccacgcgttc tccgctgggc ctggactctt ctcctatatc 1921 cgccactggg accagaatga gcgttttctg gtagtgctta actttgggga tgtgggcctc 1981 tcggctggac tgcaggcctc cgacctgcct gccagcgcca gcctgccagc caaggctgac 2041 ctcctgctca gcacccagcc aggccgtgag gagggctccc ctcttgagct ggaacgcctg 2101 aaactggagc ctcacgaagg gctgctgctc cgcttcccct acgcggcctg acttcagcct 2161 gacatggacc cactaccctt ctcctttcct tcccaggccc tttggcttct gatttttctc 2221 ttttttaaaa acaaacaaac aaactgttgc agattatgag tgaaccccca aatagggtgt 2281 tttctgcctt caaataaaag tcacccctgc atggtgaagt cttccctctg cttctctcat 2341 aaaaaaa (SEQ ID NO: 158) .

[0344] An exemplary amino acid sequence encoding SLC3A2 (NP_002385.3, isoform c) comprises or consists of:

MELQPPEASIAWSIPRQLPGSHSEAGVQGLSAGDDSELGSHCVAQTGLELLASGDPLPSASQNAEMIETGSDCV TQAGLQLLASSDPPALASKNAEVTGTMSQDTEVDMKEVELNELEPEKQPMNAASGAAMSLAGAEKNGLVKIKVAE DEAEAAAAAKFTGLSKEELLKVAGSPGWVRTRWALLLLFWLGWLGMLAGAVVIIVRAPRCRELPAQKWWHTGALY RIGDLQAFQGHGAGNLAGLKGRLDYLSSLKVKGLVLGPIHKNQKDDVAQTDLLQIDPNFGSKEDFDSLLQSAKKK SIRVILDLTPNYRGENSWFSTQVDTVATKVKDALEFWLQAGVDGFQVRDIENLKDASSFLAEWQNITKGFSEDRL LIAGTNSSDLQQILSLLESNKDLLLTSSYLSDSGSTGEHTKSLVTQYLNATGNRWCSWSLSQARLLTSFLPAQLL RLYQLMLFTLPGTPVFSYGDEIGLDAAALPGQPMEAPVMLWDESSFPDIPGAVSANMTVKGQSEDPGSLLSLFRR LSDQRSKERSLLHGDFHAFSAGPGLFSYIRHWDQNERFLWLNFGDVGLSAGLQASDLPASASLPAKADLLLSTQ PGREEGSPLELERLKLEPHEGLLLRFPYAA (SEQ ID NO: 159) .

[0345] An exemplary nucleic acid sequence encoding SLC3A2 (NM_001012664.2 transcript variant 5) comprises or consists of:

1 agttccaggg aaggagggcg tagacaaagc gccacctgaa cttgcggcgc gaaaaaggcg 61 cgcatgcgtc ctacgggagc gtgctggctc accgaccgca ttgcggcttg gttttctcac 121 ccagtgcatg tggcaggagc ggtgagatca ctgcctcacg gcgatcctgg actgacggtc 181 acgactgcct accctctaac cctgttctga gctgcccctt gcccacacac cccaaacctg 241 tgtgcaggat ccgcctccat ggagctacag cctcctgaag cctcgatcgc cgtcgtgtcg 301 attccgcgcc agttgcctgg ctcacattcg gaggctggtg tccagggtct cagcgcgggg 361 gacgactcag gcaccatgag ccaggacacc gaggtggata tgaaggaggt ggagctgaat 421 gagttagagc ccgagaagca gccgatgaac gcggcgtctg gggcggccat gtccctggcg 481 ggagccgaga agaatggtct ggtgaagatc aaggtggcgg aagacgaggc ggaggcggca 541 gccgcggcta agttcacggg cctgtccaag gaggagctgc tgaaggtggc aggcagcccc 601 ggctgggtac gcacccgctg ggcactgctg ctgctcttct ggctcggctg gctcggcatg 661 cttgctggtg ccgtggtcat aatcgtgcga gcgccgcgtt gtcgcgagct accggcgcag 721 aagtggtggc acacgggcgc cctctaccgc atcggcgacc ttcaggcctt ccagggccac 781 ggcgcgggca acctggcggg tctgaagggg cgtctcgatt acctgagctc tctgaaggtg 841 aagggccttg tgctgggtcc aattcacaag aaccagaagg atgatgtcgc tcagactgac 901 ttgctgcaga tcgaccccaa ttttggctcc aaggaagatt ttgacagtct cttgcaatcg 961 gctaaaaaaa agagcatccg tgtcattctg gaccttactc ccaactaccg gggtgagaac 1021 tcgtggttct ccactcaggt tgacactgtg gccaccaagg tgaaggatgc tctggagttt 1081 tggctgcaag ctggcgtgga tgggttccag gttcgggaca tagagaatct gaaggatgca 1141 tcctcattct tggctgagtg gcaaaatatc accaagggct tcagtgaaga caggctcttg 1201 attgcgggga ctaactcctc cgaccttcag cagatcctga gcctactcga atccaacaaa 1261 gacttgctgt tgactagctc atacctgtct gattctggtt ctactgggga gcatacaaaa 1321 tccctagtca cacagtattt gaatgccact ggcaatcgct ggtgcagctg gagtttgtct 1381 caggcaaggc tcctgacttc cttcttgccg gctcaacttc tccgactcta ccagctgatg 1441 ctcttcaccc tgccagggac ccctgttttc agctacgggg atgagattgg cctggatgca 1501 gctgcccttc ctggacagcc tatggaggct ccagtcatgc tgtgggatga gtccagcttc 1561 cctgacatcc caggggctgt aagtgccaac atgactgtga agggccagag tgaagaccct 1621 ggctccctcc tttccttgtt ccggcggctg agtgaccagc ggagtaagga gcgctcccta 1681 ctgcatgggg acttccacgc gttctccgct gggcctggac tcttctccta tatccgccac 1741 tgggaccaga atgagcgttt tctggtagtg cttaactttg gggatgtggg cctctcggct 1801 ggactgcagg cctccgacct gcctgccagc gccagcctgc cagccaaggc tgacctcctg 1861 ctcagcaccc agccaggccg tgaggagggc tcccctcttg agctggaacg cctgaaactg 1921 gagcctcacg aagggctgct gctccgcttc ccctacgcgg cctgacttca gcctgacatg 1981 gacccactac ccttctcctt tccttcccag gccctttggc ttctgatttt tctctttttt 2041 aaaaacaaac aaacaaactg ttgcagatta tgagtgaacc cccaaatagg gtgttttctg 2101 ccttcaaata aaagtcaccc ctgcatggtg aagtcttccc tctgcttctc tcataaaaaa 2161 a (SEQ ID NO: 160)

[0346] An exemplary amino acid sequence encoding SLC3A2 (NP_001012682.1 " isoform e) comprises or consists of:

MELQPPEASIAWSIPRQLPGSHSEAGVQGLSAGDDSGTMSQDTEVDMKEVELNELEPEKQPMNAASGAAMSLAG AEKNGLVKIKVAEDEAEAAAAAKFTGLSKEELLKVAGSPGWVRTRWALLLLFWLGWLGMLAGAVVI IVRAPRCRE LPAQKWWHTGALYRIGDLQAFQGHGAGNLAGLKGRLDYLSSLKVKGLVLGPIHKNQKDDVAQTDLLQIDPNFGSK EDFDSLLQSAKKKSIRVILDLTPNYRGENSWFSTQVDTVATKVKDALEFWLQAGVDGFQVRDIENLKDASSFLAE WQNITKGFSEDRLLIAGTNSSDLQQILSLLESNKDLLLTSSYLSDSGSTGEHTKSLVTQYLNATGNRWCSWSLSQ ARLLTSFLPAQLLRLYQLMLFTLPGTPVFSYGDEIGLDAAALPGQPMEAPVMLWDESSFPDIPGAVSANMTVKGQ SEDPGSLLSLFRRLSDQRSKERSLLHGDFHAFSAGPGLFSYIRHWDQNERFLWLNFGDVGLSAGLQASDLPASA SLPAKADLLLSTQPGREEGSPLELERLKLEPHEGLLLRFPYAA (SEQ ID NO: 161) .

[0347] An exemplary nucleic acid sequence encoding SLC3A2 (NM_001013251.2 transcript variant 6) comprises or consists of:

1 cagaggccgc gcctgctgct gagcagatgc agtagccgaa actgcgcgga ggcacagagg 61 ccggggagag cgttctgggt ccgagggtcc aggtaggggt tgagccacca tctgaccgca 121 agctgcgtcg tgtcgccggt tctgcaggca ccatgagcca ggacaccgag gtggatatga 181 aggaggtgga gctgaatgag ttagagcccg agaagcagcc gatgaacgcg gcgtctgggg 241 cggccatgtc cctggcggga gccgagaaga atggtctggt gaagatcaag gtggcggaag 301 acgaggcgga ggcggcagcc gcggctaagt tcacgggcct gtccaaggag gagctgctga 361 aggtggcagg cagccccggc tgggtacgca cccgctgggc actgctgctg ctcttctggc 421 tcggctggct cggcatgctt gctggtgccg tggtcataat cgtgcgagcg ccgcgttgtc 481 gcgagctacc ggcgcagaag tggtggcaca cgggcgccct ctaccgcatc ggcgaccttc 541 aggccttcca gggccacggc gcgggcaacc tggcgggtct gaaggggcgt ctcgattacc 601 tgagctctct gaaggtgaag ggccttgtgc tgggtccaat tcacaagaac cagaaggatg 661 atgtcgctca gactgacttg ctgcagatcg accccaattt tggctccaag gaagattttg 721 acagtctctt gcaatcggct aaaaaaaaga gcatccgtgt cattctggac cttactccca 781 actaccgggg tgagaactcg tggttctcca ctcaggttga cactgtggcc accaaggtga 841 aggatgctct ggagttttgg ctgcaagctg gcgtggatgg gttccaggtt cgggacatag 901 agaatctgaa ggatgcatcc tcattcttgg ctgagtggca aaatatcacc aagggcttca 961 gtgaagacag gctcttgatt gcggggacta actcctccga ccttcagcag atcctgagcc 1021 tactcgaatc caacaaagac ttgctgttga ctagctcata cctgtctgat tctggttcta 1081 ctggggagca tacaaaatcc ctagtcacac agtatttgaa tgccactggc aatcgctggt 1141 gcagctggag tttgtctcag gcaaggctcc tgacttcctt cttgccggct caacttctcc 1201 gactctacca gctgatgctc ttcaccctgc cagggacccc tgttttcagc tacggggatg 1261 agattggcct ggatgcagct gcccttcctg gacagcctat ggaggctcca gtcatgctgt 1321 gggatgagtc cagcttccct gacatcccag gggctgtaag tgccaacatg actgtgaagg 1381 gccagagtga agaccctggc tccctccttt ccttgttccg gcggctgagt gaccagcgga 1441 gtaaggagcg ctccctactg catggggact tccacgcgtt ctccgctggg cctggactct 1501 tctcctatat ccgccactgg gaccagaatg agcgttttct ggtagtgctt aactttgggg 1561 atgtgggcct ctcggctgga ctgcaggcct ccgacctgcc tgccagcgcc agcctgccag 1621 ccaaggctga cctcctgctc agcacccagc caggccgtga ggagggctcc cctcttgagc 1681 tggaacgcct gaaactggag cctcacgaag ggctgctgct ccgcttcccc tacgcggcct 1741 gacttcagcc tgacatggac ccactaccct tctcctttcc ttcccaggcc ctttggcttc 1801 tgatttttct cttttttaaa aacaaacaaa caaactgttg cagattatga gtgaaccccc 1861 aaatagggtg ttttctgcct tcaaataaaa gtcacccctg catggtgaag tcttccctct 1921 gcttctctca taaaaaaa (SEQ ID NO: 162) .

[0348] An exemplary amino acid sequence encoding SLC3A2 (NP_001013269.1, isoform f) comprises or consists of:

MSQDTEVDMKEVELNELEPEKQPMNAASGAAMSLAGAEKNGLVKIKVAEDEAEAAAAAKFTGLSKEELLKVAGSP G RTRWALLLLFWLGWLGMLAGAWIIVRAPRCRELPAQKWWHTGALYRIGDLQAFQGHGAGNLAGLKGRLDYL SSLKVKGLVLGPIHKNQKDDVAQTDLLQIDPNFGSKEDFDSLLQSAKKKSIRVILDLTPNYRGENSWFSTQVDTV ATKVKDALEFWLQAGVDGFQVRDIENLKDASSFLAEWQNITKGFSEDRLLIAGTNSSDLQQILSLLESNKDLLLT SSYLSDSGSTGEHTKSLVTQYLNATGNRWCSWSLSQARLLTSFLPAQLLRLYQLMLFTLPGTPVFSYGDEIGLDA AALPGQPMEAPVMLWDESSFPDIPGAVSANMTVKGQSEDPGSLLSLFRRLSDQRSKERSLLHGDFHAFSAGPGLF SYIRHWDQNERFLWLNFGDVGLSAGLQASDLPASASLPAKADLLLSTQPGREEGSPLELERLKLEPHEGLLLRF PYAA (SEQ ID NO: 163) . [0349] An exemplary nucleic acid sequence encoding SLC3A2 (NR_037193.1 transcript variant 7 ) comprises or consists of:

1 agttgcaacc ggtttctgaa gtaatgtgca ggactcctta catcagctcc tctgagtctc

61 gtgattcagc cttgcctccc tctctccccc tttgccccct ccccgtccca cccttaggcg 121 ctgggagaag ggagggtggg gaggtcaggg gcctctcaga ggggcctcac ttgttaaccc 181 agcccccatt tcaggtctga aggggcgtct cgattacctg agctctctga aggtgaaggg 241 ccttgtgctg ggtccaattc acaagaacca gaaggatgat gtcgctcaga ctgacttgct 301 gcagatcgac cccaattttg gctccaagga agattttgac agtctcttgc aatcggctaa 361 aaaaaagagc atccgtgtca ttctggacct tactcccaac taccggggtg agaactcgtg 421 gttctccact caggttgaca ctgtggccac caaggtgaag gcctcaggaa actgggagag 481 gggggatctt gactgacatt ttagatcctg tctgctgctc actgattatg actgtggacg 541 cgtctccctg cttctctggg tctgtttctt catctctaaa ataggatgct ctggagtttt 601 ggctgcaagc tggcgtggat gggttccagg ttcgggacat agagaatctg aaggatgcat 661 cctcattctt ggctgagtgg caaaatatca ccaagggctt cagtgaagac aggctcttga 721 ttgcggggac taactcctcc gaccttcagc agatcctgag cctactcgaa tccaacaaag 7 1 acttgctgtt gactagctca tacctgtctg attctggttc tactggggag catacaaaat

841 ccctagtcac acagtatttg aatgccactg gcaatcgctg gtgcagctgg agtttgtctc 901 aggcaaggct cctgacttcc ttcttgccgg ctcaacttct ccgactctac cagctgatgc 961 tcttcaccct gccagggacc cctgttttca gctacgggga tgagattggc ctggatgcag 1021 ctgcccttcc tggacagcct atggaggctc cagtcatgct gtgggatgag tccagcttcc 1081 ctgacatccc aggggctgta agtgccaaca tgactgtgaa gggccagagt gaagaccctg 1141 gctccctcct ttccttgttc cggcggctga gtgaccagcg gagtaaggag cgctccctac 1201 tgcatgggga cttccacgcg ttctccgctg ggcctggact cttctcctat atccgccact 1261 gggaccagaa tgagcgtttt ctggtagtgc ttaactttgg ggatgtgggc ctctcggctg 1321 gactgcaggc ctccgacctg cctgccagcg ccagcctgcc agccaaggct gacctcctgc 13 1 tcagcaccca gccaggccgt gaggagggct cccctcttga gctggaacgc ctgaaactgg 1441 agcctcacga agggctgctg ctccgcttcc cctacgcggc ctgacttcag cctgacatgg 1501 acccactacc cttctccttt ccttcccagg ccctttggct tctgattttt ctctttttta 1561 aaaacaaaca aacaaactgt tgcagattat gagtgaaccc ccaaataggg tgttttctgc 1621 cttcaaataa aagtcacccc tgcatggtga agtcttccct ctgcttctct cataaaaaaa (SEQ ID NO: 164) .

[0350] An exemplary nucleic acid sequence encoding SLC3A2 (DQ125482.1 , promoter region) comprises or consists of:

1 gcaaggtggg taagagtctg gccatggcat cttctggtct attccacaaa aaaggtggat 61 gcctctgaga cctagctctg ttatgttcat tacagcccta tcagtctctt ctggatgtct 121 gattcctagc tgccaaacat ccaggtgcta gcagctgggg gtggggtagg ataagaaggg 181 gggtgtctac ctcaaccttc ctgcccaaac cattcatttt aaagtactgt gaagaaggct 241 ggattagtgt taaattcaat aaagttaaca aagcaaagta ttgtagtgag tacacaataa 301 atagttgctg catgaggaat ttcttgaaat gaattcaaga tgagtcttga aaaacgagtg 361 ggagtaagcc gtgcacggaa gcagaggtct agcagaggtc tagcgccaag tcccagaggc 421 ctgagagggc aagccttggt gggggaaaag gcagaagttg tgactggctg cctctgagag 481 tgcaagtagc catgcaaagt tgggaaaacc agacggcggc cggagccgtg aaccaggggc 541 aaatggagga tggtgttggg gtagtcacta gcctgccgga atggaagaag aggggcgttt 601 gggggcggta aggcctaaag gacactggag gggcctcggg atttggggca ggatcacagg 661 cctagtccac ttaaaggtgg ctccgtgcca ggccttccca gaatcaggtt gaaaagaact 721 ttagggttag acaggttgga gatgagaaat tggaccatgc aggaagtact gtcggaggcg 781 tgttcctgac tttactaccc tgagccgccc acggctgggg cagtccccga ggttccacct 841 taaggggcgg gccggggcgg ggctccgctg ccccttccca gaggccgcgc ctgctgctga 901 gcagatgcag tagccgaaac tgcgcggagg cacagaggcc ggggagagcg ttctgggtcc 961 gagggtccag gtaggggttg agccaccatc tgaccgcaag ctgcgtcgtg tcgccggttc 1021 tgcaggcacc atga (SEQ ID NO: 165) .

[0351] An exemplary nucleic acid sequence encoding SP l (NM_138473.2 transcript variant 1) comprises or consists of: 1 gtccgggttc gcttgcctcg tcagcgtccg cgtttttccc ggcccccccc aacccccccg 61 gacaggaccc ccttgagctt gtccctcagc tgccaccatg agcgaccaag atcactccat 121 ggatgaaatg acagctgtgg tgaaaattga aaaaggagtt ggtggcaata atgggggcaa 181 tggtaatggt ggtggtgcct tttcacaggc tcgaagtagc agcacaggca gtagcagcag 241 cactggagga ggagggcagg agtcccagcc atcccctttg gctctgctgg cagcaacttg 301 cagcagaatt gagtcaccca atgagaacag caacaactcc cagggcccga gtcagtcagg 361 gggaacaggt gagcttgacc tcacagccac acaactttca cagggtgcca atggctggca 421 gatcatctct tcctcctctg gggctacccc tacctcaaag gaacagagtg gcagcagtac 481 caatggcagc aatggcagtg agtcttccaa gaatcgcaca gtctctggtg ggcagtatgt 541 tgtggctgcc gctcccaact tacagaacca gcaagttctg acaggactac ctggagtgat 601 gcctaatatt cagtatcaag taatcccaca gttccagacc gttgatgggc aacagctgca 661 gtttgctgcc actggggccc aagtgcagca ggatggttct ggtcaaatac agatcatacc 721 aggtgcaaac caacagatta tcacaaatcg aggaagtgga ggcaacatca ttgctgctat 781 gccaaaccta ctccagcagg ctgtccccct ccaaggcctg gctaataatg tactctcagg 841 acagactcag tatgtgacca atgtaccagt ggccctgaat gggaacatca ccttgctacc 901 tgtcaacagc gtttctgcag ctaccttgac tcccagctct caggcagtca cgatcagcag 961 ctctgggtcc caggagagtg gctcacagcc tgtcacctca gggactacca tcagttctgc 1021 cagcttggta tcatcacaag ccagttccag ctcctttttc accaatgcca atagctactc 1081 aactactact accaccagca acatgggaat tatgaacttt actaccagtg gatcatcagg 1141 gaccaactct caaggccaga caccccagag ggtcagtggg ctacaggggt ctgatgctct 1201 gaacatccag caaaaccaga catctggagg ctcattgcaa gcaggccagc aaaaagaagg 1261 agagcaaaac cagcagacac agcagcaaca aattcttatc cagcctcagc tagttcaagg 1321 gggacaggcc ctccaggccc tccaagcagc accattgtca gggcagacct ttacaactca 1381 agccatctcc caggaaaccc tccagaacct ccagcttcag gctgttccaa actctggtcc 1441 catcatcatc cggacaccaa cagtggggcc caatggacag gtcagttggc agactctaca 1501 gctgcagaac ctccaagttc agaacccaca agcccaaaca atcaccttag ccccaatgca 1561 gggtgtttcc ttggggcaga ccagcagcag caacaccact ctcacaccca ttgcctcagc 1621 tgcttccatt cctgctggca cagtcactgt gaatgctgct caactctcct ccatgccagg 1681 cctccagacc attaacctca gtgcattggg tacttcagga atccaggtgc acccaattca 1741 aggcctgccg ttggctatag caaatgcccc aggtgatcat ggagctcagc ttggtctcca 1801 tggggctggt ggtgatggaa tacatgatga cacagcaggt ggagaggaag gagaaaacag 1861 cccagatgcc caaccccaag ccggtcggag gacccggcgg gaagcatgca cctgccccta 1921 ctgtaaagac agtgaaggaa ggggctcggg ggatcctggc aaaaagaaac agcatatttg 1981 ccacatccaa ggctgtggga aagtgtatgg caagacctct cacctgcggg cacacttgcg 2041 ctggcataca ggcgagaggc catttatgtg tacctggtca tactgtggga aacgcttcac 2101 acgttcggat gagctacaga ggcacaaacg tacacacaca ggtgagaaga aatttgcctg 2161 ccctgagtgt cctaagcgct tcatgaggag tgaccacctg tcaaaacata tcaagaccca 2221 ccagaataag aagggaggcc caggtgtagc tctgagtgtg ggcactttgc ccctggacag 2281 tggggcaggt tcagaaggca gtggcactgc cactccttca gcccttatta ccaccaatat 2341 ggtagccatg gaggccatct gtccagaggg cattgcccgt cttgccaaca gtggcatcaa 2401 cgtcatgcag gtggcagatc tgcagtccat taatatcagt ggcaatggct tctgagatca 2461 ggcacccggg gccagagaca tatgggccat accccttaac cccgggatgc aaggtagcat 2521 gggtccaaga gacatggaag agagagccat gaagcattaa aatgcatggt gttgagaaga 2581 atcaggagag ggatacaaga gaggagatgg ggtcccggca cccatctgta tcatcagtgc 2641 ctctttgaag gtgggaaaca ttagtgaaaa ttctgttggt gccacgcttt gatgagcatt 2701 tgtttgaccc cagtttcttc ttacacttct taccccagcc tacccttcct gcatttctct 2761 tctcagctct tccatgatgg attccccccc ctttcctaaa gccatcatgc cttgataaat 2821 atatatgatc attgaaatac tttttaacaa aaaacagatt ctatattatt atatatatat 2881 atatatatat aaagatatat agagatgcat tcacaggggt tggctgggag gaggaagacc 2941 attctgtgac caaaatacct tggtcatttt ttttatattg ccttatttcc ctatggctga 3001 gccttgttgt gacacatcaa gcttttctgt agatgttgtc ttggcttccc accagcttaa 3061 gcgttcatat gctctgcttt tagttcatat atacatacat aatgtttttc ctttcttaat 3121 tttgtctttt tgtttgggat cagcttcttg cactccttcc ctaactcaac tgttgccgtc 3181 tcatcttctc tcatctgatc acttcatgtt ttgtttttgt tactgcctgg atgaggcact 3241 tctgtcaatt ttttcaggac cttagttcca gcagcagaat ggaaaaatcc ttgaagccca 3301 ggctgatgct tgaagtaact gtggagggag tgttcaaaat actactgacg caggcacctt 3361 cttggcgctg gagagtcaaa ggcatctccc ttcattagct gctctgagca tcaagaatta 3421 gaagtctttc agtggaattg tacaagagtc cctttgaaga taataatctt ggctcagttt 3481 gtataaactg tcaaattttc aaataatagg tagggggctt tcactaggaa aatcatgtgc 3541 tcagaagagg aaatgactcg tagtcaggtt caggagttag tggagtattt ggactttggt 3601 actgctgtct tccaaggtag ctctaagttt tgatgtgtgg gcttctgagt ttatattctg 3661 aaaggaaata cacttctttt gaacatcccc actaggttct tttccattgt caataaggag 3721 catcagccag tgaatctgtt tcaggtttcc attctgcaga actcctccaa agcatgtgct 3781 agtggcaaga cagtggttct tatgatgttt tcccttaact tttccttgta tgttcttggg 3841 tggttcctaa gggaaaggga agcacatgat catgggaatg atagcccaga acaaaaagaa 3901 atcttgtctt accacagtgt tttataggag agattgggag aaatcatcct gttttctctg 3961 tgacctgatt tcagaagaga ctgatccaaa aattataacg gcagggaacc tagtgcattt 4021 ggcactgaga tttaaatgca accagaattg tcctcaaggc ccagccataa aagcattgtc 4081 tctctcgacc ttctggtatc ttgttagaga gcttttcact gtgaggaagt gtggaaaaat 4141 agctctgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtaatctgtt aggttgggga 4201 taggttttct gctagccaat attaaaagag acctgcaata aaaaaattac cctgatctga 4261 tagaaagcaa gtgtttttgt atgtgtgggt gaatgtgtgt tcatgcccgt atatgtctac 4321 acacagatga caaattatat ttgaaatcgt tggaaaataa attcagatca aaatgccttt 4381 caggcccatt acctagaaat ctatcttaaa acctgggtat gttcctaagg tcatttcttt 4441 gcttatgcta aattaattac aattatgaat ggaggatatt ctactgtact tttttaaaaa 4501 gaaactattt ttgtgtttga aagtgaaacc aacatccaga tctatagcag agtccttatt 4561 cttctcataa atctttttac tttggctaca aatagatgat ggtatgattc tattatatat 4621 tttatataaa atccatccaa attaagtttt gggtaagtgt gttgtttaat ctgaactata 4681 gtaacttaat actctaaaca atagttcact ccatttggtc ctttctccac agatgtaatt 4741 atgttttcaa ctcaggaact atggcaagga actttcccca gatcaaattc tattaacgct 4801 gagatacaag tcatccatgc acagccacta tcataccctt tattctcact gaaaggcaga 4861 actcagaacc tgttatttta tgtctgtaat catgtacttt ggcatctttt ggaggaaagg 4921 ggcaggataa ctcactggaa tgtacagtat tttgctagtg catttcaagg aatggaatct 4981 tctccagtat gaaattacca gatataaaat aatgtaatga tgctgaggat ataagctttt 5041 agaaggtaat ttgatggtat ttctttctcg aatgaaaagc tgctggttta ccctcaaccc 5101 tattcattag cattaccatg agtgaattta tatctaatta tttccacttg ccctgttctc 5161 ttcacaccaa ggaagctcca gatccagtat cttgtttggc ctcaaaacag aagcagcttc 5221 ttttgtctcc cagcagtagt gagccactca gtctcttcca caggaagttt ggagcctaca 5281 ttccttgagt caggagctta ttacagaaaa accccgtttc cctgaacttt tggctaacag 5341 aaattaattt aactgacatg catattgatt ctgaaatttt tttcctaagt ttttttcatt 5401 tttttgaatg agttttttaa attttttaga tgaccaaaac ttgcagggca ggggatgccc 5461 agaagagtgg tgagatagta aaacacttat tccctcatcc tttcaggttt tcaggttgcc 5521 catttatatt catttacatg tcatttgact gtctcacttt ttacccagaa cagtaacaac 5581 ccacaccgtc ttccttcagg gatttccaac tggcactctg tgggtgctac acagaatgca 5641 atttaatgga tatttctcag cctggttcag aataaattga tcctttgatc ccagaaagta 5701 tatactgaag tgtgggataa agattatgat taggggaggg ttggagacaa aagctgtaaa 5761 ttactatggc tgatttattt ctactatata catatatatt ttttgctttt gtatatccta 5821 tataggaaac taagcattgt atttttttta acaaatctaa aaaagcacta tgaactacag 5881 gtgtttgact ttcaaaatat attttgtatt gttaatatct tcacattgtg tgaatactgg 5941 aagctgcaga tctttgctag gacgcaataa atttatatac tttttgaggg gttcttctgg 6001 ggtgctaatc aggcccctgt tatgcttagg gggagccctg gtgctacttg cttgaagttt 6061 tcagtgtaag taccctgatg ccttttggac cttgggatca gatcaagagt tttggagatc 6121 aggtaccaag gaaataagga cagtctagct gcctcaagtg aggggccctt tgcatagctc 6181 tccttccccc tcactgaagc tgggtagcct attggggttg agagggaaaa tgtgaaatct 6241 cagaatttat ctcccttaga agagagccag taacttatgt acaaggatga aagaaaggtc 6301 gcagcagtag ctttggggaa agggaggaag atatggcact tctccaaccc cggaaaacat 6361 tgcttttgaa aactgctgat aaaatatgag ccggttatta cttctgtttg ggagactgtg 6421 ctctctgtgg tgcctctctt ggctctactc cacagatacc agacctcttc taagaggatg 6481 agcagaccag ctttgaggtt gacctgtttc tctttgtctg ccttcccaaa acaccagccc 6541 ccaggaagac attaagcagc cttaagctta aattcctact ccctcttcca aatttggctc 6601 acttgcctta gatccaaggc agggaaagga aaagaagggg ggtctctggc tttattactc 6661 ccctaagtct ttactctgac ttccccaaac ccagaaagat tttctccaca gtgttcattt 6721 gaaagaggag tattttgtcc cattttcccc ttcctcatta tcaaacagcc ccagtcttcc 6781 ttgtctctgc taagaaagta gaggcatgat gatctgcctc tcaactgccc taagtcctag 6841 ctaagtatca ggggaaaaaa aaaaaaaaaa agcctaacaa atgggattag actagggctg 6901 caagtagtga ggattttgtt gatacctctg ctgggatgtg tgctttccca tatcttgcct 6961 tcaggaatta cactgtgcct tttccccagg gatatgggct ctgtctaccc agtgctccag 7021 tttcccggta actgctcttg aacattgtgg acaagggcag gtcttcatat ttttgatcat 7081 ccctttctcc cagtgaaatc ccatagccct tacctagagt ctagggcaca aagacttcgg 7141 ggaagataca ctgagattga cctgaggaga catctacaca caccagtggc agctgcccca 7201 gggcctgctt ccccttccta agtctgtcat cctctggaag ggatgggtgg tgctccaatc 7261 tctggtgcct aaaaacccaa gtttatttct ctcttaacac tggcaataac cagtccacac 7321 cactgttgcc ttttaaaacc tcttaataat ctcatgctgt gtttgttttg attccaatcc 7381 aattatcacc agggctgtgt gggtaaatgc ttttaaatgc tctctcatct tgttcttccc 7441 cctcaccccc cactcttagg tatgtatgat gctaatcttg tccctaagta agtttcttcc 7501 tgctcctttt gtatcttcct ttcttgtctt tcctcctacc ttttgtctct tggtgttttg 7561 ggactttttt tttttttttt ttggcctttt gtacaaagat tagtttcaat gtagtctgta 7621 gcctcctttg taaaccaatt aaaaagtttt ttaataaaaa aaaaaaa (SEQ ID NO:

166) .

[0352] An exemplary amino acid sequence encoding SP1 (NP 612482.2, isoform a) comprises or consists of:

MSDQDHSMDEMTAWKIEKGVGGNNGGNGNGGGAFSQARSSSTGSSSSTGGGGQESQPSPLALLAATCSRIESPN ENSNNSQGPSQSGGTGELDLTATQLSQGANGWQIISSSSGATPTSKEQSGSSTNGSNGSESSKNRTVSGGQYWA AAPNLQNQQVLTGLPGVMPNIQYQVIPQFQTVDGQQLQFAATGAQVQQDGSGQIQI IPGANQQI ITNRGSGGNI I AAMPNLLQQAVPLQGLANNVLSGQTQYVTNVPVALNGNITLLPVNSVSAATLTPSSQAVTISSSGSQESGSQPVT SGTTISSASLVSSQASSSSFFTNANSYSTTTTTSNMGIMNFTTSGSSGTNSQGQTPQRVSGLQGSDALNIQQNQT SGGSLQAGQQKEGEQNQQTQQQQILIQPQLVQGGQALQALQAAPLSGQTFTTQAISQETLQNLQLQAVPNSGPII IRTPTVGPNGQVSWQTLQLQNLQVQNPQAQTITLAPMQGVSLGQTSSSNTTLTPIASAASIPAGTVTVNAAQLSS MPGLQTINLSALGTSGIQVHPIQGLPLAIANAPGDHGAQLGLHGAGGDGIHDDTAGGEEGENSPDAQPQAGRRTR REACTCPYCKDSEGRGSGDPGKKKQHICHIQGCGKVYGKTSHLRAHLRWHTGERPFMCTWSYCGKRFTRSDELQR HKRTHTGEKKFACPECPKRFMRSDHLSKHIKTHQNKKGGPGVALSVGTLPLDSGAGSEGSGTATPSALITTNMVA MEAICPEGIARLANSGINVMQVADLQSINISGNGF (SEQ ID NO: 167) .

[0353] An exemplary nucleic acid sequence encoding SP 1 (NM_003109.1 transcript variant

2) comprises or consists of:

1 aggccccgcc cgggccaacc gcctgcctgg tccgccctct gaccaagatc actccatgga 61 tgaaatgaca gctgtggtga aaattgaaaa aggagttggt ggcaataatg ggggcaatgg 121 taatggtggt ggtgcctttt cacaggctcg aagtagcagc acaggcagta gcagcagcac 181 tggaggagga gggcaggagt cccagccatc ccctttggct ctgctggcag caacttgcag 241 cagaattgag tcacccaatg agaacagcaa caactcccag ggcccgagtc agtcaggggg 301 aacaggtgag cttgacctca cagccacaca actttcacag ggtgccaatg gctggcagat 361 catctcttcc tcctctgggg ctacccctac ctcaaaggaa cagagtggca gcagtaccaa 421 tggcagcaat ggcagtgagt cttccaagaa tcgcacagtc tctggtgggc agtatgttgt 481 ggctgccgct cccaacttac agaaccagca agttctgaca ggactacctg gagtgatgcc 541 taatattcag tatcaagtaa tcccacagtt ccagaccgtt gatgggcaac agctgcagtt 601 tgctgccact ggggcccaag tgcagcagga tggttctggt caaatacaga tcataccagg 661 tgcaaaccaa cagattatca caaatcgagg aagtggaggc aacatcattg ctgctatgcc 721 aaacctactc cagcaggctg tccccctcca aggcctggct aataatgtac tctcaggaca 781 gactcagtat gtgaccaatg taccagtggc cctgaatggg aacatcacct tgctacctgt 841 caacagcgtt tctgcagcta ccttgactcc cagctctcag gcagtcacga tcagcagctc 901 tgggtcccag gagagtggct cacagcctgt cacctcaggg actaccatca gttctgccag 961 cttggtatca tcacaagcca gttccagctc ctttttcacc aatgccaata gctactcaac 1021 tactactacc accagcaaca tgggaattat gaactttact accagtggat catcagggac 1081 caactctcaa ggccagacac cccagagggt cagtgggcta caggggtctg atgctctgaa 1141 catccagcaa aaccagacat ctggaggctc attgcaagca ggccagcaaa aagaaggaga 1201 gcaaaaccag cagacacagc agcaacaaat tcttatccag cctcagctag ttcaaggggg 1261 acaggccctc caggccctcc aagcagcacc attgtcaggg cagaccttta caactcaagc 1321 catctcccag gaaaccctcc agaacctcca gcttcaggct gttccaaact ctggtcccat 1381 catcatccgg acaccaacag tggggcccaa tggacaggtc agttggcaga ctctacagct 1441 gcagaacctc caagttcaga acccacaagc ccaaacaatc accttagccc caatgcaggg 1501 tgtttccttg gggcagacca gcagcagcaa caccactctc acacccattg cctcagctgc 1561 ttccattcct gctggcacag tcactgtgaa tgctgctcaa ctctcctcca tgccaggcct 1621 ccagaccatt aacctcagtg cattgggtac ttcaggaatc caggtgcacc caattcaagg 1681 cctgccgttg gctatagcaa atgccccagg tgatcatgga gctcagcttg gtctccatgg 1741 ggctggtggt gatggaatac atgatgacac agcaggtgga gaggaaggag aaaacagccc 1801 agatgcccaa ccccaagccg gtcggaggac ccggcgggaa gcatgcacct gcccctactg 1861 taaagacagt gaaggaaggg gctcggggga tcctggcaaa aagaaacagc atatttgcca 1921 catccaaggc tgtgggaaag tgtatggcaa gacctctcac ctgcgggcac acttgcgctg 1981 gcatacaggc gagaggccat ttatgtgtac ctggtcatac tgtgggaaac gcttcacacg 2041 ttcggatgag ctacagaggc acaaacgtac acacacaggt gagaagaaat ttgcctgccc 2101 tgagtgtcct aagcgcttca tgaggagtga ccacctgtca aaacatatca agacccacca 2161 gaataagaag ggaggcccag gtgtagctct gagtgtgggc actttgcccc tggacagtgg 2221 ggcaggttca gaaggcagtg gcactgccac tccttcagcc cttattacca ccaatatggt 2281 agccatggag gccatctgtc cagagggcat tgcccgtctt gccaacagtg gcatcaacgt 2341 catgcaggtg gcagatctgc agtccattaa tatcagtggc aatggcttct gagatcaggc 2401 acccggggcc agagacatat gggccatacc ccttaacccc gggatgcaag gtagcatggg 2461 tccaagagac atggaagaga gagccatgaa gcattaaaat gcatggtgtt gagaagaatc 2521 aggagaggga tacaagagag gagatggggt cccggcaccc atctgtatca tcagtgcctc 2581 tttgaaggtg ggaaacatta gtgaaaattc tgttggtgcc acgctttgat gagcatttgt 2641 ttgaccccag tttcttctta cacttcttac cccagcctac ccttcctgca tttctcttct 2701 cagctcttcc atgatggatt cccccccctt tcctaaagcc atcatgcctt gataaatata 2761 tatgatcatt gaaatacttt ttaacaaaaa acagattcta tattattata tatatatata 2821 tatatataaa gatatataga gatgcattca caggggttgg ctgggaggag gaagaccatt 2881 ctgtgaccaa aataccttgg tcattttttt tatattgcct tatttcccta tggctgagcc 2941 ttgttgtgac acatcaagct tttctgtaga tgttgtcttg gcttcccacc agcttaagcg 3001 ttcatatgct ctgcttttag ttcatatata catacataat gtttttcctt tcttaatttt 3061 gtctttttgt ttgggatcag cttcttgcac tccttcccta actcaactgt tgccgtctca 3121 tcttctctca tctgatcact tcatgttttg tttttgttac tgcctggatg aggcacttct 3181 gtcaattttt tcaggacctt agttccagca gcagaatgga aaaatccttg aagcccaggc 3241 tgatgcttga agtaactgtg gagggagtgt tcaaaatact actgacgcag gcaccttctt 3301 ggcgctggag agtcaaaggc atctcccttc attagctgct ctgagcatca agaattagaa 3361 gtctttcagt ggaattgtac aagagtccct ttgaagataa taatcttggc tcagtttgta 3421 taaactgtca aattttcaaa taataggtag ggggctttca ctaggaaaat catgtgctca 3481 gaagaggaaa tgactcgtag tcaggttcag gagttagtgg agtatttgga ctttggtact 3541 gctgtcttcc aaggtagctc taagttttga tgtgtgggct tctgagttta tattctgaaa 3601 ggaaatacac ttcttttgaa catccccact aggttctttt ccattgtcaa taaggagcat 3661 cagccagtga atctgtttca ggtttccatt ctgcagaact cctccaaagc atgtgctagt 3721 ggcaagacag tggttcttat gatgttttcc cttaactttt ccttgtatgt tcttgggtgg 3781 ttcctaaggg aaagggaagc acatgatcat gggaatgata gcccagaaca aaaagaaatc 3841 ttgtcttacc acagtgtttt ataggagaga ttgggagaaa tcatcctgtt ttctctgtga 3901 cctgatttca gaagagactg atccaaaaat tataacggca gggaacctag tgcatttggc 3961 actgagattt aaatgcaacc agaattgtcc tcaaggccca gccataaaag cattgtctct 4021 ctcgaccttc tggtatcttg ttagagagct tttcactgtg aggaagtgtg gaaaaatagc 4081 tctgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgta atctgttagg ttggggatag 4141 gttttctgct agccaatatt aaaagagacc tgcaataaaa aaattaccct gatctgatag 4201 aaagcaagtg tttttgtatg tgtgggtgaa tgtgtgttca tgcccgtata tgtctacaca 4261 cagatgacaa attatatttg aaatcgttgg aaaataaatt cagatcaaaa tgcctttcag 4321 gcccattacc tagaaatcta tcttaaaacc tgggtatgtt cctaaggtca tttctttgct 4381 tatgctaaat taattacaat tatgaatgga ggatattcta ctgtactttt ttaaaaagaa 4441 actatttttg tgtttgaaag tgaaaccaac atccagatct atagcagagt ccttattctt 4501 ctcataaatc tttttacttt ggctacaaat agatgatggt atgattctat tatatatttt 4561 atataaaatc catccaaatt aagttttggg taagtgtgtt gtttaatctg aactatagta 4621 acttaatact ctaaacaata gttcactcca tttggtcctt tctccacaga tgtaattatg 4681 ttttcaactc aggaactatg gcaaggaact ttccccagat caaattctat taacgctgag 4741 atacaagtca tccatgcaca gccactatca taccctttat tctcactgaa aggcagaact 4801 cagaacctgt tattttatgt ctgtaatcat gtactttggc atcttttgga ggaaaggggc 4861 aggataactc actggaatgt acagtatttt gctagtgcat ttcaaggaat ggaatcttct 4921 ccagtatgaa attaccagat ataaaataat gtaatgatgc tgaggatata agcttttaga 4981 aggtaatttg atggtatttc tttctcgaat gaaaagctgc tggtttaccc tcaaccctat 5041 tcattagcat taccatgagt gaatttatat ctaattattt ccacttgccc tgttctcttc 5101 acaccaagga agctccagat ccagtatctt gtttggcctc aaaacagaag cagcttcttt 5161 tgtctcccag cagtagtgag ccactcagtc tcttccacag gaagtttgga gcctacattc 5221 cttgagtcag gagcttatta cagaaaaacc ccgtttccct gaacttttgg ctaacagaaa 5281 ttaatttaac tgacatgcat attgattctg aaattttttt cctaagtttt tttcattttt 5341 ttgaatgagt tttttaaatt ttttagatga ccaaaacttg cagggcaggg gatgcccaga 5401 agagtggtga gatagtaaaa cacttattcc ctcatccttt caggttttca ggttgcccat 5461 ttatattcat ttacatgtca tttgactgtc tcacttttta cccagaacag taacaaccca 5521 caccgtcttc cttcagggat ttccaactgg cactctgtgg gtgctacaca gaatgcaatt 5581 taatggatat ttctcagcct ggttcagaat aaattgatcc tttgatccca gaaagtatat 5641 actgaagtgt gggataaaga ttatgattag gggagggttg gagacaaaag ctgtaaatta 5701 ctatggctga tttatttcta ctatatacat atatattttt tgcttttgta tatcctatat 5761 aggaaactaa gcattgtatt ttttttaaca aatctaaaaa agcactatga actacaggtg 5821 tttgactttc aaaatatatt ttgtattgtt aatatcttca cattgtgtga atactggaag 5881 ctgcagatct ttgctaggac gcaataaatt tatatacttt ttgaggggtt cttctggggt 5941 gctaatcagg cccctgttat gcttaggggg agccctggtg ctacttgctt gaagttttca 6001 gtgtaagtac cctgatgcct tttggacctt gggatcagat caagagtttt ggagatcagg 6061 taccaaggaa ataaggacag tctagctgcc tcaagtgagg ggccctttgc atagctctcc 6121 ttccccctca ctgaagctgg gtagcctatt ggggttgaga gggaaaatgt gaaatctcag 6181 aatttatctc ccttagaaga gagccagtaa cttatgtaca aggatgaaag aaaggtcgca 6241 gcagtagctt tggggaaagg gaggaagata tggcacttct ccaaccccgg aaaacattgc 6301 ttttgaaaac tgctgataaa atatgagccg gttattactt ctgtttggga gactgtgctc 6361 tctgtggtgc ctctcttggc tctactccac agataccaga cctcttctaa gaggatgagc 6421 agaccagctt tgaggttgac ctgtttctct ttgtctgcct tcccaaaaca ccagccccca 6481 ggaagacatt aagcagcctt aagcttaaat tcctactccc tcttccaaat ttggctcact 6541 tgccttagat ccaaggcagg gaaaggaaaa gaaggggggt ctctggcttt attactcccc 6601 taagtcttta ctctgacttc cccaaaccca gaaagatttt ctccacagtg ttcatttgaa 6661 agaggagtat tttgtcccat tttccccttc ctcattatca aacagcccca gtcttccttg 6721 tctctgctaa gaaagtagag gcatgatgat ctgcctctca actgccctaa gtcctagcta 6781 agtatcaggg gaaaaaaaaa aaaaaaaagc ctaacaaatg ggattagact agggctgcaa 6841 gtagtgagga ttttgttgat acctctgctg ggatgtgtgc tttcccatat cttgccttca 6901 ggaattacac tgtgcctttt ccccagggat atgggctctg tctacccagt gctccagttt 6961 cccggtaact gctcttgaac attgtggaca agggcaggtc ttcatatttt tgatcatccc 7021 tttctcccag tgaaatccca tagcccttac ctagagtcta gggcacaaag acttcgggga 7081 agatacactg agattgacct gaggagacat ctacacacac cagtggcagc tgccccaggg 7141 cctgcttccc cttcctaagt ctgtcatcct ctggaaggga tgggtggtgc tccaatctct 7201 ggtgcctaaa aacccaagtt tatttctctc ttaacactgg caataaccag tccacaccac 7261 tgttgccttt taaaacctct taataatctc atgctgtgtt tgttttgatt ccaatccaat 7321 tatcaccagg gctgtgtggg taaatgcttt taaatgctct ctcatcttgt tcttccccct 7381 caccccccac tcttaggtat gtatgatgct aatcttgtcc ctaagtaagt ttcttcctgc 7441 tccttttgta tcttcctttc ttgtctttcc tcctaccttt tgtctcttgg tgttttggga 7501 cttttttttt tttttttttg gccttttgta caaagattag tttcaatgta gtctgtagcc 7561 tcctttgtaa accaattaaa aagtttttta ataaaaaaaa aaaaaaaaaa aaaa (SEQ NO: 16? ) .

[0354] An exemplary amino acid sequence encoding SP1 (NP_003100.1" isoform b) comprises or consists of:

MDEMTAWKIEKGVGGNNGGNGNGGGAFSQARSSSTGSSSSTGGGGQESQPSPLALLAATCSRIESPNENSNNSQ GPSQSGGTGELDLTATQLSQGANGWQIISSSSGATPTSKEQSGSSTNGSNGSESSKNRTVSGGQYWAAAPNLQN QQVLTGLPGVMPNIQYQVIPQFQTVDGQQLQFAATGAQVQQDGSGQIQI IPGANQQIITNRGSGGNIIAAMPNLL QQAVPLQGLANNVLSGQTQYVTNVPVALNGNITLLPVNSVSAATLTPSSQAVTISSSGSQESGSQPVTSGTTISS ASLVSSQASSSSFFTNANSYSTTTTTSNMGIMNFTTSGSSGTNSQGQTPQRVSGLQGSDALNIQQNQTSGGSLQA GQQKEGEQNQQTQQQQILIQPQLVQGGQALQALQAAPLSGQTFTTQAISQETLQNLQLQAVPNSGPIIIRTPTVG PNGQVSWQTLQLQNLQVQNPQAQTITLAPMQGVSLGQTSSSNTTLTPIASAASIPAGTVTVNAAQLSSMPGLQTI NLSALGTSGIQVHPIQGLPLAIANAPGDHGAQLGLHGAGGDGIHDDTAGGEEGENSPDAQPQAGRRTRREACTCP YCKDSEGRGSGDPGKKKQHICHIQGCGKVYGKTSHLRAHLRWHTGERPFMCTWSYCGKRFTRSDELQRHKRTHTG EKKFACPECPKRFMRSDHLSKHIKTHQNKKGGPGVALSVGTLPLDSGAGSEGSGTATPSALITTNMVAMEAICPE GIARLANSGINVMQVADLQSINISGNGF (SEQ ID NO: 169) . [0355] An exemplary nucleic acid sequence encoding SP 1 (FN908228.1 splice variant c) comprises or consists of:

1 atgagcgacc aagatcactc catggatgaa atgacagctg tggtgaaaat tgaaaaagga

6 1 gttggtggca ataatggggg caatggtaat ggtggtggtg ccttttcaca ggctcgaagt 12 1 agcagcacag gcagtagcag cagcactgga ggaggagggc agggtgccaa tggctggcag 18 1 atcatctctt cctcctctgg ggctacccct acctcaaagg aacagagtgg cagcagtacc 24 1 aatggcagca atggcagtga gtcttccaag aatcgcacag tctctggtgg gcagtatgtt 30 1 gtggctgccg ctcccaactt acagaaccag caagttctga caggactacc tggagtgatg 36 1 cctaatattc agtatcaagt aatcccacag ttccagaccg ttgatgggca acagctgcag 42 1 tttgctgcca ctggggccca agtgcagcag gatggttctg gtcaaataca gatcatacca 48 1 ggtgcaaacc aacagattat cacaaatcga ggaagtggag gcaacatcat tgctgctatg 54 1 ccaaacctac tccagcaggc tgtccccctc caaggcctgg ctaataatgt actctcagga 60 1 cagactcagt atgtgaccaa tgtaccagtg gccctgaatg ggaacatcac cttgctacct 66 1 gtcaacagcg tttctgcagc taccttgact cccagctctc aggcagtcac gatcagcagc 72 1 tctgggtccc aggagagtgg ctcacagcct gtcacctcag ggactaccat cagttctgcc 78 1 agcttggtat catcacaagc cagttccagc tcctttttca ccaatgccaa tagctactca 84 1 actactacta ccaccagcaa catgggaatt atgaacttta ctaccagtgg atcatcaggg 90 1 accaactctc aaggccagac accccagagg gtcagtgggc tacaggggtc tgatgctctg 96 1 aacatccagc aaaaccagac atctggaggc tcattgcaag caggccagca aaaagaagga 102 1 gagcaaaacc agcagacaca gcagcaacaa attcttatcc agcctcagct agttcaaggg 108 1 ggacaggccc tccaggccct ccaagcagca ccattgtcag ggcagacctt tacaactcaa 114 1 gccatctccc aggaaaccct ccagaacctc cagcttcagg ctgttccaaa ctctggtccc 120 1 atcatcatcc ggacaccaac agtggggccc aatggacagg tcagttggca gactctacag 126 1 ctgcagaacc tccaagttca gaacccacaa gcccaaacaa tcaccttagc cccaatgcag 132 1 ggtgtttcct tggggcagac cagcagcagc aacaccactc tcacacccat tgcctcagct 13 1 gcttccattc ctgctggcac agtcactgtg aatgctgctc aactctcctc catgccaggc 144 1 ctccagacca ttaacctcag tgcattgggt acttcaggaa tccaggtgca cccaattcaa 150 1 ggcctgccgt tggctatagc aaatgcccca ggtgatcatg gagctcagct tggtctccat 156 1 ggggctggtg gtgatggaat acatgatgac acagcaggtg gagaggaagg agaaaacagc 162 1 ccagatgccc aaccccaagc cggtcggagg acccggcggg aagcatgcac ctgcccctac 168 1 tgtaaagaca gtgaaggaag gggctcgggg gatcctggca aaaagaaaca gcatatttgc 174 1 cacatccaag gctgtgggaa agtgtatggc aagacctctc acctgcgggc acacttgcgc 180 1 tggcatacag gcgagaggcc atttatgtgt acctggtcat actgtgggaa acgcttcaca 186 1 cgttcggatg agctacagag gcacaaacgt acacacacag gtgagaagaa atttgcctgc 192 1 cctgagtgtc ctaagcgctt catgaggagt gaccacctgt caaaacatat caagacccac 198 1 cagaataaga agggaggccc aggtgtagct ctgagtgtgg gcactttgcc cctggacagt 204 1 ggggcaggtt cagaaggcag tggcactgcc actccttcag cccttattac caccaatatg 210 1 gtagccatgg aggccatctg tccagagggc attgcccgtc ttgccaacag tggcatcaac 216 1 gtcatgcagg tggcagatct gcagtccatt aatatcagtg gcaatggctt ctga (SEQ NO: 170) .

[0356] An exemplary amino acid sequence encoding SP1 (CBM42955.1 , splice variant c protein) comprises or consists of:

MSDQDHSMDEMTAWKIEKGVGGNNGGNGNGGGAFSQARSSSTGSSSSTGGGGQGANGWQIISSSSGATPTSKEQ SGSSTNGSNGSESSKNRTVSGGQYWAAAPNLQNQQVLTGLPGVMPNIQYQVIPQFQTVDGQQLQFAATGAQVQQ DGSGQIQI IPGANQQI ITNRGSGGNI IAAMPNLLQQAVPLQGLANNVLSGQTQYVTNVPVALNGNITLLPVNSVS AATLTPSSQAVTISSSGSQESGSQPVTSGTTISSASLVSSQASSSSFFTNANSYSTTTTTSNMGIMNFTTSGSSG TNSQGQTPQRVSGLQGSDALNIQQNQTSGGSLQAGQQKEGEQNQQTQQQQILIQPQLVQGGQALQALQAAPLSGQ TFTTQAISQETLQNLQLQAVPNSGPI IIRTPTVGPNGQVSWQTLQLQNLQVQNPQAQTITLAPMQGVSLGQTSSS NTTLTPIASAASIPAGTVTVNAAQLSSMPGLQTINLSALGTSGIQVHPIQGLPLAIANAPGDHGAQLGLHGAGGD GIHDDTAGGEEGENSPDAQPQAGRRTRREACTCPYCKDSEGRGSGDPGKKKQHICHIQGCGKVYGKTSHLRAHLR WHTGERPFMCTWSYCGKRFTRSDELQRHKRTHTGEKKFACPECPKRFMRSDHLSKHIKTHQNKKGGPGVALSVGT LPLDSGAGSEGSGTATPSALITTNMVAMEAICPEGIARLANSGINVMQVADLQSINISGNGF (SEQ ID NO: 171) .

[0357] An exemplary nucleic acid sequence encoding SPl (NM_001251825.1 transcript variant 3) comprises or consists of:

1 gtccgggttc gcttgcctcg tcagcgtccg cgtttttccc ggcccccccc aacccccccg 61 gacaggaccc ccttgagctt gtccctcagc tgccaccatg agcgaccaag atcactccat 121 ggatgaaatg acagctgtgg tgaaaattga aaaaggagtt ggtggcaata atgggggcaa 181 tggtaatggt ggtggtgcct tttcacaggc tcgaagtagc agcacaggca gtagcagcag 241 cactggagga ggagggcagg gtgccaatgg ctggcagatc atctcttcct cctctggggc 301 tacccctacc tcaaaggaac agagtggcag cagtaccaat ggcagcaatg gcagtgagtc 361 ttccaagaat cgcacagtct ctggtgggca gtatgttgtg gctgccgctc ccaacttaca 421 gaaccagcaa gttctgacag gactacctgg agtgatgcct aatattcagt atcaagtaat 481 cccacagttc cagaccgttg atgggcaaca gctgcagttt gctgccactg gggcccaagt 541 gcagcaggat ggttctggtc aaatacagat cataccaggt gcaaaccaac agattatcac 601 aaatcgagga agtggaggca acatcattgc tgctatgcca aacctactcc agcaggctgt 661 ccccctccaa ggcctggcta ataatgtact ctcaggacag actcagtatg tgaccaatgt 721 accagtggcc ctgaatggga acatcacctt gctacctgtc aacagcgttt ctgcagctac 781 cttgactccc agctctcagg cagtcacgat cagcagctct gggtcccagg agagtggctc 841 acagcctgtc acctcaggga ctaccatcag ttctgccagc ttggtatcat cacaagccag 901 ttccagctcc tttttcacca atgccaatag ctactcaact actactacca ccagcaacat 961 gggaattatg aactttacta ccagtggatc atcagggacc aactctcaag gccagacacc 1021 ccagagggtc agtgggctac aggggtctga tgctctgaac atccagcaaa accagacatc 1081 tggaggctca ttgcaagcag gccagcaaaa agaaggagag caaaaccagc agacacagca 1141 gcaacaaatt cttatccagc ctcagctagt tcaaggggga caggccctcc aggccctcca 1201 agcagcacca ttgtcagggc agacctttac aactcaagcc atctcccagg aaaccctcca 1261 gaacctccag cttcaggctg ttccaaactc tggtcccatc atcatccgga caccaacagt 1321 ggggcccaat ggacaggtca gttggcagac tctacagctg cagaacctcc aagttcagaa 1381 cccacaagcc caaacaatca ccttagcccc aatgcagggt gtttccttgg ggcagaccag 1441 cagcagcaac accactctca cacccattgc ctcagctgct tccattcctg ctggcacagt 1501 cactgtgaat gctgctcaac tctcctccat gccaggcctc cagaccatta acctcagtgc 1561 attgggtact tcaggaatcc aggtgcaccc aattcaaggc ctgccgttgg ctatagcaaa 1621 tgccccaggt gatcatggag ctcagcttgg tctccatggg gctggtggtg atggaataca 1681 tgatgacaca gcaggtggag aggaaggaga aaacagccca gatgcccaac cccaagccgg 1741 tcggaggacc cggcgggaag catgcacctg cccctactgt aaagacagtg aaggaagggg 1801 ctcgggggat cctggcaaaa agaaacagca tatttgccac atccaaggct gtgggaaagt 1861 gtatggcaag acctctcacc tgcgggcaca cttgcgctgg catacaggcg agaggccatt 1921 tatgtgtacc tggtcatact gtgggaaacg cttcacacgt tcggatgagc tacagaggca 1981 caaacgtaca cacacaggtg agaagaaatt tgcctgccct gagtgtccta agcgcttcat 2041 gaggagtgac cacctgtcaa aacatatcaa gacccaccag aataagaagg gaggcccagg 2101 tgtagctctg agtgtgggca ctttgcccct ggacagtggg gcaggttcag aaggcagtgg 2161 cactgccact ccttcagccc ttattaccac caatatggta gccatggagg ccatctgtcc 2221 agagggcatt gcccgtcttg ccaacagtgg catcaacgtc atgcaggtgg cagatctgca 2281 gtccattaat atcagtggca atggcttctg agatcaggca cccggggcca gagacatatg 2341 ggccataccc cttaaccccg ggatgcaagg tagcatgggt ccaagagaca tggaagagag 2401 agccatgaag cattaaaatg catggtgttg agaagaatca ggagagggat acaagagagg 2461 agatggggtc ccggcaccca tctgtatcat cagtgcctct ttgaaggtgg gaaacattag 2521 tgaaaattct gttggtgcca cgctttgatg agcatttgtt tgaccccagt ttcttcttac 2581 acttcttacc ccagcctacc cttcctgcat ttctcttctc agctcttcca tgatggattc 2641 cccccccttt cctaaagcca tcatgccttg ataaatatat atgatcattg aaatactttt 2701 taacaaaaaa cagattctat attattatat atatatatat atatataaag atatatagag 2761 atgcattcac aggggttggc tgggaggagg aagaccattc tgtgaccaaa ataccttggt 2821 catttttttt atattgcctt atttccctat ggctgagcct tgttgtgaca catcaagctt 2881 ttctgtagat gttgtcttgg cttcccacca gcttaagcgt tcatatgctc tgcttttagt 2941 tcatatatac atacataatg tttttccttt cttaattttg tctttttgtt tgggatcagc 3001 ttcttgcact ccttccctaa ctcaactgtt gccgtctcat cttctctcat ctgatcactt 3061 catgttttgt ttttgttact gcctggatga ggcacttctg tcaatttttt caggacctta 3121 gttccagcag cagaatggaa aaatccttga agcccaggct gatgcttgaa gtaactgtgg 3181 agggagtgtt caaaatacta ctgacgcagg caccttcttg gcgctggaga gtcaaaggca 3241 tctcccttca ttagctgctc tgagcatcaa gaattagaag tctttcagtg gaattgtaca 3301 agagtccctt tgaagataat aatcttggct cagtttgtat aaactgtcaa attttcaaat 3361 aataggtagg gggctttcac taggaaaatc atgtgctcag aagaggaaat gactcgtagt 3421 caggttcagg agttagtgga gtatttggac tttggtactg ctgtcttcca aggtagctct 3481 aagttttgat gtgtgggctt ctgagtttat attctgaaag gaaatacact tcttttgaac 3541 atccccacta ggttcttttc cattgtcaat aaggagcatc agccagtgaa tctgtttcag 3601 gtttccattc tgcagaactc ctccaaagca tgtgctagtg gcaagacagt ggttcttatg 3661 atgttttccc ttaacttttc cttgtatgtt cttgggtggt tcctaaggga aagggaagca 3721 catgatcatg ggaatgatag cccagaacaa aaagaaatct tgtcttacca cagtgtttta 3781 taggagagat tgggagaaat catcctgttt tctctgtgac ctgatttcag aagagactga 3841 tccaaaaatt ataacggcag ggaacctagt gcatttggca ctgagattta aatgcaacca 3901 gaattgtcct caaggcccag ccataaaagc attgtctctc tcgaccttct ggtatcttgt 3961 tagagagctt ttcactgtga ggaagtgtgg aaaaatagct ctgtgtgtgt gtgtgtgtgt 4021 gtgtgtgtgt gtgtgtgtaa tctgttaggt tggggatagg ttttctgcta gccaatatta 4081 aaagagacct gcaataaaaa aattaccctg atctgataga aagcaagtgt ttttgtatgt 4141 gtgggtgaat gtgtgttcat gcccgtatat gtctacacac agatgacaaa ttatatttga 4201 aatcgttgga aaataaattc agatcaaaat gcctttcagg cccattacct agaaatctat 4261 cttaaaacct gggtatgttc ctaaggtcat ttctttgctt atgctaaatt aattacaatt 4321 atgaatggag gatattctac tgtacttttt taaaaagaaa ctatttttgt gtttgaaagt 4381 gaaaccaaca tccagatcta tagcagagtc cttattcttc tcataaatct ttttactttg 4441 gctacaaata gatgatggta tgattctatt atatatttta tataaaatcc atccaaatta 4501 agttttgggt aagtgtgttg tttaatctga actatagtaa cttaatactc taaacaatag 4561 ttcactccat ttggtccttt ctccacagat gtaattatgt tttcaactca ggaactatgg 4621 caaggaactt tccccagatc aaattctatt aacgctgaga tacaagtcat ccatgcacag 4681 ccactatcat accctttatt ctcactgaaa ggcagaactc agaacctgtt attttatgtc 4741 tgtaatcatg tactttggca tcttttggag gaaaggggca ggataactca ctggaatgta 4801 cagtattttg ctagtgcatt tcaaggaatg gaatcttctc cagtatgaaa ttaccagata 4861 taaaataatg taatgatgct gaggatataa gcttttagaa ggtaatttga tggtatttct 4921 ttctcgaatg aaaagctgct ggtttaccct caaccctatt cattagcatt accatgagtg 4981 aatttatatc taattatttc cacttgccct gttctcttca caccaaggaa gctccagatc 5041 cagtatcttg tttggcctca aaacagaagc agcttctttt gtctcccagc agtagtgagc 5101 cactcagtct cttccacagg aagtttggag cctacattcc ttgagtcagg agcttattac 5161 agaaaaaccc cgtttccctg aacttttggc taacagaaat taatttaact gacatgcata 5221 ttgattctga aatttttttc ctaagttttt ttcatttttt tgaatgagtt ttttaaattt 5281 tttagatgac caaaacttgc agggcagggg atgcccagaa gagtggtgag atagtaaaac 5341 acttattccc tcatcctttc aggttttcag gttgcccatt tatattcatt tacatgtcat 5401 ttgactgtct cactttttac ccagaacagt aacaacccac accgtcttcc ttcagggatt 5461 tccaactggc actctgtggg tgctacacag aatgcaattt aatggatatt tctcagcctg 5521 gttcagaata aattgatcct ttgatcccag aaagtatata ctgaagtgtg ggataaagat 5581 tatgattagg ggagggttgg agacaaaagc tgtaaattac tatggctgat ttatttctac 5641 tatatacata tatatttttt gcttttgtat atcctatata ggaaactaag cattgtattt 5701 tttttaacaa atctaaaaaa gcactatgaa ctacaggtgt ttgactttca aaatatattt 5761 tgtattgtta atatcttcac attgtgtgaa tactggaagc tgcagatctt tgctaggacg 5821 caataaattt atatactttt tgaggggttc ttctggggtg ctaatcaggc ccctgttatg 5881 cttaggggga gccctggtgc tacttgcttg aagttttcag tgtaagtacc ctgatgcctt 5941 ttggaccttg ggatcagatc aagagttttg gagatcaggt accaaggaaa taaggacagt 6001 ctagctgcct caagtgaggg gccctttgca tagctctcct tccccctcac tgaagctggg 6061 tagcctattg gggttgagag ggaaaatgtg aaatctcaga atttatctcc cttagaagag 6121 agccagtaac ttatgtacaa ggatgaaaga aaggtcgcag cagtagcttt ggggaaaggg 6181 aggaagatat ggcacttctc caaccccgga aaacattgct tttgaaaact gctgataaaa 6241 tatgagccgg ttattacttc tgtttgggag actgtgctct ctgtggtgcc tctcttggct 6301 ctactccaca gataccagac ctcttctaag aggatgagca gaccagcttt gaggttgacc 6361 tgtttctctt tgtctgcctt cccaaaacac cagcccccag gaagacatta agcagcctta 6421 agcttaaatt cctactccct cttccaaatt tggctcactt gccttagatc caaggcaggg 6481 aaaggaaaag aaggggggtc tctggcttta ttactcccct aagtctttac tctgacttcc 6541 ccaaacccag aaagattttc tccacagtgt tcatttgaaa gaggagtatt ttgtcccatt 6601 ttccccttcc tcattatcaa acagccccag tcttccttgt ctctgctaag aaagtagagg 6661 catgatgatc tgcctctcaa ctgccctaag tcctagctaa gtatcagggg aaaaaaaaaa 6721 aaaaaaagcc taacaaatgg gattagacta gggctgcaag tagtgaggat tttgttgata 6781 cctctgctgg gatgtgtgct ttcccatatc ttgccttcag gaattacact gtgccttttc 6841 cccagggata tgggctctgt ctacccagtg ctccagtttc ccggtaactg ctcttgaaca 6901 ttgtggacaa gggcaggtct tcatattttt gatcatccct ttctcccagt gaaatcccat 6961 agcccttacc tagagtctag ggcacaaaga cttcggggaa gatacactga gattgacctg 7021 aggagacatc tacacacacc agtggcagct gccccagggc ctgcttcccc ttcctaagtc 7081 tgtcatcctc tggaagggat gggtggtgct ccaatctctg gtgcctaaaa acccaagttt 7141 atttctctct taacactggc aataaccagt ccacaccact gttgcctttt aaaacctctt 7201 aataatctca tgctgtgttt gttttgattc caatccaatt atcaccaggg ctgtgtgggt 7261 aaatgctttt aaatgctctc tcatcttgtt cttccccctc accccccact cttaggtatg 7321 tatgatgcta atcttgtccc taagtaagtt tcttcctgct ccttttgtat cttcctttct 7381 tgtctttcct cctacctttt gtctcttggt gttttgggac tttttttttt ttttttttgg 7441 ccttttgtac aaagattagt ttcaatgtag tctgtagcct cctttgtaaa ccaattaaaa 7501 agttttttaa taaaaaaaaa aaa (SEQ ID NO: 172) .

[0358] An exemplary amino acid sequence encoding SP1 (NP 001238754.1 , isoform c ) comprises or consists of:

MSDQDHSMDEMTAWKIEKGVGGNNGGNGNGGGAFSQARSSSTGSSSSTGGGGQGANGWQIISSSSGATPTSKEQ

SGSSTNGSNGSESSKNRTVSGGQYWAAAPNLQNQQVLTGLPGVMPNIQYQVIPQFQTVDGQQLQFAATGAQVQQ

DGSGQIQI IPGANQQI ITNRGSGGNI IAAMPNLLQQAVPLQGLANNVLSGQTQYVTNVPVALNGNITLLPVNSVS

AATLTPSSQAVTISSSGSQESGSQPVTSGTTISSASLVSSQASSSSFFTNANSYSTTTTTSNMGIMNFTTSGSSG

TNSQGQTPQRVSGLQGSDALNIQQNQTSGGSLQAGQQKEGEQNQQTQQQQILIQPQLVQGGQALQALQAAPLSGQ

TFTTQAISQETLQNLQLQAVPNSGPI IIRTPTVGPNGQVSWQTLQLQNLQVQNPQAQTITLAPMQGVSLGQTSSS

NTTLTPIASAASIPAGTVTVNAAQLSSMPGLQTINLSALGTSGIQVHPIQGLPLAIANAPGDHGAQLGLHGAGGD

GIHDDTAGGEEGENSPDAQPQAGRRTRREACTCPYCKDSEGRGSGDPGKKKQHICHIQGCGKVYGKTSHLRAHLR

WHTGERPFMCTWSYCGKRFTRSDELQRHKRTHTGEKKFACPECPKRFMRSDHLSKHIKTHQNKKGGPGVALSVGT

LPLDSGAGSEGSGTATPSALITTNMVAMEAICPEGIARLANSGINVMQVADLQSINISGNGF (SEQ ID NO:

173) .

[0359] An exemplary nucleic acid sequence encoding TYRP1 (NM_000550.2 mRNA) comprises or consists of:

1 acagttctga cgtgagagga caagaaacac aagcaaatat aaaacattca attctaagag 61 aagttcatca gagacatcct tcaggattgt gagctggatt ttcctctacg tgcttcagtc 121 ttctctacac aaagagctgc aaaccaggtc tttgttttgc actcttattt caagcagaat 181 gagtgctcct aaactcctct ctctgggctg tatcttcttc cccttgctac tttttcagca 241 ggcccgggct caattcccaa gacagtgtgc cactgttgag gctttgagaa gtggtatgtg 301 ttgcccagac ctgtcccctg tgtctgggcc tgggacagac cgctgtggct catcatcagg 361 gaggggcaga tgtgaggcag tgactgcaga ctcccggccc cacagccctc agtatcccca 421 tgatggcaga gatgatcggg aggtctggcc cttgcgcttc ttcaatagga catgtcactg 481 caacggcaat ttctcaggac acaactgtgg gacgtgccgt cctggctgga gaggagctgc 541 ctgtgaccag agggttctca tagtcaggag aaatcttctg gacttaagta aagaagaaaa 601 gaaccacttt gtccgggccc tggatatggc aaagcgcaca actcaccctt tatttgtcat 661 tgccaccagg agatcagaag aaatactggg gccagatggc aacacgccac aatttgagaa 721 catttccatt tataactact ttgtttggac acactattac tcagtcaaaa agactttcct 781 tggggtagga caggaaagct ttggtgaagt ggatttctct catgagggac cagcttttct 841 cacatggcac aggtaccacc tcctgcgtct ggagaaagac atgcaggaaa tgttgcaaga 901 gccttctttc tcccttcctt actggaattt tgcaacgggg aaaaatgtct gtgatatctg 961 cacggatgac ttgatgggat ccagaagcaa ctttgattcc actctaataa gcccaaactc 1021 tgtcttttct caatggcgag tggtctgtga ctccttggaa gattatgata ccctgggaac 1081 actttgtaac agcaccgagg atgggccaat taggagaaat ccagctggaa atgtggccag 1141 accaatggtg caacgtcttc ctgaaccaca ggatgtcgct cagtgcttgg aagttggttt 1201 atttgacacg cctccttttt attccaactc tacaaacagt ttccgaaaca cagtggaagg 1261 ttacagtgac cccacgggaa agtatgaccc tgctgttcga agtcttcaca atttggctca 132 tctattcctg aatggaacag ggggacaaac ccatttgtct ccaaatgatc ctatttttgt 13 cctcctgcac accttcacag atgcagtctt tgatgaatgg ctgaggagat acaatgctga 144 tatatccaca tttccattgg aaaatgcccc tattggacat aatagacaat acaacatggt 150 gccattctgg cccccagtca ccaacacaga aatgtttgtt actgctccag acaacctggg 156 atacacttat gaaattcaat ggccaagtcg ggagtttagt gtacctgaga taattgccat 162 agcagtagtt ggcgctttgt tactggttgc actcattttt gggactgctt cttatctgat 16 tcgtgccaga cgcagtatgg atgaagctaa ccagcctctc ctcactgatc agtatcaatg 174 ctatgctgaa gaatatgaaa aactccagaa tcctaatcag tctgtggtct aacaaatgcc 180 ctactctctt atgcattagt atcacaaaac cacctggttg aatataatag attgagttat 186 taactgtatt ttctttcact ttattacctt ctttctaata caagcatatg ttagcattaa 192 agttctaggc atacttttca aagctgggaa gaccctttca gaatcttttc aatgggtttt 19 aattttcagt tctatttaaa atggtgaatg acactaaact ccatgatatt taaggatagt 204 gtgaagatct ttggcatgat ttaaaggttg agtatgtgaa gatataagta agtgaactac 210 catgctttgt ttacgtgtaa aggaaaataa tgtttgatag taaatgtcca cttaaaatac 216 atgaatgggc atttctaaaa tgttaaaaca taaacacatt tccattcatg gatatttgtc 222 aacagattta aagaaaacca cagttattaa ttaaagaaaa ttaattatgt gtagttataa 22 81 accaatgaaa ttttgattaa ccttttcaaa ttaatgttcc agtttgaaga ccaatcaaat 234 atattattta gtcaacatat actatttagt ctcaggttca aggctacaac aaaaatcacc 240 atctttgtca aactttggag agggaaaatc ttcactttct taagcaacaa tggatattgc 246 ctgtgtttgc cactgtgttt ccctgcctct caattcgctg aaaaaggaac tacctatcct 252 tacatttcac ctactaatgt ctcttctaac atcttagagg tccatggaga aggcatatgg 25 81 agaacatgtt ttatactgct ctataaatag tattccaatc actgtgctta atttaaatag 264 cattatctta tcatttatca gccttttatg tattttccaa gtaaaatatt aacatattat 270 ttcattggtc ttctttttta tctggttcta tatgaatgct attttttccc ttctcttcta 276 acatgaaata tattttctct ttttgatctt gtgctatgaa acaatcttcc aaagaactgt 2821 ataaggtggt cataagtgaa tattttaatt aaaattggta aaaataaata ataaca (SEQ ID NO: 174) .

[0360] An exemplary amino acid sequence encoding TYRP1 (NP 000541.1) comprises or consists of:

MSAPKLLSLGCIFFPLLLFQQARAQFPRQCATVEALRSGMCCPDLSPVSGPGTDRCGSSSGRGRCEAVTADSRPH SPQYPHDGRDDREVWPLRFFNRTCHCNGNFSGHNCGTCRPGWRGAACDQRVLIVRRNLLDLSKEEKNHFVRALDM AKRTTHPLFVIATRRSEEILGPDGNTPQFENISIYNYFVWTHYYSVKKTFLGVGQESFGEVDFSHEGPAFLTWHR YHLLRLEKDMQEMLQEPSFSLPYWNFATGKNVCDICTDDLMGSRSNFDSTLISPNSVFSQWRWCDSLEDYDTLG TLCNSTEDGPIRRNPAGNVARPMVQRLPEPQDVAQCLEVGLFDTPPFYSNSTNSFRNTVEGYSDPTGKYDPAVRS LHNLAHLFLNGTGGQTHLSPNDPIFVLLHTFTDAVFDEWLRRYNADISTFPLENAPIGHNRQYNMVPFWPPVTNT EMFVTAPDNLGYTYEIQWPSREFSVPEI IAIAWGALLLVALIFGTASYLIRARRSMDEANQPLLTDQYQCYAEE YEKLQNPNQSW (SEQ ID NO: 175) .

[0361] An exemplary nucleic acid sequence encoding TYRP1 (L38952.1 , 5 ' end of cds) comprises or consists of:

1 aagctttatt tttatcattg ttaaaaaaat ccttcttttg agtaacacaa tcacaaagta 61 aagaatgtta tcattgattt aaccagtaaa aaaacaatac ttaacaataa aatttttcaa 121 acatggctcc aggcatccag atgacttagt tatcctcctt tgatgccctt ctcttcttcg 181 aatgaatcac aatgaggcag aaaaattttc atgggtgcag agtaggtgta tatatttatg 241 gagtatgtga gatattttga tacaggcata caacatgaaa taagcacatc atggagaatg 301 gggtattcat acctcaagca tttatccttt gagttacaaa caatccaata acacttttta 361 agttatttaa aaatatacag ttatgattga ctatagtcac cctattgtgc tatcaaacag 421 taggtcttat tcattcttgc taattttttt gtacctattg actatcccta cttccctact 481 cccctcagac acccactacc tttcccagcc tccattcttc tactctttat gtccataagt 541 tcaattgttt tgaggtttag attccacaaa taagtgagaa taagtgatgt ttgtctttct 601 gtgcctggct tatttcactt aacagaatgt ctagttccat ccatgttggt gcaaatgact 661 ggatctcatt gttttactgc attttgcata tgtaccatat tttcttaatc cattcatcta 721 ttgatgaaca cttaggttgc ttccaaattt tagctttgta aacagtgctg caataaacat 781 aggagtgcag atatctcttc aatatattga tttcctttct tttgggtata tactagcagt 841 gggattgctg gatcatatat gtggctcaat tttagttttt gaggaactca aactttgctc 901 catagtggtt gtactaattt acattactac caacgctgta tgagggtttc cttttctcca 961 catccttgtc aacatttctt attgcctgaa ttttggacat aagccatttt aattggggta 1021 agagggtatc tcacaatagt tttgatttgt acttctctaa tgatcaataa tgttgagtat 1081 cttttcataa gtctgtttgc catttgtatg tcttcttttg ataaatgtct gctcaaatat 1141 tttgcccatt tttttattgg attattaatt tttttctata gaattttttg agcttctcat 1201 atattctgga tattaatccc ttgtcaaatg ggtagtttac aaatatctta tcccattctg 1261 tgggttgtct cttcacttca ttgattgtac tctttgctgt gcagaagatt tttaactaga 1321 tgtgatccca tttgttcatt tttgctttgg ctacctgtgc ttgtgtggta ttgctcaaga 1381 aatctttgtc aagaccaatg tcctcaagat tttcctcaat gtttcttcat tgtagtttca 1441 tagtttgagg tctcagattt aaatatttaa tcaaatcatt ttttatttga ttgttgtata 1501 tggaacgaga tagggaccta atttcattct tttgcatatg ggtatgtagt ttgccagcac 1561 catttattaa aaagactgtc ttttccccag tgtatgttct tggtatcttg gtgaaaaatg 1621 tctttactgt aggtgtgtga ttttgttttt gggttctcct gttccattgc tctatgtgtc 1681 tgtttttagg ccagtaccat gctgtttttg ctactatcac tccgtagtat aatttgaagt 1741 aaagtaatat gattcctcca gttttgttat ttttgcttag gagaactttg cctcttcaag 1801 gtttggtgtt ccatataaat tttaggattt tctttctgtt tctgtgaaga atgtctttgg 1861 tattttgata ggaattgcat tgaatctgta gattgcttta ggtaatacgg actttttaac 1921 aatcttgatt ctcccaatcc atgaacatat aatatttttc cattatttgg tgtcttcttc 1981 aatttctttc atcaatgttt tgtacttatc attatagaga cctttcattc attggttaat 2041 tcctaggtat ttaattttat gtgtggctat tgtaatggga ttactttttt atttcttttt 2101 cacatttttc actgttggta tatggaaact ttgctgattt tggtatgctg attttgtatc 2161 ctgcaacttt actgaatttg tttgtcagct ctaatagttt tttagaggag tctttaggtt 2221 ttattcaaat ataagatctt atcatcagca aacaaggata atttgacttc ttcatttcca 2281 atttggatgc tctttatacc ttctcttgcc tggttgctct agcaaggtaa tatgttgaat 2341 aacagttgaa taacagaata aaaaaaaatc tctgcaaagt aaacaaatct cactagttta 2401 tctgacttgt attccaaatt agtgcttctg gccttttctt aaaactttaa gcatcacaag 2461 gaaatcagtt ggaagggaat catgtgctga tcaagtcctt aaagggcaga aatattcact 2521 gaagtgaaaa ggattagtaa agggtggaaa aaaagaccag ccccccgcct agtttgggtg 2581 agcagatttg ggattaatta tcaggcagca atccacatgc acttaacagt tctgacgtga 2641 gaggacaaga aacacaagca aatataaaac attcaattct aagagaagtt catcagagac 2701 atccttcagg attgtgaggt actggaaaga agtcctatgg ggagtgggtg gacacgtgcc 2761 aaaactccat tagtgtaagg gactttaaat cacagaaatt aacttgctgg aaatctgttc 2821 ccaattcttc cttcagctcc aaggttaaat taaatgtaat taatgatggt gacctgctaa 2881 ttcatgcttt tgataactga tatctagtat gtatatatat ataaacaaaa tgacgaggac 2941 agggaattta attatttggg tatcacacat gcaggtgtta tatatgccaa attttaaagg 3001 taaattacta cttttattat ttgtgtgaaa tgtcatttta catatgggtt ccattttgaa 3061 agtggtttgg gaagggggca taccatttta agtaccaaga aaaacttgca taatctcatt 3121 ttactttctc tttttcagct ggattttcct ctacgtgctt cagtcttctc tacacaaaga 3181 gctgcaaacc aggtctttgt tttgcactct tatttcaagc agaatgagtg ctcctaaact 3241 cctctctctg ggctgtatct tcttcccctt gctacttttt cagcaggccc gggctcaatt 3301 cccaagacag tgtgccactg ttgaggcttt gagaagtggt atgtgttgcc cagacctgtc 3361 ccctgtgtct gggcctggga cagaccgctg tggctcatca tcagggaggg gcagatgtga 3421 ggcagtgact gcagactccc ggccccacag ccctcagtat ccccatgatg gcagagatga 3481 tcgggaggtc tggcccttgc gcttcttcaa taggacatgt cactgcaacg gcaatttctc 3541 aggacacaac tgtgggacgt gccgtcctgg ctggagagga gctgcctgtg accagagggt 3601 tctcataggt aagtggag (SEQ ID NO: 176) .

[0362] An exemplary nucleic acid sequence encoding TYRPl (L33830.1 , dinucleotide repeat region) comprises or consists of:

1 ggcctttata cgttccagag taagtagcat atggtgtgtg catgcatgtt tctctctctc 61 tctctctctc tcattctgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtcagtg 121 gagagagaga gagacgaaga aaagggagga gtgataatcc (SEQ ID NO: 177) .

[0363] An exemplary nucleic acid sequence encoding VEGFC (NM_005429.4 mRNA) comprises or consists of: 1 acttcgggga aggggaggga ggagggggac gagggctctg gcgggtttgg aggggctgaa 61 catcgcgggg tgttctggtg tcccccgccc cgcctctcca aaaagctaca ccgacgcgga 121 ccgcggcggc gtcctccctc gccctcgctt cacctcgcgg gctccgaatg cggggagctc 181 ggatgtccgg tttcctgtga ggcttttacc tgacacccgc cgcctttccc cggcactggc 241 tgggagggcg ccctgcaaag ttgggaacgc ggagccccgg acccgctccc gccgcctccg 301 gctcgcccag ggggggtcgc cgggaggagc ccgggggaga gggaccagga ggggcccgcg 361 gcctcgcagg ggcgcccgcg cccccacccc tgcccccgcc agcggaccgg tcccccaccc 421 ccggtccttc caccatgcac ttgctgggct tcttctctgt ggcgtgttct ctgctcgccg 481 ctgcgctgct cccgggtcct cgcgaggcgc ccgccgccgc cgccgccttc gagtccggac 541 tcgacctctc ggacgcggag cccgacgcgg gcgaggccac ggcttatgca agcaaagatc 601 tggaggagca gttacggtct gtgtccagtg tagatgaact catgactgta ctctacccag 661 aatattggaa aatgtacaag tgtcagctaa ggaaaggagg ctggcaacat aacagagaac 721 aggccaacct caactcaagg acagaagaga ctataaaatt tgctgcagca cattataata 781 cagagatctt gaaaagtatt gataatgagt ggagaaagac tcaatgcatg ccacgggagg 841 tgtgtataga tgtggggaag gagtttggag tcgcgacaaa caccttcttt aaacctccat 901 gtgtgtccgt ctacagatgt gggggttgct gcaatagtga ggggctgcag tgcatgaaca 961 ccagcacgag ctacctcagc aagacgttat ttgaaattac agtgcctctc tctcaaggcc 1021 ccaaaccagt aacaatcagt tttgccaatc acacttcctg ccgatgcatg tctaaactgg 1081 atgtttacag acaagttcat tccattatta gacgttccct gccagcaaca ctaccacagt 1141 gtcaggcagc gaacaagacc tgccccacca attacatgtg gaataatcac atctgcagat 1201 gcctggctca ggaagatttt atgttttcct cggatgctgg agatgactca acagatggat 1261 tccatgacat ctgtggacca aacaaggagc tggatgaaga gacctgtcag tgtgtctgca 1321 gagcggggct tcggcctgcc agctgtggac cccacaaaga actagacaga aactcatgcc 1381 agtgtgtctg taaaaacaaa ctcttcccca gccaatgtgg ggccaaccga gaatttgatg 1441 aaaacacatg ccagtgtgta tgtaaaagaa cctgccccag aaatcaaccc ctaaatcctg 1501 gaaaatgtgc ctgtgaatgt acagaaagtc cacagaaatg cttgttaaaa ggaaagaagt 1561 tccaccacca aacatgcagc tgttacagac ggccatgtac gaaccgccag aaggcttgtg 1621 agccaggatt ttcatatagt gaagaagtgt gtcgttgtgt cccttcatat tggaaaagac 1681 cacaaatgag ctaagattgt actgttttcc agttcatcga ttttctatta tggaaaactg 1741 tgttgccaca gtagaactgt ctgtgaacag agagaccctt gtgggtccat gctaacaaag 1801 acaaaagtct gtctttcctg aaccatgtgg ataactttac agaaatggac tggagctcat 1861 ctgcaaaagg cctcttgtaa agactggttt tctgccaatg accaaacagc caagattttc 1921 ctcttgtgat ttctttaaaa gaatgactat ataatttatt tccactaaaa atattgtttc 1981 tgcattcatt tttatagcaa caacaattgg taaaactcac tgtgatcaat atttttatat 2041 catgcaaaat atgtttaaaa taaaatgaaa attgtattat aagctgaaaa aaaaaaaaaa 2101 aaa (SEQ ID NO: 178) .

[0364] An exemplary amino acid sequence encoding VEGFC (NP_005420.1) comprises or consists of:

MHLLGFFSVACSLLAAALLPGPREAPAAAAAFESGLDLSDAEPDAGEATAYASKDLEEQLRSVSSVDELMTVLYP EYWKMYKCQLRKGGWQHNREQANLNSRTEETIKFAAAHYNTEILKSIDNEWRKTQCMPREVCIDVGKEFGVATNT FFKPPCVSVYRCGGCCNSEGLQCMNTSTSYLSKTLFEITVPLSQGPKPVTISFANHTSCRCMSKLDVYRQVHSII RRSLPATLPQCQAANKTCPTNYMWNNHICRCLAQEDFMFSSDAGDDSTDGFHDICGPNKELDEETCQCVCRAGLR PASCGPHKELDRNSCQCVCKNKLFPSQCGANREFDENTCQCVCKRTCPRNQPLNPGKCACECTESPQKCLLKGKK FHHQTCSCYRRPCTNRQKACEPGFSYSEEVCRCVPSYWKRPQMS (SEQ ID NO: 179) .

Components of Immune Checkpoints

[0365] Compositions of the disclosure may comprise a nucleic acid, protein or small molecule that hybridizes or binds to a sequence of a component of an immune checkpoint or to a component of an immune checkpoint. Exemplary, not nonlimiting, sequences for components of immune checkpoints of the disclosure are provided below. [0366] An exemplary nucleic acid sequence encoding CTLA4 (NM_005214.4 transcript variant 1) comprises or consists of:

1 cttctgtgtg tgcacatgtg taatacatat ctgggatcaa agctatctat ataaagtcct

6 1 tgattctgtg tgggttcaaa cacatttcaa agcttcagga tcctgaaagg ttttgctcta 12 1 cttcctgaag acctgaacac cgctcccata aagccatggc ttgccttgga tttcagcggc 1 1 acaaggctca gctgaacctg gctaccagga cctggccctg cactctcctg ttttttcttc

24 1 tcttcatccc tgtcttctgc aaagcaatgc acgtggccca gcctgctgtg gtactggcca 30 1 gcagccgagg catcgccagc tttgtgtgtg agtatgcatc tccaggcaaa gccactgagg 36 1 tccgggtgac agtgcttcgg caggctgaca gccaggtgac tgaagtctgt gcggcaacct 42 1 acatgatggg gaatgagttg accttcctag atgattccat ctgcacgggc acctccagtg 48 1 gaaatcaagt gaacctcact atccaaggac tgagggccat ggacacggga ctctacatct 54 1 gcaaggtgga gctcatgtac ccaccgccat actacctggg cataggcaac ggaacccaga 60 1 tttatgtaat tgatccagaa ccgtgcccag attctgactt cctcctctgg atccttgcag 66 1 cagttagttc ggggttgttt ttttatagct ttctcctcac agctgtttct ttgagcaaaa 72 1 tgctaaagaa aagaagccct cttacaacag gggtctatgt gaaaatgccc ccaacagagc 78 1 cagaatgtga aaagcaattt cagccttatt ttattcccat caattgagaa accattatga 84 1 agaagagagt ccatatttca atttccaaga gctgaggcaa ttctaacttt tttgctatcc 90 1 agctattttt atttgtttgt gcatttgggg ggaattcatc tctctttaat ataaagttgg 96 1 atgcggaacc caaattacgt gtactacaat ttaaagcaaa ggagtagaaa gacagagctg 102 1 ggatgtttct gtcacatcag ctccactttc agtgaaagca tcacttggga ttaatatggg 108 1 gatgcagcat tatgatgtgg gtcaaggaat taagttaggg aatggcacag cccaaagaag 114 1 gaaaaggcag ggagcgaggg agaagactat attgtacaca ccttatattt acgtatgaga 120 1 cgtttatagc cgaaatgatc ttttcaagtt aaattttatg ccttttattt cttaaacaaa 126 1 tgtatgatta catcaaggct tcaaaaatac tcacatggct atgttttagc cagtgatgct 132 1 aaaggttgta ttgcatatat acatatatat atatatatat atatatatat atatatatat 13 1 atatatatat atatatattt taatttgata gtattgtgca tagagccacg tatgtttttg 144 1 tgtatttgtt aatggtttga atataaacac tatatggcag tgtctttcca ccttgggtcc 150 1 cagggaagtt ttgtggagga gctcaggaca ctaatacacc aggtagaaca caaggtcatt 156 1 tgctaactag cttggaaact ggatgaggtc atagcagtgc ttgattgcgt ggaattgtgc 162 1 tgagttggtg ttgacatgtg ctttggggct tttacaccag ttcctttcaa tggtttgcaa 168 1 ggaagccaca gctggtggta tctgagttga cttgacagaa cactgtcttg aagacaatgg 174 1 cttactccag gagacccaca ggtatgacct tctaggaagc tccagttcga tgggcccaat 180 1 tcttacaaac atgtggttaa tgccatggac agaagaaggc agcaggtggc agaatggggt 186 1 gcatgaaggt ttctgaaaat taacactgct tgtgttttta actcaatatt ttccatgaaa 192 1 atgcaacaac atgtataata tttttaatta aataaaaatc tgtggtggtc gttttaaaaa 198 1 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaa (SEQ NO: 180) .

[0367] An exemplary amino acid sequence encoding CTLA4 (NP_005205.2 isoform CTLA4-TM precursor) comprises or consists of:

MACLGFQRHKAQLNLATRTWPCTLLFFLLFIPVFCKAMHVAQPAWLASSRGIASFVCEYASPGKATEVRVTVLR QADSQVTEVCAATY MGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIY VIDPEPCPDSDFLLWILAAVSSGLFFYSFLLTAVSLSKMLKKRSPLTTGVYVKMPPTEPECEKQFQPYFIPIN

(SEQ ID NO: 181) .

[0368] An exemplary nucleic acid sequence encoding CTLA4 (NM_001037631.2 transcript variant 2) comprises or consists of:

1 cttctgtgtg tgcacatgtg taatacatat ctgggatcaa agctatctat ataaagtcct

61 tgattctgtg tgggttcaaa cacatttcaa agcttcagga tcctgaaagg ttttgctcta

121 cttcctgaag acctgaacac cgctcccata aagccatggc ttgccttgga tttcagcggc

181 acaaggctca gctgaacctg gctaccagga cctggccctg cactctcctg ttttttcttc

241 tcttcatccc tgtcttctgc aaagcaatgc acgtggccca gcctgctgtg gtactggcca

301 gcagccgagg catcgccagc tttgtgtgtg agtatgcatc tccaggcaaa gccactgagg 361 tccgggtgac agtgcttcgg caggctgaca gccaggtgac tgaagtctgt gcggcaacct 421 acatgatggg gaatgagttg accttcctag atgattccat ctgcacgggc acctccagtg 481 gaaatcaagt gaacctcact atccaaggac tgagggccat ggacacggga ctctacatct 541 gcaaggtgga gctcatgtac ccaccgccat actacctggg cataggcaac ggaacccaga 601 tttatgtaat tgctaaagaa aagaagccct cttacaacag gggtctatgt gaaaatgccc 661 ccaacagagc cagaatgtga aaagcaattt cagccttatt ttattcccat caattgagaa 721 accattatga agaagagagt ccatatttca atttccaaga gctgaggcaa ttctaacttt 781 tttgctatcc agctattttt atttgtttgt gcatttgggg ggaattcatc tctctttaat 841 ataaagttgg atgcggaacc caaattacgt gtactacaat ttaaagcaaa ggagtagaaa 901 gacagagctg ggatgtttct gtcacatcag ctccactttc agtgaaagca tcacttggga 961 ttaatatggg gatgcagcat tatgatgtgg gtcaaggaat taagttaggg aatggcacag 1021 cccaaagaag gaaaaggcag ggagcgaggg agaagactat attgtacaca ccttatattt 1081 acgtatgaga cgtttatagc cgaaatgatc ttttcaagtt aaattttatg ccttttattt 1141 cttaaacaaa tgtatgatta catcaaggct tcaaaaatac tcacatggct atgttttagc 1201 cagtgatgct aaaggttgta ttgcatatat acatatatat atatatatat atatatatat 1261 atatatatat atatatatat atatatattt taatttgata gtattgtgca tagagccacg 1321 tatgtttttg tgtatttgtt aatggtttga atataaacac tatatggcag tgtctttcca 1381 ccttgggtcc cagggaagtt ttgtggagga gctcaggaca ctaatacacc aggtagaaca 1441 caaggtcatt tgctaactag cttggaaact ggatgaggtc atagcagtgc ttgattgcgt 1501 ggaattgtgc tgagttggtg ttgacatgtg ctttggggct tttacaccag ttcctttcaa 1561 tggtttgcaa ggaagccaca gctggtggta tctgagttga cttgacagaa cactgtcttg 1621 aagacaatgg cttactccag gagacccaca ggtatgacct tctaggaagc tccagttcga 1681 tgggcccaat tcttacaaac atgtggttaa tgccatggac agaagaaggc agcaggtggc 1741 agaatggggt gcatgaaggt ttctgaaaat taacactgct tgtgttttta actcaatatt 1801 ttccatgaaa atgcaacaac atgtataata tttttaatta aataaaaatc tgtggtggtc 1861 gttttaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1921 aaa (SEQ ID NO: 182) .

[0369] An exemplary amino acid sequence encoding CTLA4 (NP_001032720.1, isoform CTLA-4delTM precursor) comprises or consists of:

MACLGFQRHKAQLNLATRTWPCTLLFFLLFIPVFCKAMHVAQPAWLASSRGIASFVCEYASPGKATEVRVTVLR QADSQVTEVCAATY MGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIY VIAKEKKPSYNRGLCENAPNRARM (SEQ ID NO: 183) .

[0370] An exemplary nucleic acid sequence encoding PD-L1 (NM 014143.3 transcript variant 1) comprises or consists of:

1 ggcgcaacgc tgagcagctg gcgcgtcccg cgcggcccca gttctgcgca gcttcccgag 61 gctccgcacc agccgcgctt ctgtccgcct gcagggcatt ccagaaagat gaggatattt 121 gctgtcttta tattcatgac ctactggcat ttgctgaacg catttactgt cacggttccc 181 aaggacctat atgtggtaga gtatggtagc aatatgacaa ttgaatgcaa attcccagta 241 gaaaaacaat tagacctggc tgcactaatt gtctattggg aaatggagga taagaacatt 301 attcaatttg tgcatggaga ggaagacctg aaggttcagc atagtagcta cagacagagg 361 gcccggctgt tgaaggacca gctctccctg ggaaatgctg cacttcagat cacagatgtg 421 aaattgcagg atgcaggggt gtaccgctgc atgatcagct atggtggtgc cgactacaag 481 cgaattactg tgaaagtcaa tgccccatac aacaaaatca accaaagaat tttggttgtg 541 gatccagtca cctctgaaca tgaactgaca tgtcaggctg agggctaccc caaggccgaa 601 gtcatctgga caagcagtga ccatcaagtc ctgagtggta agaccaccac caccaattcc 661 aagagagagg agaagctttt caatgtgacc agcacactga gaatcaacac aacaactaat 721 gagattttct actgcacttt taggagatta gatcctgagg aaaaccatac agctgaattg 781 gtcatcccag aactacctct ggcacatcct ccaaatgaaa ggactcactt ggtaattctg 841 ggagccatct tattatgcct tggtgtagca ctgacattca tcttccgttt aagaaaaggg 901 agaatgatgg atgtgaaaaa atgtggcatc caagatacaa actcaaagaa gcaaagtgat 961 acacatttgg aggagacgta atccagcatt ggaacttctg atcttcaagc agggattctc 1021 aacctgtggt ttaggggttc atcggggctg agcgtgacaa gaggaaggaa tgggcccgtg 1081 ggatgcaggc aatgtgggac ttaaaaggcc caagcactga aaatggaacc tggcgaaagc 1141 agaggaggag aatgaagaaa gatggagtca aacagggagc ctggagggag accttgatac 1201 tttcaaatgc ctgaggggct catcgacgcc tgtgacaggg agaaaggata cttctgaaca 1261 aggagcctcc aagcaaatca tccattgctc atcctaggaa gacgggttga gaatccctaa 1321 tttgagggtc agttcctgca gaagtgccct ttgcctccac tcaatgcctc aatttgtttt 1381 ctgcatgact gagagtctca gtgttggaac gggacagtat ttatgtatga gtttttccta 1441 tttattttga gtctgtgagg tcttcttgtc atgtgagtgt ggttgtgaat gatttctttt 1501 gaagatatat tgtagtagat gttacaattt tgtcgccaaa ctaaacttgc tgcttaatga 1561 tttgctcaca tctagtaaaa catggagtat ttgtaaggtg cttggtctcc tctataacta 1621 caagtataca ttggaagcat aaagatcaaa ccgttggttg cataggatgt cacctttatt 1681 taacccatta atactctggt tgacctaatc ttattctcag acctcaagtg tctgtgcagt 1741 atctgttcca tttaaatatc agctttacaa ttatgtggta gcctacacac ataatctcat 1801 ttcatcgctg taaccaccct gttgtgataa ccactattat tttacccatc gtacagctga 1861 ggaagcaaac agattaagta acttgcccaa accagtaaat agcagacctc agactgccac 1921 ccactgtcct tttataatac aatttacagc tatattttac tttaagcaat tcttttattc 1981 aaaaaccatt tattaagtgc ccttgcaata tcaatcgctg tgccaggcat tgaatctaca 2041 gatgtgagca agacaaagta cctgtcctca aggagctcat agtataatga ggagattaac 2101 aagaaaatgt attattacaa tttagtccag tgtcatagca taaggatgat gcgaggggaa 2161 aacccgagca gtgttgccaa gaggaggaaa taggccaatg tggtctggga cggttggata 2221 tacttaaaca tcttaataat cagagtaatt ttcatttaca aagagaggtc ggtacttaaa 2281 ataaccctga aaaataacac tggaattcct tttctagcat tatatttatt cctgatttgc 2341 ctttgccata taatctaatg cttgtttata tagtgtctgg tattgtttaa cagttctgtc 2401 ttttctattt aaatgccact aaattttaaa ttcatacctt tccatgattc aaaattcaaa 2461 agatcccatg ggagatggtt ggaaaatctc cacttcatcc tccaagccat tcaagtttcc 2521 tttccagaag caactgctac tgcctttcat tcatatgttc ttctaaagat agtctacatt 2581 tggaaatgta tgttaaaagc acgtattttt aaaatttttt tcctaaatag taacacattg 2641 tatgtctgct gtgtactttg ctatttttat ttattttagt gtttcttata tagcagatgg 2701 aatgaatttg aagttcccag ggctgaggat ccatgccttc tttgtttcta agttatcttt 2761 cccatagctt ttcattatct ttcatatgat ccagtatatg ttaaatatgt cctacatata 2821 catttagaca accaccattt gttaagtatt tgctctagga cagagtttgg atttgtttat 2881 gtttgctcaa aaggagaccc atgggctctc cagggtgcac tgagtcaatc tagtcctaaa 2941 aagcaatctt attattaact ctgtatgaca gaatcatgtc tggaactttt gttttctgct 3001 ttctgtcaag tataaacttc actttgatgc tgtacttgca aaatcacatt ttctttctgg 3061 aaattccggc agtgtacctt gactgctagc taccctgtgc cagaaaagcc tcattcgttg 3121 tgcttgaacc cttgaatgcc accagctgtc atcactacac agccctccta agaggcttcc 3181 tggaggtttc gagattcaga tgccctggga gatcccagag tttcctttcc ctcttggcca 3241 tattctggtg tcaatgacaa ggagtacctt ggctttgcca catgtcaagg ctgaagaaac 3301 agtgtctcca acagagctcc ttgtgttatc tgtttgtaca tgtgcatttg tacagtaatt 3361 ggtgtgacag tgttctttgt gtgaattaca ggcaagaatt gtggctgagc aaggcacata 3421 gtctactcag tctattccta agtcctaact cctccttgtg gtgttggatt tgtaaggcac 3481 tttatccctt ttgtctcatg tttcatcgta aatggcatag gcagagatga tacctaattc 3541 tgcatttgat tgtcactttt tgtacctgca ttaatttaat aaaatattct tatttatttt 3601 gttacttggt acaccagcat gtccattttc ttgtttattt tgtgtttaat aaaatgttca 3661 gtttaacatc ccagtggaga aagttaaaaa a (SEQ ID NO: 184) .

[0371] An exemplary amino acid sequence encoding PD-Ll (NP 054862.1, isoform a) comprises or consists of:

MRIFAVFIFMTYWHLLNAFTVTVPKDLYWEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLK VQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILWDPVTSE HELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELV IPELPLAHPPNERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLEET (SEQ ID NO: 185) .

[0372] An exemplary nucleic acid sequence encoding PD-Ll (NM_001267706.1 transcript variant 2) comprises or consists of: 1 ggcgcaacgc tgagcagctg gcgcgtcccg cgcggcccca gttctgcgca gcttcccgag 61 gctccgcacc agccgcgctt ctgtccgcct gcagggcatt ccagaaagat gaggatattt 121 gctgtcttta tattcatgac ctactggcat ttgctgaacg ccccatacaa caaaatcaac 181 caaagaattt tggttgtgga tccagtcacc tctgaacatg aactgacatg tcaggctgag 241 ggctacccca aggccgaagt catctggaca agcagtgacc atcaagtcct gagtggtaag 301 accaccacca ccaattccaa gagagaggag aagcttttca atgtgaccag cacactgaga 361 atcaacacaa caactaatga gattttctac tgcactttta ggagattaga tcctgaggaa 421 aaccatacag ctgaattggt catcccagaa ctacctctgg cacatcctcc aaatgaaagg 481 actcacttgg taattctggg agccatctta ttatgccttg gtgtagcact gacattcatc 541 ttccgtttaa gaaaagggag aatgatggat gtgaaaaaat gtggcatcca agatacaaac 601 tcaaagaagc aaagtgatac acatttggag gagacgtaat ccagcattgg aacttctgat 661 cttcaagcag ggattctcaa cctgtggttt aggggttcat cggggctgag cgtgacaaga 721 ggaaggaatg ggcccgtggg atgcaggcaa tgtgggactt aaaaggccca agcactgaaa 781 atggaacctg gcgaaagcag aggaggagaa tgaagaaaga tggagtcaaa cagggagcct 841 ggagggagac cttgatactt tcaaatgcct gaggggctca tcgacgcctg tgacagggag 901 aaaggatact tctgaacaag gagcctccaa gcaaatcatc cattgctcat cctaggaaga 961 cgggttgaga atccctaatt tgagggtcag ttcctgcaga agtgcccttt gcctccactc 1021 aatgcctcaa tttgttttct gcatgactga gagtctcagt gttggaacgg gacagtattt 1081 atgtatgagt ttttcctatt tattttgagt ctgtgaggtc ttcttgtcat gtgagtgtgg 1141 ttgtgaatga tttcttttga agatatattg tagtagatgt tacaattttg tcgccaaact 1201 aaacttgctg cttaatgatt tgctcacatc tagtaaaaca tggagtattt gtaaggtgct 1261 tggtctcctc tataactaca agtatacatt ggaagcataa agatcaaacc gttggttgca 1321 taggatgtca cctttattta acccattaat actctggttg acctaatctt attctcagac 1381 ctcaagtgtc tgtgcagtat ctgttccatt taaatatcag ctttacaatt atgtggtagc 1441 ctacacacat aatctcattt catcgctgta accaccctgt tgtgataacc actattattt 1501 tacccatcgt acagctgagg aagcaaacag attaagtaac ttgcccaaac cagtaaatag 1561 cagacctcag actgccaccc actgtccttt tataatacaa tttacagcta tattttactt 1621 taagcaattc ttttattcaa aaaccattta ttaagtgccc ttgcaatatc aatcgctgtg 1681 ccaggcattg aatctacaga tgtgagcaag acaaagtacc tgtcctcaag gagctcatag 1741 tataatgagg agattaacaa gaaaatgtat tattacaatt tagtccagtg tcatagcata 1801 aggatgatgc gaggggaaaa cccgagcagt gttgccaaga ggaggaaata ggccaatgtg 1861 gtctgggacg gttggatata cttaaacatc ttaataatca gagtaatttt catttacaaa 1921 gagaggtcgg tacttaaaat aaccctgaaa aataacactg gaattccttt tctagcatta 1981 tatttattcc tgatttgcct ttgccatata atctaatgct tgtttatata gtgtctggta 2041 ttgtttaaca gttctgtctt ttctatttaa atgccactaa attttaaatt catacctttc 2101 catgattcaa aattcaaaag atcccatggg agatggttgg aaaatctcca cttcatcctc 2161 caagccattc aagtttcctt tccagaagca actgctactg cctttcattc atatgttctt 2221 ctaaagatag tctacatttg gaaatgtatg ttaaaagcac gtatttttaa aatttttttc 2281 ctaaatagta acacattgta tgtctgctgt gtactttgct atttttattt attttagtgt 2341 ttcttatata gcagatggaa tgaatttgaa gttcccaggg ctgaggatcc atgccttctt 2401 tgtttctaag ttatctttcc catagctttt cattatcttt catatgatcc agtatatgtt 2461 aaatatgtcc tacatataca tttagacaac caccatttgt taagtatttg ctctaggaca 2521 gagtttggat ttgtttatgt ttgctcaaaa ggagacccat gggctctcca gggtgcactg 2581 agtcaatcta gtcctaaaaa gcaatcttat tattaactct gtatgacaga atcatgtctg 2641 gaacttttgt tttctgcttt ctgtcaagta taaacttcac tttgatgctg tacttgcaaa 2701 atcacatttt ctttctggaa attccggcag tgtaccttga ctgctagcta ccctgtgcca 2761 gaaaagcctc attcgttgtg cttgaaccct tgaatgccac cagctgtcat cactacacag 2821 ccctcctaag aggcttcctg gaggtttcga gattcagatg ccctgggaga tcccagagtt 2881 tcctttccct cttggccata ttctggtgtc aatgacaagg agtaccttgg ctttgccaca 2941 tgtcaaggct gaagaaacag tgtctccaac agagctcctt gtgttatctg tttgtacatg 3001 tgcatttgta cagtaattgg tgtgacagtg ttctttgtgt gaattacagg caagaattgt 3061 ggctgagcaa ggcacatagt ctactcagtc tattcctaag tcctaactcc tccttgtggt 3121 gttggatttg taaggcactt tatccctttt gtctcatgtt tcatcgtaaa tggcataggc 3181 agagatgata cctaattctg catttgattg tcactttttg tacctgcatt aatttaataa 3241 aatattctta tttattttgt tacttggtac accagcatgt ccattttctt gtttattttg 3301 tgtttaataa aatgttcagt ttaacatccc agtggagaaa gttaaaaaa (SEQ ID NO:) 3] An exemplary amino acid sequence encoding PD-Ll (NP 001254635.1, isoform b) comprises or consists of:

MRIFAVFIFMTYWHLLNAPYNKINQRILWDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEK LFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTHLVILGAILLCLGVALTFIFRLRKG RMMDVKKCGIQDTNSKKQSDTHLEET (SEQ ID NO: 187) .

[0374] An exemplary nucleic acid sequence encoding PD-Ll (NR 052005.1 transcript variant 3) comprises or consists of:

1 ggcgcaacgc tgagcagctg gcgcgtcccg cgcggcccca gttctgcgca gcttcccgag 61 gctccgcacc agccgcgctt ctgtccgcct gcagggcatt ccagaaagat gaggatattt 121 gctgtcttta tattcatgac ctactggcat ttgctgaacg catttactgt cacggttccc 181 aaggacctat atgtggtaga gtatggtagc aatatgacaa ttgaatgcaa attcccagta 241 gaaaaacaat tagacctggc tgcactaatt gtctattggg aaatggagga taagaacatt 301 attcaatttg tgcatggaga ggaagacctg aaggttcagc atagtagcta cagacagagg 361 gcccggctgt tgaaggacca gctctccctg ggaaatgctg cacttcagat cacagatgtg 421 aaattgcagg atgcaggggt gtaccgctgc atgatcagct atggtggtgc cgactacaag 481 cgaattactg tgaaagtcaa tgccccatac aacaaaatca accaaagaat tttggttgtg 541 gatccagtca cctctgaaca tgaactgaca tgtcaggctg agggctaccc caaggccgaa 601 gtcatctgga caagcagtga ccatcaagtc ctgagtggag attagatcct gaggaaaacc 661 atacagctga attggtcatc ccagaactac ctctggcaca tcctccaaat gaaaggactc 721 acttgggaga atgatggatg tgaaaaaatg tggcatccaa gatacaaact caaagaagca 781 aagtgataca catttggagg agacgtaatc cagcattgga acttctgatc ttcaagcagg 841 gattctcaac ctgtggttta ggggttcatc ggggctgagc gtgacaagag gaaggaatgg 901 gcccgtggga tgcaggcaat gtgggactta aaaggcccaa gcactgaaaa tggaacctgg 961 cgaaagcaga ggaggagaat gaagaaagat ggagtcaaac agggagcctg gagggagacc 1021 ttgatacttt caaatgcctg aggggctcat cgacgcctgt gacagggaga aaggatactt 1081 ctgaacaagg agcctccaag caaatcatcc attgctcatc ctaggaagac gggttgagaa 1141 tccctaattt gagggtcagt tcctgcagaa gtgccctttg cctccactca atgcctcaat 1201 ttgttttctg catgactgag agtctcagtg ttggaacggg acagtattta tgtatgagtt 1261 tttcctattt attttgagtc tgtgaggtct tcttgtcatg tgagtgtggt tgtgaatgat 1321 ttcttttgaa gatatattgt agtagatgtt acaattttgt cgccaaacta aacttgctgc 1381 ttaatgattt gctcacatct agtaaaacat ggagtatttg taaggtgctt ggtctcctct 1441 ataactacaa gtatacattg gaagcataaa gatcaaaccg ttggttgcat aggatgtcac 1501 ctttatttaa cccattaata ctctggttga cctaatctta ttctcagacc tcaagtgtct 1561 gtgcagtatc tgttccattt aaatatcagc tttacaatta tgtggtagcc tacacacata 1621 atctcatttc atcgctgtaa ccaccctgtt gtgataacca ctattatttt acccatcgta 1681 cagctgagga agcaaacaga ttaagtaact tgcccaaacc agtaaatagc agacctcaga 1741 ctgccaccca ctgtcctttt ataatacaat ttacagctat attttacttt aagcaattct 1801 tttattcaaa aaccatttat taagtgccct tgcaatatca atcgctgtgc caggcattga 1861 atctacagat gtgagcaaga caaagtacct gtcctcaagg agctcatagt ataatgagga 1921 gattaacaag aaaatgtatt attacaattt agtccagtgt catagcataa ggatgatgcg 1981 aggggaaaac ccgagcagtg ttgccaagag gaggaaatag gccaatgtgg tctgggacgg 2041 ttggatatac ttaaacatct taataatcag agtaattttc atttacaaag agaggtcggt 2101 acttaaaata accctgaaaa ataacactgg aattcctttt ctagcattat atttattcct 2161 gatttgcctt tgccatataa tctaatgctt gtttatatag tgtctggtat tgtttaacag 2221 ttctgtcttt tctatttaaa tgccactaaa ttttaaattc atacctttcc atgattcaaa 2281 attcaaaaga tcccatggga gatggttgga aaatctccac ttcatcctcc aagccattca 2341 agtttccttt ccagaagcaa ctgctactgc ctttcattca tatgttcttc taaagatagt 2401 ctacatttgg aaatgtatgt taaaagcacg tatttttaaa atttttttcc taaatagtaa 2461 cacattgtat gtctgctgtg tactttgcta tttttattta ttttagtgtt tcttatatag 2521 cagatggaat gaatttgaag ttcccagggc tgaggatcca tgccttcttt gtttctaagt 2581 tatctttccc atagcttttc attatctttc atatgatcca gtatatgtta aatatgtcct 2641 acatatacat ttagacaacc accatttgtt aagtatttgc tctaggacag agtttggatt 2701 tgtttatgtt tgctcaaaag gagacccatg ggctctccag ggtgcactga gtcaatctag 2761 tcctaaaaag caatcttatt attaactctg tatgacagaa tcatgtctgg aacttttgtt 2821 ttctgctttc tgtcaagtat aaacttcact ttgatgctgt acttgcaaaa tcacattttc 2881 tttctggaaa ttccggcagt gtaccttgac tgctagctac cctgtgccag aaaagcctca 2941 ttcgttgtgc ttgaaccctt gaatgccacc agctgtcatc actacacagc cctcctaaga

3001 ggcttcctgg aggtttcgag attcagatgc cctgggagat cccagagttt cctttccctc

3061 ttggccatat tctggtgtca atgacaagga gtaccttggc tttgccacat gtcaaggctg

3121 aagaaacagt gtctccaaca gagctccttg tgttatctgt ttgtacatgt gcatttgtac

3181 agtaattggt gtgacagtgt tctttgtgtg aattacaggc aagaattgtg gctgagcaag

3241 gcacatagtc tactcagtct attcctaagt cctaactcct ccttgtggtg ttggatttgt

3301 aaggcacttt atcccttttg tctcatgttt catcgtaaat ggcataggca gagatgatac

3361 ctaattctgc atttgattgt cactttttgt acctgcatta atttaataaa atattcttat

3421 ttattttgtt acttggtaca ccagcatgtc cattttcttg tttattttgt gtttaataaa

3481 atgttcagtt taacatccca gtggagaaag ttaaaaaa (SEQ ID NO: 188).

[0375] An exemplary nucleic acid sequence encoding PD-Ll (NM_001314029.1 transcript variant 4) comprises or consists of:

1 ggcgcaacgc tgagcagctg gcgcgtcccg cgcggcccca gttctgcgca gcttcccgag

61 gctccgcacc agccgcgctt ctgtccgcct gcagggcatt ccagaaagat gaggatattt

121 gctgtcttta tattcatgac ctactggcat ttgctgaacg catttactgt cacggttccc

181 aaggacctat atgtggtaga gtatggtagc aatatgacaa ttgaatgcaa attcccagta

241 gaaaaacaat tagacctggc tgcactaatt gtctattggg aaatggagga taagaacatt

301 attcaatttg tgcatggaga ggaagacctg aaggttcagc atagtagcta cagacagagg

361 gcccggctgt tgaaggacca gctctccctg ggaaatgctg cacttcagat cacagatgtg

421 aaattgcagg atgcaggggt gtaccgctgc atgatcagct atggtggtgc cgactacaag

481 cgaattactg tgaaagtcaa tgccccatac aacaaaatca accaaagaat tttggttgtg

541 gatccagtca cctctgaaca tgaactgaca tgtcaggctg agggctaccc caaggccgaa

601 gtcatctgga caagcagtga ccatcaagtc ctgagtggta agaccaccac caccaattcc

661 aagagagagg agaagctttt caatgtgacc agcacactga gaatcaacac aacaactaat

721 gagattttct actgcacttt taggagatta gatcctgagg aaaaccatac agctgaattg

781 gtcatcccag gtaatattct gaatgtgtcc attaaaatat gtctaacact gtcccctagc

841 acctagcatg atgtctgcct atcatagtca ttcagtgatt gttgaataaa tgaatgaatg 901 aataaca (SEQ ID NO: 189) .

[0376] An exemplary amino acid sequence encoding PD-Ll (NP 001300958.1, isoform c) comprises or consists of:

MRIFAVFIFMTYWHLLNAFTVTVPKDLYWEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLK VQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILWDPVTSE HELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELV IPGNILNVSIKICLTLSPST (SEQ ID NO: 190) .

[0377] An exemplary nucleic acid sequence encoding PD1 (NM_005018.2 mRNA) comprises or consists of:

1 agtttccctt ccgctcacct ccgcctgagc agtggagaag gcggcactct ggtggggctg

61 ctccaggcat gcagatccca caggcgccct ggccagtcgt ctgggcggtg ctacaactgg

121 gctggcggcc aggatggttc ttagactccc cagacaggcc ctggaacccc cccaccttct

181 ccccagccct gctcgtggtg accgaagggg acaacgccac cttcacctgc agcttctcca

241 acacatcgga gagcttcgtg ctaaactggt accgcatgag ccccagcaac cagacggaca

301 agctggccgc cttccccgag gaccgcagcc agcccggcca ggactgccgc ttccgtgtca

361 cacaactgcc caacgggcgt gacttccaca tgagcgtggt cagggcccgg cgcaatgaca

421 gcggcaccta cctctgtggg gccatctccc tggcccccaa ggcgcagatc aaagagagcc

481 tgcgggcaga gctcagggtg acagagagaa gggcagaagt gcccacagcc caccccagcc

541 cctcacccag gccagccggc cagttccaaa ccctggtggt tggtgtcgtg ggcggcctgc

601 tgggcagcct ggtgctgcta gtctgggtcc tggccgtcat ctgctcccgg gccgcacgag

661 ggacaatagg agccaggcgc accggccagc ccctgaagga ggacccctca gccgtgcctg

721 tgttctctgt ggactatggg gagctggatt tccagtggcg agagaagacc ccggagcccc 781 ccgtgccctg tgtccctgag cagacggagt atgccaccat tgtctttcct agcggaatgg 841 gcacctcatc ccccgcccgc aggggctcag ctgacggccc tcggagtgcc cagccactga 901 ggcctgagga tggacactgc tcttggcccc tctgaccggc ttccttggcc accagtgttc 961 tgcagaccct ccaccatgag cccgggtcag cgcatttcct caggagaagc aggcagggtg 1021 caggccattg caggccgtcc aggggctgag ctgcctgggg gcgaccgggg ctccagcctg 1081 cacctgcacc aggcacagcc ccaccacagg actcatgtct caatgcccac agtgagccca 1141 ggcagcaggt gtcaccgtcc cctacaggga gggccagatg cagtcactgc ttcaggtcct 1201 gccagcacag agctgcctgc gtccagctcc ctgaatctct gctgctgctg ctgctgctgc 1261 tgctgctgcc tgcggcccgg ggctgaaggc gccgtggccc tgcctgacgc cccggagcct 1321 cctgcctgaa cttgggggct ggttggagat ggccttggag cagccaaggt gcccctggca 1381 gtggcatccc gaaacgccct ggacgcaggg cccaagactg ggcacaggag tgggaggtac 1441 atggggctgg ggactcccca ggagttatct gctccctgca ggcctagaga agtttcaggg 1501 aaggtcagaa gagctcctgg ctgtggtggg cagggcagga aacccctcca cctttacaca 1561 tgcccaggca gcacctcagg ccctttgtgg ggcagggaag ctgaggcagt aagcgggcag 1621 gcagagctgg aggcctttca ggcccagcca gcactctggc ctcctgccgc cgcattccac 1681 cccagcccct cacaccactc gggagaggga catcctacgg tcccaaggtc aggagggcag 1741 ggctggggtt gactcaggcc cctcccagct gtggccacct gggtgttggg agggcagaag 1801 tgcaggcacc tagggccccc catgtgccca ccctgggagc tctccttgga acccattcct 1861 gaaattattt aaaggggttg gccgggctcc caccagggcc tgggtgggaa ggtacaggcg 1921 ttcccccggg gcctagtacc cccgccgtgg cctatccact cctcacatcc acacactgca 1981 cccccactcc tggggcaggg ccaccagcat ccaggcggcc agcaggcacc tgagtggctg 2041 ggacaaggga tcccccttcc ctgtggttct attatattat aattataatt aaatatgaga 2101 gcatgctaag gaaaa (SEQ ID NO: 191)

[0378] An exemplary amino acid sequence encoding PD1 (NP 005009.2) comprises or consists of:

MQIPQAPWPV AVLQLGWRPGWFLDSPDRPWNPPTFSPALLWTEGDNATFTCSFSNTSESFVLNWYRMSPSNQ TDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSWRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAE VPTAHPSPSPRPAGQFQTLWGWGGLLGSLVLLV VLAVICSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGE LDFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL (SEQ ID NO: 192) .

[0379] An exemplary nucleic acid sequence encoding PD1 (U64864.1 , promoter and partial cds) comprises or consists of:

1 tcgatctgga actgtggcca tggtgtgagg ccatccacaa ggtggaagct ttgaggggga 61 gccgattagc catggacagt tgtcattcag tagggtcacc tgtgccccag cgaaggggga 121 tgggccggga aggcagaggc caggcacctg cccccagcag ggcagaggct gtgggcagcc 181 gggaggctcc cagaggctcc gacagaatgg gagtggggtt gagccacccc tcactgcagc 241 ccaggaacct gagcccagag gggccaccca ccttccccag gcagggaggc ccggccccca 301 gggagatggg ggggatgggg gaggagaagg gcctgccccc acccggcagc ctcaggaggg 361 gcagctcggg cgggatatgg aaagaggcca cagcagtgag cagagacaca gaggaggaag 421 gggccctgag ctggggagac ccccacgggg tagggcgtgg gccacgggca cctcctcccc 481 atctcctctg tctccctgtc tctgtctctc tctccctccc ccaccctctc cccagtccta 541 ccccctcctc acccctcctc ccccagcact gcctctgtca ctctcgccca cgtggatgtg 601 gaggaagagg gggcgggagc aaggggcggg caccctccct tcaacctgac ctgggacagt 661 ttcccttccg ctcacctccg cctgagcagt ggagaaggcg gcactctggt ggggctgctc 721 caggcatgca gatcccacag gcgccctggc ca (SEQ ID NO: 193) .

[0380] An exemplary amino acid sequence encoding PD1 (AAC41700.1) comprises or consists of:

MQIPQAPWPV AVLQLGWRPGWFLDSPDRPWNPPTFSPALLWTEGDNATFTCSFSNTSESFVLNWYRMSPSNQ TDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSWRARRNDSGTYLCGAI SLAPKAQIKESLRAELRVTERRAE VPTAHP SP SPRSAGQFQTLWGWGGLLGSLVLLV VLAVI CSRAARGT IGARRTGQPLKEDPSAVPVFSVDYGE LDFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTS SPARRGSADGPRSAQPLRPEDGHCSWPL ( SEQ I D NO : 1 94 ) .

EXAMPLES

Example 1: Targeting DDR2 enhances tumour response to anti-PD-1 immunotherapy Methods

Mouse cancer cell lines

[0381] NA13 cell line was isolated and cultured from N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) carcinogen-induced bladder tumor of C57BL/6 female mice. 7-8 week old C57BL/6 mice were treated with 0.05% BBN in water for 12 weeks. After 12 weeks of BBN treatment, mice were kept for an additional 12 weeks on the regular water. Mice were then sacrificed, a part of the bladder tumour was washed in PBS and minced into small pieces with RPMI media supplemented with 20% FBS, lmM Sodium pyruvate and 1%

antibiotic/antimycotic solution. The culture dish was then kept in a C02 incubator with 5% CCh and 95% humidity to allow the tumour cells to attach and grow. After two days in culture, the excess floating tumour tissue was removed and cells were further maintained in culture for 6-8 weeks before freezing in Liquid N₂.

[0382] B16F10 was obtained from the American Type Culture Collection (ATCC) through the University of Colorado Tissue Culture Core. B16F10 was a kind gift from Dr. Traci Lyons (University of Colorado). All cell lines have been authenticated and tested to be mycoplasma-free. E0771 was maintained in RPMI with 5% fetal bovine serum (FBS).

B16F10 is maintained in DMEM media with 10% FBS. MC38 is maintained in RPMI media supplemented with, 25 mM HEPES and 10% fetal calf serum (FCS). All cells were grown at 37°C in a humidified atmosphere (5% CCh).

Whole Exome Sequencing ofNA13

[0383] Genomic DNA was extracted from the NA13 cell line using the Puregene Cell and Tissue Kit (Qiagen). Exome capture was performed using the SureSelectXT Mouse All Exon Kit (Agilent). Novogene (https://en.novogene.com/) performed whole exome sequencing (WES) using the Illumina NovaSeq 6000 platform. Paired end 150bp reads were sequenced at a depth of 100X.

[0384] Reads from the raw FASTQ file were aligned to the mouse reference genome (MM9) using BWA (V0.7.8-R455)¹. The BAM file generated from BWA was sorted using Samtools (vl.O) and Picard (v 1.111) was used to mark duplicates and recalibrate base quality scores. SNPs and small indels were called according to the GATK command line tools (v3.8.0), including programs Haplotypecaller, SelectVariants, and VariantFiltration using default parameters. We lifted over the mouse MM9 coordinates to genome version MM10 using the UCSC Genome Browser liftover tool (genome.ucsc.edu/cgi-bin/hgLiftOver). To characterize the alterations on gene location and impact on the associated protein, the NA13 SNPs and small indels were annotated using SnpEff

Library Design and Analysis

[0385] The custom pooled 34 gene mouse shRNA library was prepared by the University of Colorado Functional Genomics Core using MISSION® shRNA lentiviral transduction particles (Sigma) (Table 1). Each gene is targeted by an average of five distinct shRNA TRC constructs for a total of 169 shRNAs. NA13 cells were transfected with lentivirus, and underwent puromycin selection (l^g/mL) 48 hours later. Cells underwent selection for four days prior to expansion in RPMI supplemented with 10% FBS and ImM sodium pyruvate. Cells were expanded for at least two days prior to subcutaneous hind flank injection into 8 week old C57BL/6 female mice. Once tumours reached 50-100mm³, mice were injected with 5C^g mouse anti-PD-1 antibody (IgGl-D265A) or isotype control (IgGl, clone 4F7) (Bristol- Myers Squibb) every three days for a total of three doses. Mice were euthanized once tumours reached 500mm³. Tumour were harvested, snap frozen in liquid N and stored at - 80°C until DNA isolation. Genomic DNA (gDNA) was isolated from each tumor using the Gentra Puregene kit (Valencia, CA, USA). Custom dual indexed primers were utilized to amplify the shRNA constructs, ^g of total gDNA were used in each NGS library PCR reaction with Herculase II Fusion Enzyme (Agilent Technologies, Cedar Creek, TX, USA) for 26 cycles. The 290bp amplicon of interest from each reaction was purified using

SPRIselect beads (Beckman Coulter, Brea, CA, USA). Each sample was quantified by Qubit dsDNA HS Assay kit (Invitrogen, Eugene, OR, USA) and KAPA Library Quant kit for Illumina based sequencers (Cape Town, South Africa) prior to equimolar pooling for sequencing. Sequencing was performed on an Illumina HiSeq4000 (San Diego, CA, USA) at lxl51bp through the University of Colorado Microarray and Sequencing Core.

Deconvolution of samples was dependent on the unique dual indices based on Illumina P5 and P7 sequences.

[0386] shRNA counts were normalized using the following equation: where CN is the normalized count, AT is the averaged total count across samples, and ST is the total shRNA count of the normalized sample.

Treatment and control samples were normalized separately using separate (treatment-specific and control-specific) total count averages. Outliers were identified using Grubbs test. The shRNAs were counted by comparing the shRNA library against the obtained sequences and searching for exact sequence match. This method assumed that sequencing errors are equally distributed among nucleotides and shRNAs. Percentage of reduced shRNAs was calculated by comparing the mean read count of the checkpoint blockade treated sample to the IgG control treated sample for the same shRNA. A reduction was considered to be true if the read counts were 80% or less of that of the IgG control group. The percentage of reduced shRNAs was then determined based on the number of shRNAs that were reduced, compared to the total shRNAs per a given gene.

qPCR and Immunob lotting (Western blot analysis)

[0387] NA13, B16F10 and E0771 cell lines were homogenized using QIAshredder (Qiagen), followed by RNA extraction using a RNeasy Plus Mini Kit with gDNA Eliminator (Qiagen). cDNA was synthesized using iScript Reverse Transcription Supermix (Bio-Rad). qPCR for DDR2 was performed using 5' TGGC ATGAGC AGAAAC CTGT 3' (SEQ ID NO: X) forward and 5' ACTTGCCGTGGTGAATTTGC 3' (SEQ ID NO: XI) reverse primers with iQ SYBR Green Supermix (Bio-Rad) run on a Quant Studio 6 Flex Real-Time PCR system (Applied Biosystems). To determine the changes in mRNA expression as measured by qRT- PCR, the AACt method was used. Expression was normalized to internal control β-actin, and the level of gene knockdown was determined by comparing with control cells.

[0388] Whole cell extracts were prepared from NA13, B16F10 and E0771 cell lines using RIPA buffer (50 mM Tris, pH 8.0, 150 mM NaCl, 0.1 % Triton X-100, 0.1 % sodium dodecyl sulfate (SDS) and protease inhibitors (Roche). Following total protein quantification, lysates were separated by SDS-PAGE, and transferred to polyvinylidene difluoride (PVDF, Bio-Rad) membrane using a transfer apparatus according to the manufacturer's instruction (Bio-Rad). After incubation with 5% nonfat milk in TBST (25 mM Tris, 150 mM NaCl. 0.1 % Tween 20, pH 7.5) for one hour, the membrane probed with antibodies against DDR2 (AF2538, 1 : 1,000, R & D Systems) or anti- -actin AC-74 (1 :20,000, Sigma Chemical Co.) monoclonal antibodies overnight. Membranes were washed three times for 10 min with TBST and incubated with a 1 :5,000 dilution of horseradish peroxidase-conjugated anti-Goat (SC-2020, Santa Cruz Biotechnology) or anti-mouse (Bio-Rad) antibodies for 2 hours. Blots were washed with TBST three times and incubated in SuperSignal West Pico Plus

Chemiluminescent Substrate for 5 min at room temperature (Thermo Scientific). The blots were imaged by ChemiDoc imaging system according to the manufacturer's instruction (Bio- Rad).

In vivo studies

[0389] All experiments were approved by the University of Colorado Denver Animal Care and Use Committee, and carried out according to approved protocols. Female C57BL/6 mice (Charles River) were received at 6 weeks old and allowed to acclimate for at least one week in sterile micro isolator cages with constant temperature and humidity. Mice had free access to food and water.

[0390] For NA13, mice were injected with lxlO⁶ cells in ΙΟΟμί sterile PBS subcutaneously in the right hind flank. For the E0771 mammary tumour model, mice were injected with 5 ^χ 10⁴ cells into the in the third left thoracic mammary fat pad. For the MC38 colon carcinoma model, 6-8 week old mice were injected with lxlO⁶ cells. All tumour cells were harvested in log-phase growth on the day of injection.

[0391] Mice were monitored twice weekly for tumour development. Measurements commenced from when the tumour was first palpable. Tumor size was determined using an electronic caliper to measure the length and width, and calculated by (L ^χ W²) 1 2, where L is largest diameter measurement of the tumour and W is, the shorter perpendicular tumor measurement. Animals were randomized into treatment groups ensuring similar average tumour volumes amongst the groups, weighed and identified via ear punch. For treatment randomization, MC38 tumors were allowed to grow to 75-200 mm³ (tumors outside the range were excluded) and animals were evenly distributed to various treatment and control groups.

[0392] Dasatinib was synthesized by Bristol-Myers Squibb laboratories (Princeton, NJ), as previously described. Dasatinib was formulated in 80 mM citrate buffer and administered orally to mice by body weight at a dose of 30mg/kg (MC38, initiated on Day 5 post tumour injection for 10 doses) or 60mg/kg (NA13, initiated on Day 16 post tumour injection for three doses). Mouse anti-PD-1 antibody (IgGl-D265A) and isotype control (IgGl, clone 4F7) were produced by Bristol-Myers Squibb laboratories (Redwood City, CA) and was formulated in PBS and administered IP at a dose of 50 μg/mouse (NA13, initiated on Day 16 for 3 doses; E0771, initiated on Day 7 for 3 doses ), 100 μg/mouse (B16F10, initiated on Day 8 for 3 doses) or 200 μg/mouse (MC38, initiated on Day 5 for two doses). The health of the mice was closely monitored and mice were immediately euthanized if any signs of distress were observed or tumour volume exceeded 15mm in diameter.

[0393] For the B16F10-induced pulmonary metastases model, mice were intravenously challenged with 2 l0⁵ B16F10 cells in 100 μΐ. sterile PBS. Treatment with anti-PD-1 commenced on Day 8 and mice were euthanized on Day 22. Lungs were harvested, formalin- fixed, paraffin-embedded with 5μηι sections cut and H&E stained by the University of Colorado Histology Core. Lungs were analyzed by an American College of Veterinary Pathologists board certified veterinary pathologist.

Single Cells Mass Cytometry by Time-of-Flight (CyTOF)

[0394] NA13 tumours were collected after final measurement day. Tumours were weighed, mechanically dissociated, and enzymatically digested using Liberase DL (Roche) in HBSS for 30 min at 37°C. The solution was passed through a 70μιη cell strainer (Fisherbrand) to obtain a single cell suspension. Cells were counted using a TC-20 (Bio-Rad) with trypan blue exclusion.

[0395] Metal-conjugated antibodies were purchased from Fluidigm and used at manufacturer recommended concentrations. Live tumor and spleen cells were washed with Maxpar PBS (Fluidigm) and counted on a Vi-CELL Cell Viability Analyzer (Beckman Coulter), normalizing to a final count of 2-3x10⁶ cells per sample in RPMI 1640 medium (Corning cellgro). Live vs dead staining was achieved by resuspending cells in a solution of 25mM cisplatin (Fluidigm) in RPMI 1640 medium and incubating for 1 minute at room temperature. Samples were quenched with Maxpar Cell Staining Buffer (Fluidigm), spun down at 500g for 5 minutes, and then fixed by resuspending 1.6% PFA in PBS for 10 minutes at room temperature. The cells were washed once with Maxpar Cell Staining Buffer to remove fixative from the solution and once with Maxpar Barcode Perm Buffer to begin cell permeabilization for barcoding, centrifuging at 800g at 22°C per spin. Barcoding was performed as per manufacturer's recommendations with palladium metal barcoding reagents (Fluidigm) where samples were eventually pooled together, with spleen samples pooled separately from tumor samples. Treatment with anti-mouse FcyE/FCym-blocking antibody 2.4G2 (prepared in-house) for 10 minutes was followed by surface staining at manufacturer's recommended antibody staining concentrations (Fluidigm). The cells were stained for 30 minutes at room temperature, then washed with Maxpar Cell Staining Buffer, and permeabilized in a 4X FoxP3 Fix/Perm Buffer overnight at 4°C. The cells were washed once with IX FoxP3 Fix/Perm Buffer, intracellular staining was done for 2 hours at 4°C following the manufacturer's protocol (Fluidigm), then washed twice with IX FoxP3 Perm Buffer. The cells were incubated in 1.6% PFA in PBS with ΙΟΟηΜ Iridium nucleic acid intercalator (Fluidigm) overnight and washed twice in ddFhO prior to analysis on a Helios mass cytometer (CyTOF, Fluidigm) at an event rate of 400 to 500 events per second.

[0396] MC38 tumours were collected in RPMI medium, and then enzymatically dissociated using mouse tumor dissociation kit and gentleMACS dissociator (Miltenyi Biotec) according to the manufacturer's protocol. The cells were stained with a panel of metal isotope conjugated anti-mouse antibodies (DVS Sciences).

[0397] Data was analyzed with Phenograph. The 1.0.153 version of R studio was downloaded from the official R Web site (www.r-project.org/). Release 3.6 of the cytofkit package was downloaded from Bioconductor (www.

bioconductor.org/packages/release/bioc/html/cytofkit.html) and opened in R. Manually gated singlet (19Ir + 193Ir +), viable (195Pt +) events were imported into cytofkit, subjected to PhenoGraph analysis, and clustered based on 30 markers, with the following settings: merge method: 'min' (100,380 events total, 25,095 events from each file), transformation:

cytofAsinh, cluster method: Rphenograph, visualization method: tSNE, and cellular progression: NULL. PhenoGraph identified 23 unique clusters. These results were visualized via the R package "Shiny" where labels, dot size, and cluster color were customized. Clusters were colored according to phenotype based on the median expression of various markers. The frequency of each cluster was determined via csv files generated by the algorithm. All graphs were made using GraphPad Prism 7. P-values are calculated using the 2-Way ANOVA with multiple comparisons with statistical analyses subjected to multiple testing correction.

Next-generation sequencing for mouse T-cell receptor clonality

[0398] Immunosequencing of the CDR3 regions of mouse TCRP chains and clonality quantification of tumor-infiltrated T-cells was performed using the ImmunoSEQTM Assay (Adaptive Biotechnologies) Tumors were excised from mice and immediately snap frozen in liquid nitrogen and stored at -80°C. Genomic DNA was isolated by mincing, followed by extraction using a DNeasy kit (Qiagen). TCR-β CDR3 regions were amplified in a bias- controlled multiplex PCR and subjected to high-throughput sequencing. Sequence were collapsed and filtered to identify and quantitate the absolute abundance of each unique TCR- β CRD3 region as previously described.

Analyses of TCR- β Sequencing data

[0399] Clonality was defined as the entropy of the TCR-β frequency distribution and was calculated as: Clonality =l-(entropy/log2[No. of unique TCRs])

[0400] Here entropy, a measure of diversity within a complex data set, is also known as the Shannon- Wiener index, Shannon's diversity index or Shannon's entropy. Thus "0" represents a diverse repertoire and "1" is a completely clonal repertoire.

Tumor expression analysis (RNAseq)

[0401] Tumours were mechanically disassociated with a homogenizer (Omni International), then passed through a QIAshredder (Qiagen), gDNA Eliminator columns (Qiagen), and RNeasy Plus Mini Kit, as per manufacturer's instructions, for RNA extraction. Library preparation and sequencing were performed by Novogene. Quality and quantity of RNA was analyzed using Nanodrop, agarose gel electrophoresis, and Agilent 2100. mRNA was purified from total RNA using poly-T oligo-attached magnetic beads. mRNA is first fragmented randomly by fragmentation buffer followed by NEB library preparation (New England BioLabs). First strand cDNA was synthesized using random hexamer primer and M-MuLV Reverse Transcriptase (RNase H-), with second strand cDNA synthesized using DNA Polymerase I and RNase H. Double-stranded cDNA was purified using AMPure XP beads (Beckman Coulter). Exonuclease was used to eliminate overhangs on the double-stranded cDNA. 3' ends were adenylated, and NEBNext adaptors were ligated in preparation for hybridization. Library fragments were purified with AMPure XP system (Beckman Coulter). Sequencing was performed by Novogene on an Illumina platform paired end 150bp with 20 million reads per sample.

[0402] Transcript quantification was done using RSEM (vl.2.31) with default parameters and Bowtie2 (v2.1.0) as the read aligner. Reads were mapped directly to mouse transcripts and summarized at the gene level using annotations from Ensembl r91, genome build

GRCm38.p5. Quantification of genes as expected counts were compiled. Differential expression was performed using voom function in the limma R package. Genes with an average expected count less than 5 were removed, normalization factors were calculated, and comparisons between groups were made using the voom function using default parameters.

[0403] The curated gene set, canonical pathways (C2.CP) was downloaded from the MSigDB collection of genes sets (v6.1). Human genes were mapped then replaced with mouse genes using the vertebrate homology mapping from the Mouse Genome Informatics resources (www.informatics.jax.org/downloads/reports/HOM_A110rganism.rpt). The updated C2.CP gene set with mouse genes and the log fold change ranked list of genes from the RNAseq experiment comparing control and shDDR2 NA13 tumours grown in syngeneic mice treated with anti-PD-1 were used as input to Gene Set Enrichment Analysis (GSEA). GSEA was run in Pre-Ranked mode with default parameters.

[0404] To identify immune related gene sets that were significantly up-regulated, we further filtered the full set of GSEA results, based on the jaccard distance (number of genes in the intersection divided by the number of genes in the union between any two gene sets). This quantifies the overlap in genes between two gene sets. We selected gene sets that shared > 0.25, were significantly up-regulated (FDR < 0.01) and were immune related. From the comparison of control and shDDR2 NA13 tumours grown in syngeneic mice treated with anti-PD-1, we found 39 gene sets that met these criteria. These are the gene sets displayed in Figure 11.

[0405] Results from CIBERSORT (Mootha, V.K et al. Nature Genetics 34, 267-273 (2003); the contents of which are incorporated herein by reference in their entirety) using TCGA bladder cancer gene expression was downloaded from The Cancer Immune Atlas (TCIA) and processed according to TCIA protocols.

Example 2: Targeting DDR2 enhances tumour response to anti-PD-1 immunotherapy

[0406] Targeting antibodies to programmed cell death protein- 1 (PD-1) has proven to be an effective treatment for a range of cancer types, including bladder cancer. While increased overall survival and durable responses are observed in a subset of patients, the majority still do not benefit from these treatment modalities. Furthermore, immune related adverse events (irAEs) occur in a subset of patients, stemming from an over-stimulation of the immune system and result in patient morbidity. Utilizing an shRNA-based screen of select druggable targets for which there are FDA-approved drugs, this study identified genes whose knockdown in tumours were able to potentiate response to anti-PD-1 immunotherapy. The top gene identified through our screen was Discoidin Domain Receptor 2 (DDR2), a collagen receptor, which when activated, triggers a signalling cascade involving SHP-2, SRC and MAP kinases. Here we show that both shRNA-mediated knockdown and pharmacologic inhibition of DDR2, when combined with anti-PD-1 leads to tumour shrinkage and clearance in multiple cancer models.

[0407] To assess tumour responses to anti-PD-1 in an immune-competent animal, a syngeneic cell line model of murine bladder cancer derived from chemically induced tumours that are known to have molecular characteristics similar to those found in human bladder cancer was established. Tumours were excised from N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-treated C57BL/6 mice and adapted to in vitro cell culture to generate the NA13 cell line. Whole exome sequencing of NA13 revealed missense mutations in Trp53, Airdla, and EP300 which are commonly found in BBN-induced mouse bladder tumours, and in human bladder cancer datasets.

[0408] Using NA13, we performed an in vivo screen by subcutaneously injecting NA13 cells containing a pooled 34-gene shRNA library (5 shRNAs per gene) into syngeneic immune- competent mice. To identify candidate genes whose depletion led to enhanced cell death mediated by the immune-activating anti-PD-1, shRNA constructs were quantified in tumour samples using next-generation sequencing, then genes were prioritized that were

preferentially lost in the anti-PD-1 -treated compared to IgG-treated group (Fig. 9a).

Preferential loss was determined using three different methods: (1) percentage of total shRNAs per gene with reduced counts (Fig. 9b); (2) ranking genes by their first and second- most reduced shRNA based on their average fold change (Fig. 9c); and (3) the number of shRNA constructs per gene identified among the top 15% most depleted shRNAs in the library (Fig. 9d). Across all three methods, DDR2 was identified as the top ranked gene.

[0409] To validate the screening results, DDR2 was knocked-down in the NA13 cell line and tumour growth was tracked in the presence and absence of anti-PD-1 treatment. Stable shRNA-mediated knockdown of DDR2 was confirmed by qPCR (Fig. 13a) and immunoblot (Fig. 10a). The combination of DDR2 depletion and treatment with anti-PD-1 was highly effective in controlling NA13 tumours producing a synergistic reduction in tumor volume compared to anti-PD-1 or sDDR2 alone. (Fig. 10b). Since DDR2 alterations

(overexpression, amplification and mutations) are known to drive more aggressive phenotypes in several types of cancer, we tested the generalizability of our NA13 results using breast, melanoma, and colon cancer cell lines. Knockdown of DDR2 in B16F10, a melanoma cell line, was confirmed (Fig 2c, and Fig. 13b). Anti-PD-1 treatment of mice was effective at reducing pulmonary metastases only in shDDR2 B16F10 cells (Fig. lOd, e). A dramatic reduction or elimination of visible tumours on the lung surface was observed (Fig. lOd). Upon histologic evaluation, both shControl and shDDR2 allografts treated with IgG presented with high tumour infiltration, areas of focal inflammation and necrosis, and loss of bronchial epithelium (Fig. 14). In contrast, the mice bearing shDDR2 tumours treated with anti-PD-1 exhibited minimal tumour burden, and in some, a complete absence of visible tumours (Fig. 14). Single gene validation with shDDR2 in the mammary tumour cell line E0771 showed a similar effect, where knockdown of DDR2 (Fig. lOf and Fig. 13c) rendered the tumours more sensitive to anti-PD-1 treatment (Fig. lOg, h). [0410] RNAseq and Gene-Set Enrichment Analysis (GSEA) from mice bearing shControl and shDDR2 NA13 tumours treated with anti-PD-1 were analysed to discern differences in the tumour expression profile. This analysis revealed a strong immune response in the shDDR2 tumours treated with anti-PD-1. Upregulation of immune-related pathways was specific to the shDDR2 tumours treated with anti-PD-1 compared to IgG treatment; this strong immune response was not found in shControl tumours treated with anti-PD-1. A strong T cell signature was observed with multiple T cell receptor (TCR) signalling pathways significantly enriched in the former group (Fig. 11a). Cytometry by time of flight (CyTOF) analysis of these tumours revealed increased CD8⁺ T cell infiltration into shDDR2 tumours treated with anti-PD-1 (Fig lib), which was not seen in the spleen (Fig. 15).

[0411] DDR2 is a target of multiple FDA-approved kinase inhibitors. Dasatinib, the most potent of these FDA-approved inhibitors, has been studied in multiple clinical trials, including lung cancer patients with activating DDR2 mutations. To further evaluate the efficacy of targeting DDR2, the combination of dasatinib and anti-PD-1 was tested. Whereas therapeutic blockade of PD-1 or DDR2 alone had little or no effect on NA13 tumours, treatment with the combination of dasatinib and anti-PD-1 showed a significant reduction in tumour burden (Fig. 12a). Importantly, similar results were replicated in a murine colon cancer model, MC38 (Fig. 12b, c). The anti-tumour effect of dasatinib and anti-PD-1 may represent an effect of dasatinib, not only on the tumour, but on the host immune response as well, since dasatinib has been shown to reduce T regulatory cell numbers.

[0412] CyTOF analysis of MC38 tumours in mice receiving dasatinib and anti-PD-1 showed a significant and synergystic increase in both splenic and tumour-infiltrating CD8⁺ T cells (Fig. 12e, Fig. 16). Since these findings with dasatinib and anti-PD-1 combination reflect a similar pattern as seen in the shDDR2 and anti-PD-1 combination, this suggests a direct role of tumour DDR2 expression in mediating this immune response (Fig. lib). While dasatinib and anti-PD-1 treatment increased CD8⁺ T cells in both the tumour and spleen, treatment of shDDR2 tumours with anti-PD-1 led to increased CD8⁺ T cells only in the tumour. In both cases, the observed increase in CD8⁺ T cells is unique to the combination therapy, and indicates a specific immune response to tumour antigens as a result of both treatments. The presence of CD8⁺ T cells in the tumour microenvironment and the expansion of pre-existing, tumour antigen-specific T cell clones is critical too, and predictive of a favourable response with anti-PD-1 therapy. Hence, it was hypothesized that the enhanced anti -tumour activity and the accompanied increase in tumour CD8⁺ T cells upon combined shDDR2 or dasatinib and anti-PD-1 immunotherapy may both be accounted for by clonal expansion of tumour antigen-specific T cell clones. Assessment of MC38 tumours revealed increased clonality as shown by a more pronounced expansion of specific TCR Vb sequences in response to dasatinib and anti-PD-1 combination therapy compared to either dasatinib or anti-PD-1 monotherapy (Fig. 12f).

[0413] To identify associations between DDR2 expression and inferred immune infiltration in human tumours, the relative abundance of immune populations were estimated using the CIBERSORT method and bulk tumour RNAseq data from The Cancer Genome Atlas (TCGA) (Fig. 17). Low DDR2 expression is associated with increased CD8⁺ T cells, and activated dendritic cell infiltration (Fig. 12g), which has been shown to be predictive of better patient outcome. Human tumours with low DDR2 expression also exhibit reduced levels of macrophages (Fig. 12f), whose presence has been shown to negatively impact the efficacy of anti-PD-1²⁹.

[0414] These results demonstrate the synergistic effects of targeting DDR2, a collagen receptor in combination with PD-1 inhibition. The pre-clinical efficacy of the DDR2 and PD-1 -targeted combination provided compelling evidence for the initiation of, and support for the dasatinib arm of the FRACTION-Lung trial (NCT02750514), which evaluates nivolumab in combination with a variety of therapeutic options in immunooncology refractory patients.

Table 1: Gene shRNA Library

OTHER EMBODIMENTS

[0415] It is to be understood that while the disclosure has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the disclosure, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. A method of treating cancer in a subject in need thereof, the method comprising, administering to the subject,

(a) a therapeutically-effective amount of a first composition that specifically targets a target gene,

(b) a therapeutically-effective amount of a second composition that specifically targets a component of an immune checkpoint or

(c) a combination of a therapeutically-effective amount of the composition of (a) and a therapeutically-effective amount of the composition of (b),

wherein the administration of (a), (b) or (c) reduces viability of a cancer cell, reduces or inhibits proliferation of a cancer cell or induces death of a cancer cell of the subject.

2. The method of claim 1, wherein a level of expression of a coding sequence or a non- coding sequence associated with the target gene is higher in the cancer cell than the level of expression of the coding sequence or the non-coding sequence associated with the target gene in a non-cancer cell.

3. The method of claim 1, wherein a level of activity of a coding sequence or a non-coding sequence associated with the target gene is higher in the cancer cell than the level of activity of the coding sequence or the non-coding sequence associated with the target gene in a non-cancer cell.

4. The method of claim 1, wherein a level of activity of a target protein encoded by the target gene is higher in the cancer cell than the level of activity of the target protein encoded by the target gene in a non-cancer cell.

5. The method of claim 1, wherein a level of expression of a coding sequence or a non- coding sequence associated with the target gene is lower in the cancer cell than the level of expression of the coding sequence or the non-coding sequence associated with the target gene in a non-cancer cell.

6. The method of claim 1, wherein a level of activity of a coding sequence or a non-coding sequence associated with the target gene is lower in the cancer cell than the level of activity of the coding sequence or the non-coding sequence associated with the target gene in a non-cancer cell.

7. The method of claim 1, wherein a level of activity of a target protein encoded by the target gene is lower in the cancer cell than the level of activity of the target protein encoded by the target gene in a non-cancer cell.

8. The method of any one of claims 1-7, wherein a level of expression of a coding sequence or a non-coding sequence associated with component of an immune checkpoint is higher in the cancer cell than the level of expression of the coding sequence or the non-coding sequence associated with component of an immune checkpoint in a non-cancer cell.

9. The method of any one of claims 1-7, wherein a level of activity of a coding sequence or a non-coding sequence associated with the component of an immune checkpoint is higher in the cancer cell than the level of activity of the coding sequence or the non-coding sequence associated with the component of an immune checkpoint in a non-cancer cell.

10. The method of any one of claims 1-7, wherein a level of activity of the component of an immune checkpoint is higher in the cancer cell than the level of activity of the component of an immune checkpoint in a non-cancer cell.

11. The method of any one of claims 1-7, wherein a level of expression of a coding sequence or a non-coding sequence associated with component of an immune checkpoint is lower in the cancer cell than the level of expression of the coding sequence or the non-coding sequence associated with component of an immune checkpoint in a non-cancer cell.

12. The method of any one of claims 1-7, wherein a level of activity of a coding sequence or a non-coding sequence associated with the component of an immune checkpoint is lower in the cancer cell than the level of activity of the coding sequence or the non-coding sequence associated with the component of an immune checkpoint in a non-cancer cell.

13. The method of any one of claims 1-7, wherein a level of activity of the component of an immune checkpoint is lower in the cancer cell than the level of activity of the component of an immune checkpoint in a non-cancer cell.

14. The method of any one of claims 1-13, wherein the non-cancer cell is a healthy cell.

15. The method of any one of claims 2-14, wherein the cancer cell is in vivo, ex vivo, in vitro or in situ.

16. The method of any one of claims 2-15, wherein the non-cancer cell is in vivo, ex vivo, in vitro or in situ.

17. The method of any one of claims 1-16, wherein the cancer comprises a solid cancer.

18. The method of any one of claims 1-17, wherein the cancer comprises a cancer derived from an epithelial cell, a mesenchymal cell, or a neural cell.

19. The method of any one of claims 1-18, wherein the cancer comprises a lung cancer.

20. The method of any one of claims 1-18, wherein the cancer is a breast cancer.

21. The method of any one of claims 1-18, wherein the cancer is a bladder cancer.

22. The method of any one of claims 1-18, wherein the cancer is a skin cancer.

23. The method of any one of claims 1-16, wherein the cancer comprises a liquid cancer.

24. The method of claim 23, wherein the cancer is a leukemia.

25. The method of any one of claims 1-24, wherein the cancer comprises a stem cell or is derived from a stem cell.

26. The method of any one of claims 1-25, wherein the cancer is metastatic.

27. The method of any one of claims 1-26, wherein the target gene is selected from the group consisting of ADAM metallopeptidase domain 10 (ADAMIO), alanyl aminopeptidase (ANPEP), carbonic anhydrase (CA1), carbonic anhydrase (CA2), carbonic anhydrase (CA9), C-C motif chemokine ligand 2 (CCL2), cluster of differentiation 37 (CD37), collagen type I alpha 1 chain (COL1A1), C-X-C motif chemokine ligand 12 (CXCL12), C-X-C motif chemokine receptor 4 (CXCR4), discoidin domain receptor tyrosine kinase 2 (DDR2), dipeptidyl peptidase 4 (DPP4), E2F transcription factor 1 (E2F1), erb-b2 receptor tyrosine kinase 2 (ERBB2), coagulation factor III, tissue factor (F3), fatty acid amide hydrolase (FAAH), fibroblast activation protein alpha (FAP), glutathione S-transf erase pi 1 (GSTP1), interleukin 7 receptor (IL7R), matrix

metallopeptidase 1 (MMP1), matrix metallopeptidase 14 (MMP14), matrix metallopeptidase 2 (MMP2), matrix metallopeptidase 9 (MMP9), MPL proto-oncogene thrombopoietin receptor (MPL), pyruvate dehydrogenase kinase 1 (PDK1), progesterone receptor (PGR), presenilin 1 (PSEN1), protein tyrosine kinase 2 beta (PTK2B), ribosomal protein S6 kinase Bl (RPS6KB1), solute carrier family 16 member 1 (SLC16A1), solute carrier family 3 member 2 (SLC3A2), Spl transcription factor (SP1), tyrosinase related protein 1 (TYRPl) and vascular endothelial growth factor C (VEGFC).

28. The method of claim 27, wherein the target gene is DDR2.

29. The method of any one of claims 1-28, wherein the composition of (a) comprises a nucleic acid sequence that hybridizes with a coding sequence or a non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

30. The method of claim 29, wherein the composition of (a) comprises an antisense RNA, a short hairpin RNA (shRNA), an interfering RNA (RNAi), a small interfering RNA (siRNA), a piwi RNA (piRNA), a microRNA (miRNA) or combination thereof that hybridizes with a coding sequence or a non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

31. The method of claim 29, wherein the composition of (a) comprises a guide RNA (gRNA) that hybridizes with a coding sequence or a non-coding sequence associated with the target gene.

32. The method of claim 31, wherein the gRNA is a single- stranded gRNA (sgRNA).

33. The method of claim 31 or 32, wherein the gRNA is operably linked to an effector.

34. The method of claim 33, wherein the effector comprise a nuclease or a nuclease domain.

35. The method of claim 34, wherein the nuclease or a nuclease domain comprises a sequence isolated or derived from a RNA-guided DNA endonuclease enzyme associated with CRISPR, a Transcription activator-like effector nucleases (TALEN), a Zinc-finger nuclease (ZFN), an endonuclease or a Type IIS endonuclease.

36. The method of claim 35, wherein the RNA-guided DNA endonuclease enzyme associated with CRISPR is Cas9.

37. The method of any one of claims 34-36, wherein the nuclease or a nuclease domain induces a single-strand break in a coding sequence or a non-coding sequence associated with the target gene.

38. The method of any one of claims 34-36, wherein the nuclease or a nuclease domain induces a double-strand break in a coding sequence or a non-coding sequence associated with the target gene.

39. The method of claim 29, wherein the composition of (a) comprises a short hairpin RNA (shRNA) that hybridizes with a coding sequence or a non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

40. The method of claim 29, wherein the composition of (a) comprises an aptamer that binds to a coding sequence or a non-coding sequence associated with the target gene, and wherein the binding of the aptamer to the sequence associated with the target gene reduces or inhibits transcription or translation of the coding sequence or the non-coding sequence associated with the target gene.

41. The method of claim 29, wherein the composition of (a) comprises an aptamer that binds to a target protein encoded by the target gene, and wherein the binding of the aptamer to the target protein encoded by the target gene reduces or inhibits an activity of the target protein encoded by the target gene.

42. The method of claim 40 or 41, wherein the aptamer comprises a DNA sequence.

43. The method of any one of claims 1-28, wherein the composition of (a) comprises a protein that binds a coding sequence or a non-coding sequence associated with the target gene, and wherein the binding of the protein to the sequence associated with the target gene reduces or inhibits transcription or translation of the coding sequence or the non-coding sequence associated with the target gene.

44. The method of any one of claims 1-28, wherein the composition of (a) comprises a protein that binds a target protein encoded by the target gene, and wherein the binding of the protein to the target protein encoded by the target gene reduces or inhibits an activity of the target protein encoded by the target gene.

45. The method of claim 43 or 44, wherein the composition of (a) comprises an antibody, an antibody fragment or an antibody mimetic.

46. The method of claim 45, wherein the antibody comprises a monoclonal antibody.

47. The method of claim 46, wherein the monoclonal antibody is a human monoclonal antibody or a humanized monoclonal antibody.

48. The method of claim 43 or 44, wherein the composition of (a) comprises an aptamer.

49. The method of any one of claims 1-28, wherein the composition of (a) comprises a small molecule that binds a coding sequence or a non-coding sequence associated with the target gene, and wherein the binding of the small molecule to the sequence associated with the target gene reduces or inhibits transcription or translation of the coding sequence or the non-coding sequence associated with the target gene.

50. The method of any one of claims 1-28, wherein the composition of (a) comprises a small molecule that binds a target protein encoded by the target gene, and wherein the binding of the small molecule to the target protein encoded by the target gene reduces or inhibits an activity of the target protein encoded by the target gene.

51. The method of 49 or 50, wherein the small molecule comprises an organic small molecule.

52. The method of claim 51, wherein the small molecule is a kinase inhibitor.

53. The method of claim 52, wherein the kinase inhibitor is abemaciclib, acalabrutinib, afatinib, alectinib, axitinib, baricitinib, binimetinib, bosutinib, brigatinib,cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, encorafenib, erlotinib, everolimus, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, midostaurin, neratinib, nilotinib, nintedanib, osimertinib, palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, ruxolitinib, sirolimus, sorafenib, sunitinib, temsirolimus, tofacitinib, trametinib, vandetanib or vemurafenib.

54. The method of claim 53, wherein the kinase inhibitor is dasatinib.

55. The method of 49 or 50, wherein the small molecule comprises an inorganic small molecule.

56. The method of any one of claims 1 to 55, wherein the composition of (b) comprises an antagonist or an inhibitor of the component of an immune checkpoint, wherein the antagonist or the inhibitor disrupts or blocks an immune checkpoint in an immune cell.

57. The method of claim 56, wherein the composition of (b) comprises a nucleic acid sequence that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

58. The method of claim 57, wherein the composition of (b) comprises an antisense RNA, a short hairpin RNA (shRNA), an interfering RNA (RNAi), a small interfering RNA (siRNA), a piwi RNA (piRNA), a microRNA (miRNA) or combination thereof that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

59. The method of claim 57, wherein the composition of (b) comprises a guide RNA (gRNA) that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint.

60. The method of claim 59, wherein the gRNA is a single- stranded gRNA (sgRNA).

61. The method of claim 59 or 60, wherein the gRNA is operably linked to an effector.

62. The method of claim 61, wherein the effector comprise a nuclease or a nuclease domain.

63. The method of claim 62, wherein the nuclease or a nuclease domain comprises a sequence isolated or derived from a RNA-guided DNA endonuclease enzyme associated with CRISPR, a transcription activator-like effector nucleases (TALEN), a zinc-finger nuclease (ZFN), an endonuclease or a type IIS endonuclease.

64. The method of claim 63, wherein the RNA-guided DNA endonuclease enzyme associated with CRISPR is Cas9.

65. The method of any one of claims 62-64, wherein the nuclease or a nuclease domain induces a single-strand break in a coding sequence or a non-coding sequence associated with the component of an immune checkpoint.

66. The method of any one of claims 62-64, wherein the nuclease or a nuclease domain induces a double-strand break in a coding sequence or a non-coding sequence associated with the component of an immune checkpoint.

67. The method of claim 57, wherein the composition of (b) comprises a short hairpin RNA (shRNA) that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

68. The method of claim 57, wherein the composition of (b) comprises an aptamer that binds to a coding sequence or a non-coding sequence associated with the component of an immune checkpoint, and wherein the binding of the aptamer to the sequence associated with the component of an immune checkpoint reduces or inhibits transcription or translation of the coding sequence or the non-coding sequence associated with the component of an immune checkpoint.

69. The method of claim 57, wherein the composition of (b) comprises an aptamer that binds to the component of an immune checkpoint, and wherein the binding of the aptamer to the component of an immune checkpoint reduces or inhibits an activity of the component of an immune checkpoint.

70. The method of claim 68 or 69, wherein the aptamer comprises a DNA sequence.

71. The method of claim 57, wherein the composition of (b) comprises a small molecule that binds a coding sequence or a non-coding sequence associated with the component of an immune checkpoint, and wherein the binding of the small molecule to the sequence associated with the component of an immune checkpoint reduces or inhibits transcription or translation of the coding sequence or the non-coding sequence associated with the component of an immune checkpoint.

72. The method of claim 57, wherein the composition of (b) comprises a small molecule that binds a component of an immune checkpoint, and wherein the binding of the small molecule to the component of an immune checkpoint reduces or inhibits an activity of the component of an immune checkpoint.

73. The method of 71 or 72, wherein the small molecule comprises an organic small molecule.

74. The method of 71 or 72, wherein the small molecule comprises an inorganic small molecule.

75. The method of claim 57, wherein the composition of (b) comprises a protein that binds a coding sequence or a non-coding sequence associated with the component of an immune checkpoint, and wherein the binding of the protein to the sequence associated with the component of an immune checkpoint reduces or inhibits transcription or translation of the coding sequence or the non-coding sequence associated with the component of an immune checkpoint.

76. The method of claim 57, wherein the composition of (b) comprises a protein that binds a component of an immune checkpoint, and wherein the binding of the protein to the component of an immune checkpoint reduces or inhibits an activity of the component of an immune

checkpoint.

77. The method of claim 75 or 76, wherein the composition of (b) comprises an antibody, an antibody fragment or an antibody mimetic.

78. The method of claim 77, wherein the antibody comprises a monoclonal antibody.

79. The method of claim 78, wherein the monoclonal antibody is a human monoclonal antibody or a humanized monoclonal antibody.

80. The method of claim 75 or 76, wherein the composition of (b) comprises an aptamer.

81. The method of any one of claims 1-80, wherein the component of an immune checkpoint is selected from the group consisting of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death-ligand 1 (PD-Ll) and programmed death-1 (PD-1).

82. The method of any one of claims 1-80, wherein the component of an immune checkpoint is CTLA-4 and wherein the antagonist or the inhibitor of the component of an immune checkpoint comprises Tremelimumab or Ipilumamab.

83. The method of any one of claims 1-80, wherein the component of an immune checkpoint is PD-Ll and wherein the antagonist or the inhibitor of the component of an immune checkpoint comprises Atezolizumab.

84. The method of any one of claims 1-80, wherein the component of an immune checkpoint is PD-1 and wherein the antagonist or the inhibitor of the component of an immune checkpoint comprises Nivolumab or Pembrolizumab.

85. The method of any one of claims 1-84, wherein the target gene is DDR2 and wherein the component of the immune checkpoint is PD-1.

86. The method of claim XI, wherein the antagonist or the inhibitor of DDR2 comprises dasatinib and wherein the antagonist or the inhibitor of PD-1 comprises an anti-PD-1 antibody.

87. A method of identifying a gene as a therapeutic target, comprising,

(a) generating a plurality of nucleic acid molecules each comprising a sequence having at least 50% complementarity to a coding sequence or a non-coding sequence associated with at least one target gene, wherein the at least one target gene is expressed in a cancer cell;

(b) introducing the plurality of nucleic acid molecules of (a) into at least one cell of a cultured cell line under conditions sufficient to allow for hybridization of at least one nucleic acid molecule of (a) to a sequence encoding a target gene to produce at least one nucleic acid duplex, wherein the formation of the duplex induces a reduction or an elimination of expression of the target gene in the cell, to produce a plurality of transformed cells;

(c) introducing the plurality of transformed cells of (b) into a non-human animal to produce a tumor in an in vivo model system; and

(d) administering to the non-human animal an amount of a composition comprising an antagonist or an inhibitor of a component of an immune checkpoint, wherein the antagonist or the inhibitor induces an immune checkpoint blockade in at least one cell of the tumor of (c).

88. The method of claim 87, further comprising

(e) removing the tumor of (c) to produce a biological sample and

(f) assaying for a presence or an absence of each nucleic acid molecule of the plurality of nucleic acid molecules of (a) obtained from the biological sample of (e),

wherein an absence of a nucleic acid molecule of the plurality of nucleic acid molecules of (a) indicates that the nucleic acid molecule hybridized with a sequence associated with at least one target gene and

wherein an identity of the absent nucleic acid molecule indicates an identity of the target gene.

89. The method of claim 87, further comprising

(e) removing the tumor of (c) to produce a biological sample and

(f) assaying for an abundance of each nucleic acid molecule of the plurality of nucleic acid molecules of (a) obtained from the biological sample of (e),

wherein an reduced abundance of a nucleic acid molecule of the plurality of nucleic acid molecules of (a) compared to an abundance level of the nucleic acid in a non-cancer cell indicates that the nucleic acid molecule having reduced abundance hybridized with a sequence associated with at least one target gene and wherein an identity of the nucleic acid molecule having a reduced abundance indicates an identity of the target gene.

90. The method of claim 89, wherein the non-cancer cell is isolated or derived from the non- human animal of (c) and (d).

91. The method of claim 90, wherein the non-cancer cell is isolated or derived prior to the introduction of the plurality of transformed cells to form the tumor of (c).

92. The method of claim 90, wherein the non-cancer cell is isolated or derived during the formation of the tumor of (c).

93. The method of claim 90, wherein the non-cancer cell is isolated or derived after the introduction of the plurality of transformed cells to form the tumor of (c).

94. The method of any one of claims 87-93, wherein the non-cancer cell is the same cell type as the cancer cell, prior to the transformation of the cancer cell from a benign to a malignant cell.

95. A method of treating cancer in a subject in need thereof, the method comprising, administering to the subject,

(a) a therapeutically-effective amount of a first composition that specifically targets a gene identified according to the method of any one of claims 87-94,

96. A method of producing a cultured cell line, comprising,

(a) contacting one or more mutagens and a non-human animal under conditions sufficient for the one or more mutagens to access a nucleic acid sequence of the non-human animal to produce a plurality of transformed cells;

(b) isolating the plurality of transformed cells of (a) from the non-human animal; and

(c) maintaining the isolated plurality of transformed cells of (b) ex vivo under conditions sufficient to produce a cultured cell line.

97. The method of claim 96, wherein the non-human animal is a mouse.

98. The method of claim 96 or 97, wherein the one or more mutagens comprise radiation, a plurality of nanoparticles, an inhibitor of one or more DNA repair pathway(s), a DNA intercalating agent, a nuclease, an endonuclease, a DNase and an RNase.

99. The method of claim 98, wherein the plurality of nanoparticles comprise a component of or derived from component of a cigarette, a burnt remnant of a cigarette, cigarette smoke or any combination thereof.

100. A cultured cell line produced by the method of any one of claims 96-99.

101. A method of treating cancer in a subject in need thereof, the method comprising,

administering to the subject a therapeutically-effective amount of a composition that specifically targets a target gene,

wherein the subject is identified as having

(1) an equal level or an increased level of expression of a coding sequence or a non- coding sequence associated with the target gene in a least one cancer cell compared to a level of expression of the coding sequence or the non-coding sequence associated with the target gene in at least one non-cancer cell,

(2) an equal level or an increased level of activity of a coding sequence or a non-coding sequence associated with the target gene in a least one cancer cell compared to a level of activity of the coding sequence or the non-coding sequence associated with the target gene in at least one non-cancer cell, or

(3) an equal level or an increased level of activity of a target protein encoded by the target gene in a least one cancer cell compared to a level of activity of the target protein encoded by the target gene in at least one non-cancer cell;

wherein the composition comprises a nucleic acid, a protein or a small molecule that reduces the level of expression or the level of activity of the coding sequence or the non-coding sequence associated with the target gene or reduces the level of activity of the target protein encoded by the target gene, and

wherein the composition reduces viability of a cancer cell, reduces or inhibits

proliferation of a cancer cell or induces death of a cancer cell of the subject.

102. The method of claim 101, wherein the method further comprises

administering to the subject a therapeutically-effective amount of a second composition that specifically targets a component of an immune checkpoint,

wherein the second composition comprises a nucleic acid, a protein or a small molecule reduces the level of expression or the level of activity of the coding sequence or the non-coding sequence associated with the component of an immune checkpoint or reduces the level of activity of the component of the immune checkpoint, and

wherein the second composition reduces viability of a cancer cell, reduces or inhibits proliferation of a cancer cell or induces death of a cancer cell of the subject.

103. A method of treating cancer in a subject in need thereof, the method comprising,

administering to the subject a therapeutically-effective amount of a composition that specifically targets a component of an immune checkpoint,

wherein the subject is identified as having

(1) an equal level or a decreased level of expression of a coding sequence or a non-coding sequence associated with the target gene in a least one cancer cell compared to a level of expression of the coding sequence or the non-coding sequence associated with the target gene in at least one non-cancer cell,

(2) an equal level or a decreased level of activity of a coding sequence or a non-coding sequence associated with the target gene in a least one cancer cell compared to a level of activity of the coding sequence or the non-coding sequence associated with the target gene in at least one non-cancer cell, or (3) an equal level or a decreased level of activity of a target protein encoded by the target gene in a least one cancer cell compared to a level of activity of the target protein encoded by the target gene in at least one non-cancer cell;

wherein the composition comprises a nucleic acid, a protein or a small molecule reduces the level of expression or the level of activity of the coding sequence or the non-coding sequence associated with the component of an immune checkpoint or reduces the level of activity of the component of the immune checkpoint, and

wherein the composition reduces viability of a cancer cell, reduces or inhibits

104. The method of any one of claims 101-103, wherein the non-cancer cell is a healthy cell.

105. The method of any one of claims 101-104, wherein the cancer cell is in vivo, ex vivo, in vitro or in situ.

106. The method of any one of claims 101-105, wherein the non-cancer cell is in vivo, ex vivo, in vitro or in situ.

107. The method of any one of claims 101-106, wherein the cancer comprises a solid cancer.

108. The method of any one of claims 101-107, wherein the cancer comprises a cancer derived from an epithelial cell, a mesenchymal cell, or a neural cell.

109. The method of any one of claims 101-107, wherein the cancer comprises a lung cancer.

110. The method of any one of claims 101-107, wherein the cancer is a breast cancer.

111. The method of any one of claims 101-107, wherein the cancer is a bladder cancer.

112. The method of any one of claims 101-107, wherein the cancer is a skin cancer.

113. The method of any one of claims 101-106, wherein the cancer comprises a liquid cancer.

114. The method of claim 113, wherein the cancer is a leukemia.

115. The method of any one of claims 102-114, wherein the cancer comprises a stem cell or is derived from a stem cell.

116. The method of any one of claims 102-115, wherein the cancer is metastatic.

117. The method of any one of claims 102-116, wherein the target gene is selected from the group consisting of ADAM 10, A PEP, CA1, CA2, CA9, CCL2, CD37, COL1A1, CXCL12, CXCR4, DDR2, DPP4, E2F1, ERBB2, F3, FAAH, FAP, GSTP1, IL7R, MMP1, MMP14, MMP2, MMP9, MPL, PDKl, PGR, PSENl, PTK2B, RPS6KB1, SLC16A1, SLC3A2, SPl, TYRP1 and VEGFC.

118. The method of claim 117, wherein the target gene is DDR2.

119. The method of any one of claims 102-103 and 105-117, wherein the composition comprises a nucleic acid sequence that hybridizes with a coding sequence or a non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

120. The method of claim 119, wherein the composition comprises an antisense RNA, a short hairpin RNA (shRNA), an interfering RNA (RNAi), a small interfering RNA (siRNA), a piwi RNA (piRNA), a microRNA (miRNA) or combination thereof that hybridizes with a coding sequence or a non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

121. The method of claim 119, wherein the composition comprises a guide RNA (gRNA) that hybridizes with a coding sequence or a non-coding sequence associated with the target gene.

122. The method of claim 121, wherein the gRNA is a single- stranded gRNA (sgRNA).

123. The method of claim 121 or 122, wherein the gRNA is operably linked to an effector.

124. The method of claim 123, wherein the effector comprise a nuclease or a nuclease domain.

125. The method of claim 124, wherein the nuclease or a nuclease domain comprises a sequence isolated or derived from a RNA-guided DNA endonuclease enzyme associated with CRISPR, a Transcription activator-like effector nucleases (TALEN), a Zinc-finger nuclease (ZFN), an endonuclease or a Type IIS endonuclease.

126. The method of claim 125, wherein the RNA-guided DNA endonuclease enzyme associated with CRISPR is Cas9.

127. The method of any one of claims 124-126, wherein the nuclease or a nuclease domain induces a single-strand break in a coding sequence or a non-coding sequence associated with the target gene.

128. The method of any one of claims 124-126, wherein the nuclease or a nuclease domain induces a double-strand break in a coding sequence or a non-coding sequence associated with the target gene.

129. The method of claim 119, wherein the composition comprises a short hairpin RNA (shRNA) that hybridizes with a coding sequence or a non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

130. The method of claim 119, wherein the composition comprises an aptamer that binds a coding sequence or non-coding sequence associated with the target gene, and wherein the binding of the aptamer to the sequence associated with the target gene reduces or inhibits transcription or translation of the coding sequence or the non-coding sequence associated with the target gene.

131. The method of claim 119, wherein the composition comprises an aptamer that binds a target protein encoded by the target gene, and wherein the binding of the aptamer to the target protein encoded by the target gene reduces or inhibits an activity of the target protein encoded by the target gene.

132. The method of claim 130 or 131, wherein the aptamer comprises a DNA sequence.

133. The method of any one of claims 102-103 and 105-117, wherein the composition comprises a protein that binds a coding sequence or a non-coding sequence associated with the target gene, and wherein the binding of the protein to the sequence associated with the target gene reduces or inhibits transcription or translation of the coding sequence or the non-coding sequence associated with the target gene.

134. The method of any one of claims 102-103 and 105-117, wherein the composition comprises a protein that binds a target protein encoded by the target gene, and wherein the binding of the protein to the target protein encoded by the target gene reduces or inhibits an activity of the target protein encoded by the target gene.

135. The method of claim 133 or 134, wherein the composition comprises an antibody, an antibody fragment or an antibody mimetic.

136. The method of claim 135, wherein the antibody comprises a monoclonal antibody.

137. The method of claim 136, wherein the monoclonal antibody is a human monoclonal antibody or a humanized monoclonal antibody.

138. The method of claim 133 or 134, wherein the composition comprises an aptamer.

139. The method of any one of claims 102-103 and 105-117, wherein the composition comprises a small molecule that binds a coding sequence or a non-coding sequence associated with the target gene, and wherein the binding of the small molecule to the sequence associated with the target gene reduces or inhibits transcription or translation of the coding sequence or the non-coding sequence associated with the target gene.

140. The method of any one of claims 102-103 and 105-117, wherein the composition comprises a small molecule that binds a target protein encoded by the target gene, and wherein the binding of the small molecule to the target protein encoded by target gene reduces or inhibits an activity of the target protein encoded by the target gene.

141. The method of 139 or 140, wherein the small molecule comprises an organic small molecule.

142. The method of claim 141, wherein the small molecule is a kinase inhibitor.

143. The method of claim 142, wherein the kinase inhibitor is abemaciclib, acalabrutinib, afatinib, alectinib, axitinib, baricitinib, binimetinib, bosutinib, brigatinib,cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, encorafenib, erlotinib, everolimus, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, midostaurin, neratinib, nilotinib, nintedanib, osimertinib, palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, ruxolitinib, sirolimus, sorafenib, sunitinib, temsirolimus, tofacitinib, trametinib, vandetanib or vemurafenib.

144. The method of claim 143, wherein the kinase inhibitor is dasatinib.

145. The method of 139 or 140, wherein the small molecule comprises an inorganic small molecule.

146. The method of any one of claims 103-117, wherein the second composition comprises an antagonist or an inhibitor of the component of an immune checkpoint, and wherein the antagonist or the inhibitor disrupts or blocks an immune checkpoint in an immune cell.

147. The method of any one of claims 104-117, wherein the composition comprises an antagonist or an inhibitor of the component of an immune checkpoint, and wherein the antagonist or the inhibitor disrupts or blocks an immune checkpoint in an immune cell.

148. The method of claim 146 or 147, wherein the composition or the second composition comprises a nucleic acid sequence that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

149. The method of claim 148, wherein the composition or the second composition comprises an antisense RNA, a short hairpin RNA (shRNA), an interfering RNA (RNAi), a small interfering RNA (siRNA), a piwi RNA (piRNA), a microRNA (miRNA) or combination thereof that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

150. The method of claim 148, wherein the composition or the second composition comprises a guide RNA (gRNA) that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint.

151. The method of claim 150, wherein the gRNA is a single- stranded gRNA (sgRNA).

152. The method of claim 150 or 151, wherein the gRNA is operably linked to an effector.

153. The method of claim 152, wherein the effector comprise a nuclease or a nuclease domain.

154. The method of claim 153, wherein the nuclease or a nuclease domain comprises a sequence isolated or derived from a RNA-guided DNA endonuclease enzyme associated with CRISPR, a transcription activator-like effector nucleases (TALEN), a zinc-finger nuclease (ZFN), an endonuclease or a type IIS endonuclease.

155. The method of claim 154, wherein the RNA-guided DNA endonuclease enzyme associated with CRISPR is Cas9.

156. The method of any one of claims 153-155, wherein the nuclease or a nuclease domain induces a single-strand break in a coding sequence or a non-coding sequence associated with the component of an immune checkpoint.

157. The method of any one of claims 153-155, wherein the nuclease or a nuclease domain induces a double-strand break in a coding sequence or a non-coding sequence associated with the component of an immune checkpoint.

158. The method of claim 148, wherein the composition or the second composition comprises a short hairpin RNA (shRNA) that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

159. The method of claim 148, wherein the composition or the second composition comprises an aptamer that binds a coding sequence or a non-coding sequence associated with the component of an immune checkpoint, and wherein the binding of the aptamer to the sequence associated with the component of an immune checkpoint reduces or inhibits transcription or translation of the coding sequence or the non-coding sequence associated with the component of an immune checkpoint.

160. The method of claim 148, wherein the composition or the second composition comprises an aptamer that binds a component of an immune checkpoint, and wherein the binding of the aptamer to the component of an immune checkpoint reduces or inhibits an activity of the component of an immune checkpoint.

161. The method of claim 159 or 160, wherein the aptamer comprises a DNA sequence.

162. The method of claim 148, wherein the composition or the second composition comprises a small molecule that binds a coding sequence or a non-coding sequence associated with the component of an immune checkpoint, and wherein the binding of the small molecule to the sequence associated with the component of an immune checkpoint reduces or inhibits transcription or translation of the coding sequence or the non-coding sequence associated with the component of an immune checkpoint.

163. The method of claim 148, wherein the composition or the second composition comprises a small molecule that binds a component of an immune checkpoint, and wherein the binding of the small molecule to the component of an immune checkpoint reduces or inhibits an activity of the component of an immune checkpoint.

164. The method of 162 or 163, wherein the small molecule comprises an organic small molecule.

165. The method of 162 or 163, wherein the small molecule comprises an inorganic small molecule.

166. The method of claim 148, wherein the composition or the second composition comprises a protein that binds a coding sequence or a non-coding sequence associated with the component of an immune checkpoint, and wherein the binding of the protein to the sequence associated with the component of an immune checkpoint reduces or inhibits transcription or translation of the coding sequence or the non-coding sequence associated with the component of an immune checkpoint.

167. The method of claim 148, wherein the composition or the second composition comprises a protein that binds a component of an immune checkpoint, and wherein the binding of the protein to the component of an immune checkpoint reduces or inhibits an activity of the component of an immune checkpoint.

168. The method of claim 166 or 167, wherein the composition or the second composition comprises an antibody, an antibody fragment or an antibody mimetic.

169. The method of claim 168, wherein the antibody comprises a monoclonal antibody.

170. The method of claim 169, wherein the monoclonal antibody is a human monoclonal antibody or a humanized monoclonal antibody.

171. The method of claim 166 or 167, wherein the composition or the second composition comprises an aptamer.

172. The method of any one of claims 101-171, wherein the component of an immune checkpoint is selected from the group consisting of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death-ligand 1 (PD-Ll) and programmed death- 1 (PD-1).

173. The method of any one of claims 101-171, wherein the component of an immune checkpoint is CTLA-4 and wherein the antagonist or the inhibitor of the component of an immune checkpoint comprises Tremelimumab or Ipilumamab.

174. The method of any one of claims 101-171, wherein the component of an immune checkpoint is PD-Ll and wherein the antagonist or the inhibitor of the component of an immune checkpoint comprises Atezolizumab.

175. The method of any one of claims 101-171, wherein the component of an immune checkpoint is PD-1 and wherein the antagonist or the inhibitor of the component of an immune checkpoint comprises Nivolumab or Pembrolizumab.

176. The method of any one of claims 101-175, wherein the subject comprises a modification in a coding sequence or a non-coding sequence associated with the target gene.

177. The method of claim 176, wherein the modification is a mutation in the coding sequence or the non-coding sequence associated with the target gene.

178. The method of claim 177, wherein the mutation is a substitution, a deletion, an insertion, an inversion, a translocation or a combination thereof.

179. The method of claim 177 or 178, wherein the mutation is an inherited mutation.

180. The method of claim 177 or 178, wherein the mutation is a de novo mutation.

181. The method of any one of claims 176-180, wherein the coding sequence or the non- coding sequence associated with the target gene or the component of the immune checkpoint is a genomic sequence.

182. The method of any one of claims 176-180, wherein the coding sequence or the non- coding sequence associated with the target gene or the component of the immune checkpoint is a transcript.

183. The method of any one of claims 176-182, wherein the modification is an epigenetic modification.

184. The method of claim 183, wherein the epigenetic modification is a methylation.

185. The method of claim 184, wherein the modification is a hypomethylation that results in an increased expression of the target gene.

186. A composition comprising:

a therapeutically-effective amount of a first composition that specifically targets a target gene and

a therapeutically-effective amount of a second composition that specifically targets a component of an immune checkpoint.

187. The composition of claim 186, wherein the target gene is selected from the group consisting of ADAMIO, ANPEP, CAl, CA2, CA9, CCL2, CD37, COLlAl, CXCL12, CXCR4, DDR2, DPP4, E2F1, ERBB2, F3, FAAH, FAP, GSTPl, IL7R, MMPl, MMPl 4, MMP2, MMP9, MPL, PDKl, PGR, PSENl, TK2B, RPS6KB 1, SLC16A1, SLC3A2, SPl, TYRPl and VEGFC.

188. The composition of claim 187, wherein the tharget gene is DDR2.

189. The composition of claim 186 or 187, wherein the first composition comprises a nucleic acid sequence that hybridizes with a coding sequence or a non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

190. The composition of claim 189, wherein the first composition comprises an antisense RNA, a short hairpin RNA (shRNA), an interfering RNA (RNAi), a small interfering RNA (siRNA), a piwi RNA (piRNA), a microRNA (miRNA) or combination thereof that hybridizes with a coding sequence or a non-coding sequence associated with the target gene to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

191. The composition of claim 190, wherein the first composition comprises a guide RNA (gRNA) that hybridizes with a coding sequence or a non-coding sequence associated with the target gene.

192. The composition of claim 191, wherein the gRNA is a single-stranded gRNA (sgRNA).

193. The composition of claim 191 or 192, wherein the gRNA is operably linked to an effector.

194. The composition of claim 193, wherein the effector comprise a nuclease or a nuclease domain.

195. The composition of claim 194, wherein the nuclease or a nuclease domain comprises a sequence isolated or derived from a RNA-guided DNA endonuclease enzyme associated with CRISPR, a Transcription activator-like effector nucleases (TALEN), a Zinc-finger nuclease (ZFN), an endonuclease or a Type IIS endonuclease.

196. The composition of claim 195, wherein the RNA-guided DNA endonuclease enzyme associated with CRISPR is Cas9.

197. The composition of any one of claims 194-196, wherein the nuclease or a nuclease domain induces a single-strand break in a coding sequence or a non-coding sequence associated with the target gene.

198. The composition of any one of claims 194-196, wherein the nuclease or a nuclease domain induces a double-strand break in a coding sequence or a non-coding sequence associated with the target gene.

199. The composition of claim 190, wherein the first composition comprises a short hairpin RNA (shRNA) that hybridizes with a coding sequence or a non-coding sequence associated with the target gene. Target gene to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

200. The composition of claim 190, wherein the first composition comprises an aptamer that binds a coding sequence or a non-coding sequence associated with the target gene, and wherein the binding of the aptamer to the sequence associated with the target gene reduces or inhibits transcription or translation of the coding sequence or the non-coding sequence associated with the target gene.

201. The composition of claim 190, wherein the first composition comprises an aptamer that binds a target protein encoded by the target gene, and wherein the binding of the aptamer to the target protein encoded by the target gene reduces or inhibits an activity of the target protein encoded by the target gene.

202. The composition of claim 200 or 201, wherein the aptamer comprises a DNA sequence.

203. The composition of claim 190, wherein the first composition comprises a protein that binds a coding sequence or a non-coding sequence associated with the target gene, and wherein the binding of the protein to the sequence associated with the target gene reduces or inhibits transcription or translation of the coding sequence or the non-coding sequence associated with the target gene.

204. The composition of claim 190, wherein the first composition comprises a protein that binds a target protein encoded by the target gene, and wherein the binding of the protein to the target protein encoded by the target gene reduces or inhibits an activity of the target protein encoded by the target gene.

205. The composition of claim 203 or 204, wherein the first composition comprises an antibody, an antibody fragment or an antibody mimetic.

206. The composition of claim 205, wherein the antibody comprises a monoclonal antibody.

207. The composition of claim 206, wherein the monoclonal antibody is a human monoclonal antibody or a humanized monoclonal antibody.

208. The composition of claim 203 or 204, wherein the first composition comprises an aptamer.

209. The composition of claim 190, wherein the first composition comprises a small molecule that binds a coding sequence or a non-coding sequence associated with the target gene, and wherein the binding of the small molecule to the sequence associated with the target gene reduces or inhibits transcription or translation of the coding sequence or the non-coding sequence associated with the target gene.

210. The composition of claim 190, wherein the first composition comprises a small molecule that binds a target protein encoded by the target gene, and wherein the binding of the small molecule to the target protein encoded by the target gene reduces or inhibits an activity of the target protein encoded by the target gene.

211. The composition of 209 or 210, wherein the small molecule comprises an organic small molecule.

212. The method of claim 211, wherein the small molecule is a kinase inhibitor.

213. The method of claim 212, wherein the kinase inhibitor is abemaciclib, acalabrutinib, afatinib, alectinib, axitinib, baricitinib, binimetinib, bosutinib, brigatinib,cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, encorafenib, erlotinib, everolimus, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, midostaurin, neratinib, nilotinib, nintedanib, osimertinib, palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, ruxolitinib, sirolimus, sorafenib, sunitinib, temsirolimus, tofacitinib, trametinib, vandetanib or vemurafenib.

214. The method of claim 213, wherein the kinase inhibitor is dasatinib.

215. The composition of 209 or 210, wherein the small molecule comprises an inorganic small molecule.

216. The composition of any one of claims 186-215, wherein the second composition comprises an antagonist or an inhibitor of the component of an immune checkpoint, wherein the antagonist or the inhibitor disrupts or blocks an immune checkpoint in an immune cell.

217. The composition of claim 216, wherein the second composition comprises a nucleic acid sequence that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

218. The composition of claim 217, wherein the second composition comprises an antisense

RNA, a short hairpin RNA (shRNA), an interfering RNA (RNAi), a small interfering RNA

(siRNA), a piwi RNA (piRNA), a microRNA (miRNA) or combination thereof that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

219. The composition of claim 217, wherein the second composition comprises a guide RNA (gRNA) that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint.

220. The composition of claim 219, wherein the gRNA is a single-stranded gRNA (sgRNA).

221. The composition of claim 219 or 220, wherein the gRNA is operably linked to an effector.

222. The composition of claim 221, wherein the effector comprise a nuclease or a nuclease domain.

223. The composition of claim 222, wherein the nuclease or a nuclease domain comprises a sequence isolated or derived from a RNA-guided DNA endonuclease enzyme associated with CRISPR, a transcription activator-like effector nucleases (TALEN), a zinc-finger nuclease (ZFN), an endonuclease or a type IIS endonuclease.

224. The composition of claim 223, wherein the RNA-guided DNA endonuclease enzyme associated with CRISPR is Cas9.

225. The composition of any one of claims 219-224, wherein the nuclease or a nuclease domain induces a single-strand break in a coding sequence or a non-coding sequence associated with the component of an immune checkpoint.

226. The composition of any one of claims 219-224, wherein the nuclease or a nuclease domain induces a coding sequence or a non-coding sequence associated with the component of an immune checkpoint.

227. The composition of claim 217, wherein the second composition comprises a short hairpin RNA (shRNA) that hybridizes with a coding sequence or a non-coding sequence associated with the component of an immune checkpoint to form an RNA/RNA or RNA/DNA duplex, and wherein the duplex is depleted from the cancer cell.

228. The composition of claim 217, wherein the second composition comprises an aptamer that binds a coding sequence or a non-coding sequence associated with the component of an immune checkpoint, and wherein the binding of the aptamer to the sequence associated with the component of an immune checkpoint reduces or inhibits transcription or translation of the coding sequence or the non-coding sequence associated with the component of an immune checkpoint.

229. The composition of claim 217, wherein the second composition comprises an aptamer that binds a component of an immune checkpoint, and wherein the binding of the aptamer to the component of an immune checkpoint reduces or inhibits an activity of the component of an immune checkpoint.

230. The composition of claim 228 or 229, wherein the aptamer comprises a DNA sequence.

231. The composition of claim 217, wherein the second composition comprises a small molecule that binds a coding sequence or a non-coding sequence associated with the component of an immune checkpoint and wherein the binding of the small molecule to the sequence associated with the component of an immune checkpoint reduces or inhibits transcription or translation of the coding sequence or the non-coding sequence associated with the component of an immune checkpoint.

232. The composition of claim 217, wherein the second composition comprises a small molecule that binds a component of an immune checkpoint and wherein the binding of the small molecule to the component of an immune checkpoint reduces or inhibits an activity of the component of an immune checkpoint.

233. The composition of 231 or 232, wherein the small molecule comprises an organic small molecule.

234. The composition of 231 or 232, wherein the small molecule comprises an inorganic small molecule.

235. The composition of claim 217, wherein the second composition comprises a protein that binds a coding sequence or a non-coding sequence associated with the component of an immune checkpoint and wherein the binding of the protein to the sequence associated with the component of an immune checkpoint reduces or inhibits transcription or translation of the coding sequence or the non-coding sequence associated with the component of an immune checkpoint.

236. The composition of claim 217, wherein the second composition comprises a protein that binds a component of an immune checkpoint and wherein the binding of the protein to the component of an immune checkpoint reduces or inhibits an activity of the component of an immune checkpoint.

237. The composition of claim 235 or 236, wherein the second composition comprises an antibody, an antibody fragment or an antibody mimetic.

238. The composition of claim 237, wherein the antibody comprises a monoclonal antibody.

239. The composition of claim 238, wherein the monoclonal antibody is a human monoclonal antibody or a humanized monoclonal antibody.

240. The composition of claim 235 or 236, wherein the second composition comprises an aptamer.

241. The composition of any one of claims 186-240, wherein the component of an immune checkpoint is selected from the group consisting of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death-ligand 1 (PD-L1) and programmed death- 1 (PD-1).

242. The composition of any one of claims 186-240, wherein the component of an immune checkpoint is CTLA-4 and wherein the antagonist or the inhibitor of the component of an immune checkpoint comprises Tremelimumab or Ipilumamab.

243. The composition of any one of claims 186-240, wherein the component of an immune checkpoint is PD-Ll and wherein the antagonist or the inhibitor of the component of an immune checkpoint comprises Atezolizumab.

244. The composition of any one of claims 186-240, wherein the component of an immune checkpoint is PD-1 and wherein the antagonist or the inhibitor of the component of an immune checkpoint comprises Nivolumab or Pembrolizumab.

245. The composition of any one of claims 186-244, wherein the first composition or the second composition is administered systemically.

246. The composition of claim 245, wherein the first composition or the second composition is administered intravenously.

247. The composition of claim 245, wherein the first composition or the second composition is administered orally.

248. The composition of any one of claims 186-247, wherein the wherein the first composition or the second composition is administered simultaneously.

249. The composition of any one of claims 186-247, wherein the wherein the first composition or the second composition is administered sequentially.

250. The composition of claim 249, wherein the first composition is administered before the second composition.