WO2018204786A1 - Compositions and methods of treating amyotrophic lateral sclerosis (als) - Google Patents

Compositions and methods of treating amyotrophic lateral sclerosis (als) Download PDF

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WO2018204786A1
WO2018204786A1 PCT/US2018/031089 US2018031089W WO2018204786A1 WO 2018204786 A1 WO2018204786 A1 WO 2018204786A1 US 2018031089 W US2018031089 W US 2018031089W WO 2018204786 A1 WO2018204786 A1 WO 2018204786A1
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aav
seq
aavhu
aavrh
region
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French (fr)
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Dinah Wen-Yee Sah
Qingmin Chen
Jinzhao Hou
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Voyager Therapeutics Inc
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Voyager Therapeutics Inc
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Priority to US16/611,054 priority Critical patent/US11603542B2/en
Priority to CN201880045093.6A priority patent/CN110913866A/zh
Priority to AU2018261790A priority patent/AU2018261790B2/en
Priority to SG11201909870S priority patent/SG11201909870SA/en
Priority to CA3061652A priority patent/CA3061652A1/en
Priority to EP18794385.7A priority patent/EP3618839A4/en
Priority to JP2019560226A priority patent/JP2020518258A/ja
Publication of WO2018204786A1 publication Critical patent/WO2018204786A1/en
Anticipated expiration legal-status Critical
Priority to US18/173,618 priority patent/US20230295663A1/en
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    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
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    • C12N9/0089—Oxidoreductases (1.) acting on superoxide as acceptor (1.15)
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    • C12N2750/00011—Details
    • C12N2750/14011—Parvoviridae
    • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
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    • C12Y115/01001—Superoxide dismutase (1.15.1.1)

Definitions

  • the present invention relates to compositions, methods and processes for the design, preparation, manufacture, use and/or formulation of AAV particles comprising modulatory polynucleotides, e.g., polynucleotides encoding at least one small interfering RNA (siRNA) molecules which target the superoxide dismutase 1 (SOD1) gene. Targeting of the SOD1 gene may interfere with SOD1 gene expression and the resultant SOD1 protein production.
  • the AAV particles comprising modulatory polynucleotides encoding at least one siRNA molecules may be inserted into recombinant adeno-associated virus (AAV) vectors.
  • AAV adeno-associated virus
  • ALS Amyotrophic lateral sclerosis
  • MNs motor neurons
  • the loss of motor neurons devastates basic, fundamental movements, such as breathing, and typically causes death to patients within 2-5 years after diagnosis.
  • Progressive deterioration of motor function in patients severely disrupts their breathing ability, requiring some form of breathing aid for survival of the patients.
  • Other symptoms also include muscle weakness in hands, arms, legs or the muscles of swallowing.
  • Some patients may also develop frontotemporal dementia.
  • ALS According to the ALS Association, approximately 5,600 people in the United States of America are diagnosed with ALS each year. The incidence of ALS is two per 100,000 people, and it is estimated that as many as 30,000 Americans may have the disease at any given time.
  • sALS sporadic ALS
  • fALS familial ALS
  • ROS reactive oxygen species
  • ALS causes of ALS are complicated and heterogeneous.
  • ALS is considered to be a complex genetic disorder in which multiple genes in combination with environmental exposures combine to render a person susceptible. More than a dozen genes associated with ALS have been discovered, including, SOD-1 (Cu 2+ /Zn 2+ superoxide dismutase), TDP-43 (TARDBP, TAR DNA binding protein-43), FUS (Fused in Sarcoma/Translocated in Sarcoma), ANG (Angiogenin), ATXN2 (Ataxin-2), valosin containing protein (VCP), OPTN (Optineurin) and an expansion of the noncoding GGGGCC hexanucleotide repeat in the chromosome 9, open reading frame 72 (C90RF72).
  • SOD-1 Cu 2+ /Zn 2+ superoxide dismutase
  • TARDBP TARDBP
  • TAR DNA binding protein-43 FUS
  • ANG Angiogenin
  • ATXN2 Ataxin-2
  • One strategy is based on the neuroprotective and/or regenerative effect of neurotrophic factors, such as Insulin-like growth factor I (IGF -I), Glial cell line-derived neurotrophic factor (GDNF), Vascular endothelial growth factor (VEGF), Colivelin and Activity dependent neurotrophic factor (ADNF) derived peptide, which can promote neuronal survival.
  • neurotrophic factors such as Insulin-like growth factor I (IGF -I), Glial cell line-derived neurotrophic factor (GDNF), Vascular endothelial growth factor (VEGF), Colivelin and Activity dependent neurotrophic factor (ADNF) derived peptide.
  • IGF -I Insulin-like growth factor I
  • GDNF Glial cell line-derived neurotrophic factor
  • VEGF Vascular endothelial growth factor
  • ADNF Activity dependent neurotrophic factor
  • ALS a progressive neurodegenerative disease 2019
  • Stem cells have the potential to generate motor neurons, thereby replacing degenerating motor neurons in the ALS -affected CNS such as primary motor cortex, brainstem and spinal cord.
  • iPSCs induced pluripotent stem cells
  • MSCs mesenchymal stromal cells
  • BMSCs bone marrow mesenchymal stromal cells
  • ASCs adipocyte stem cells
  • neural tissue origin neural stem cells e.g., fetal spinal neural stem cells (NSCs), multipotent neural progenitor cells (NPCs)
  • NPCs multipotent neural progenitor cells
  • SOD1 superoxide dismutase type I
  • Cu 2+ /Zn 2+ superoxide dismutase type I are the most common cause of fALS, accounting for about 20 to 30% of all fALS cases.
  • Recent reports indicate that SOD1 mutations may also be linked to about 4% of all sALS cases (Robberecht and Philip, Nat. Rev. Neurosci., 2013, 14, 248-264).
  • SODl-linked fALS is most likely not caused by loss of the normal SOD1 activity, but rather by a gain of a toxic function.
  • mutant SODl-linked fALS toxicity proposes that an aberrant SOD1 enzyme causes small molecules such as peroxynitrite or hydrogen peroxide to produce damaging free radicals.
  • Other hypotheses for mutant SOD1 neurotoxicity include inhibition of the proteasome activity, mitochondrial damage, disruption of RNA processing and formation of intracellular aggregates.
  • Abnormal accumulation of mutant SOD1 variants and/or wild-type SOD1 in ALS forms insoluble fibrillar aggregates which are identified as pathological inclusions.
  • Aggregated SOD1 protein can induce mitochondria stress (Vehvilainen P et al., Front Cell Neurosci., 2014, 8, 126) and other toxicity to cells, particularly to motor neurons.
  • RNA interfering (RNAi) mediated gene silencing has drawn researchers' interest in recent years. Small double stranded RNA (small interfering RNA) molecules that target the SODl gene haven been taught in the art for their potential in treating ALS (See, e.g., U.S. Pat. No. 7,632,938 and U.S. Patent Publication No. 20060229268, the contents of which is herein incorporated by reference in its entirety).
  • the present invention develops an RNA interference based approach to inhibit or prevent the expression of SODl in ALS patients for treatment of the disease.
  • the present invention provides novel double stranded RNA (dsRNA) constructs and siRNA constructs and methods of their design.
  • these novel siRNA constructs may be synthetic molecules or be encoded in an expression vector (one or both strands) for delivery into cells.
  • vectors include, but are not limited to adeno-associated viral vectors such as vector genomes of any of the AAV serotypes or other viral delivery vehicles such as lentivirus, etc.
  • a disease and/or disorder e.g., amyotrophic lateral sclerosis (ALS)
  • the present invention relates to RNA molecule mediated gene specific interference with gene expression and protein production. Methods for treating motor neuron degeneration diseases such as amyotrophic lateral sclerosis are also included in the present invention.
  • the siRNA included in the compositions featured herein encompass a dsRNA having an antisense strand (the antisense strand) having a region that is 30 nucleotides or less, generally 19-24 nucleotides in length, that is substantially complementary to at least part of an mRNA transcript of the SODl gene.
  • the present invention provides short double stranded RNA molecules such as small interfering RNA (siRNA) duplexes that target SODl mRNA to interfere with SODl gene expression and/or SODl protein production.
  • siRNA duplexes of the present invention may interfere with both alleles of the SODl gene irrespective of any particular mutation in the SODl gene, and may particularly interact with those found in ALS disease.
  • siRNA molecules, or a single strand of the siRNA molecules are inserted into adeno-associated viral (AAV) vectors to be introduced into cells, specifically motor neurons and/or other surrounding cells in the central nervous system.
  • AAV vector may comprise sequences encoding 1, 2, 3, 4, or more than 4 siRNA duplexes.
  • the siRNA duplex of the present invention comprises an antisense strand and a sense strand hybridized together forming a duplex structure, wherein the antisense strand is
  • the 5 'end of the antisense strand has a 5' phosphate group and the 3 'end of the sense strand contains a 3'hydroxyl group. In other aspects, there are none, one or 2 nucleotides overhangs at the 3 'end of each strand.
  • each strand of the siRNA duplex targeting the SODl gene is about 19-25 nucleotides in length, preferably about 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, or 25 nucleotides in length.
  • the siRNAs may be unmodified RNA molecules.
  • the siRNAs may contain at least one modified nucleotide, such as base, sugar or backbone modification.
  • an siRNA or dsRNA includes at least two sequences that are complementary to each other.
  • the dsRNA includes a sense strand having a first sequence and an antisense strand having a second sequence.
  • the antisense strand includes a nucleotide sequence that is substantially complementary to at least part of an mRNA encoding SODl, and the region of complementarity is 30 nucleotides or less, and at least 15 nucleotides in length.
  • the dsRNA is 19 to 24, e.g., 19 to 21 nucleotides in length.
  • the dsRNA is from about 15 to about 25 nucleotides in length, and in other embodiments the dsRNA is from about 25 to about 30 nucleotides in length.
  • dsRNA either upon contacting with a cell expressing SODl or upon
  • transcription within a cell expressing SODl inhibits or suppresses the expression of a SODl gene by at least 10%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40% or more, such as when assayed by a method as described herein.
  • AAV vectors comprising the nucleic acids encoding the siRNA duplexes, one strand of the siRNA duplex or the dsRNA targeting SODl gene are produced, the AAV vector serotype may be AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV9.47, AAV9(hul4), AAV10, AAV1 1, AAV 12, AAVrh8, AAVrhlO, AAV-DJ8 and/or AAV-DJ, and variants thereof.
  • the present invention also provides pharmaceutical compositions comprising at least one siRNA duplex targeting the SODl gene and a pharmaceutically acceptable carrier.
  • a nucleic acid sequence encoding the siRNA duplex is inserted into an AAV vector.
  • the present invention provides methods for
  • the siRNA duplexes or dsRNA can be used to substantially inhibit SODl gene expression in a cell, in particular in a motor neuron.
  • the inhibition of SODl gene expression refers to an inhibition by at least about 20%, preferably by at least about 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95% and 100%.
  • the protein product of the targeted gene may be inhibited by at least about 20%, preferably by at least about 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95% and 100%).
  • the SODl gene can be either a wild type gene or a mutated SODl gene with at least one mutation.
  • the SODl protein is either wild type protein or a mutated polypeptide with at least one mutation.
  • the present invention provides methods for treating, or ameliorating amyotrophic lateral sclerosis associated with abnormal SODl gene and/or SODl protein in a subject in need of treatment, the method comprising administering to the subject a pharmaceutically effective amount of at least one siRNA duplex targeting the SODl gene, delivering said siRNA duplex into targeted cells, inhibiting SODl gene expression and protein production, and ameliorating symptoms of ALS in the subject.
  • an AAV vector comprising the nucleic acid sequence encoding at least one siRNA duplex targeting the SOD l gene is administered to the subject in need for treating and/or ameliorating ALS.
  • the AAV vector serotype may be selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV9.47, AAV9(hul4), AAV10, AAV1 1, AAV 12, AAVrh8, AAVrhlO and AAV-DJ, and variants thereof.
  • ALS is familial ALS linked to SODl mutations.
  • ALS is sporadic ALS which is characterized by abnormal aggregation of SODl protein or disruption of SODl protein function or localization, though not necessarily as a result of genetic mutation.
  • the symptoms of ALS ameliorated by the present method may include motor neuron degeneration, muscle weakness, stiffness of muscles, slurred speech and /or difficulty in breathing.
  • the siRNA duplexes or dsRNA targeting SOD1 gene or the AAV vectors comprising such siRNA-encoding molecules may be introduced directly into the central nervous system of the subject, for example, by intracranial injection.
  • the pharmaceutical composition of the present invention is used as a solo therapy. In other embodiments, the pharmaceutical composition of the present invention is used in combination therapy.
  • the combination therapy may be in combination with one or more neuroprotective agents such as small molecule compounds, growth factors and hormones which have been tested for their neuroprotective effect on motor neuron degeneration.
  • the present invention provides methods for treating, or ameliorating amyotrophic lateral sclerosis by administering to a subject in need thereof a therapeutically effective amount of a plasmid or AAV vector described herein.
  • the ALS may be familial ALS or sporadic ALS.
  • FIG. 1 is a schematic of a viral genome of the invention
  • FIG. 2 is a schematic of a viral genome of the invention
  • FIG. 3 is a schematic of a viral genome of the invention
  • FIG. 4 is a schematic of a viral genome of the invention
  • FIG. 5 is a schematic of a viral genome of the invention
  • FIG. 6 is a schematic of a viral genome of the invention
  • FIG. 7 is a schematic of a viral genome of the invention
  • FIG. 8 is a schematic of a viral genome of the invention
  • FIG. 9 is a schematic of a viral genome of the invention.
  • compositions for delivering modulatory polynucleotides and/or modulatory polynucleotide-based compositions by adeno-associated viruses are provided.
  • AAV particles of the invention may be provided via any of several routes of administration, to a cell, tissue, organ, or organism, in vivo, ex vivo or in vitro.
  • an "AAV particle” is a virus which comprises a viral genome with at least one payload region and at least one inverted terminal repeat (ITR) region.
  • ITR inverted terminal repeat
  • viral genome or “vector genome” or “viral vector” refers to the nucleic acid sequence(s) encapsulated in an AAV particle. Viral genomes comprise at least one payload region encoding polypeptides or fragments thereof.
  • a "payload” or “payload region” is any nucleic acid molecule which encodes one or more polypeptides of the invention.
  • a payload region comprises nucleic acid sequences that encode a sense and antisense sequence, an siRNA-based
  • composition or a fragment thereof, but may also optionally comprise one or more functional or regulatory elements to facilitate transcriptional expression and/or polypeptide translation.
  • nucleic acid sequences and polypeptides disclosed herein may be engineered to contain modular elements and/or sequence motifs assembled to enable expression of the modulatory polynucleotides and/or modulatory polynucleotide-based compositions of the invention.
  • the nucleic acid sequence comprising the payload region may comprise one or more of a promoter region, an intron, a Kozak sequence, an enhancer or a polyadenylation sequence.
  • Payload regions of the invention typically encode at least one sense and antisense sequence, an siRNA-based compositions, or fragments of the foregoing in combination with each other or in combination with other polypeptide moieties.
  • the payload regions of the invention may be delivered to one or more target cells, tissues, organs or organisms within the viral genome of an AAV particle.
  • Adeno-associated viruses and AAV particles
  • Viruses of the Parvoviridae family are small non-enveloped icosahedral capsid viruses characterized by a single stranded DNA genome. Parvoviridae family viruses consist of two subfamilies: Parvovirinae, which infect vertebrates, and Densovirinae, which infect invertebrates. Due to its relatively simple structure, and due to the fact that it is easily
  • the genome of the virus may be modified to contain a minimum of components for the assembly of a functional recombinant virus, or viral particle, which is loaded with or engineered to express or deliver a desired payload, which may be delivered to a target cell, tissue, organ, or organism.
  • parvoviruses and other members of the Parvoviridae family are generally described in Kenneth I. Berns, "Parvoviridae: The Viruses and Their Replication," Chapter 69 in FIELDS VIROLOGY (3d Ed. 1996), the contents of which are incorporated by reference in their entirety.
  • the Parvoviridae family comprises the Dependovirus genus which includes adeno- associated viruses (AAV) capable of replication in vertebrate hosts including, but not limited to, human, primate, bovine, canine, equine, and ovine species.
  • AAV adeno- associated viruses
  • the AAV viral genome is a linear, single-stranded DNA (ssDNA) molecule approximately 5,000 nucleotides (nt) in length.
  • the AAV viral genome can comprise a payload region and at least one inverted terminal repeat (ITR) or ITR region. ITRs traditionally flank the coding nucleotide sequences for the non-structural proteins (encoded by Rep genes) and the structural proteins (encoded by capsid genes or Cap genes). While not wishing to be bound by theory, an AAV viral genome typically comprises two ITR sequences.
  • the AAV viral genome comprises a characteristic T-shaped hairpin structure defined by the self-complementary terminal 145 nt of the 5' and 3' ends of the ssDNA which form an energetically stable double stranded region.
  • the double stranded hairpin structures comprise multiple functions including, but not limited to, acting as an origin for DNA replication by functioning as primers for the endogenous DNA polymerase complex of the host viral replication cell.
  • AAV vectors may comprise the viral genome, in whole or in part, of any naturally occurring and/or recombinant AAV serotype nucleotide sequence or variant.
  • AAV variants may have sequences of significant homology at the nucleic acid (genome or capsid) and amino acid levels (capsids), to produce constructs which are generally physical and functional equivalents, replicate by similar mechanisms, and assemble by similar mechanisms.
  • AAV particles of the present invention are recombinant AAV vectors which are replication defective, lacking sequences encoding functional Rep and Cap proteins within their viral genome. These defective AAV vectors may lack most or all parental coding sequences and essentially carry only one or two AAV ITR sequences and the nucleic acid of interest for delivery to a cell, a tissue, an organ or an organism.
  • the viral genome of the AAV particles of the present invention comprise at least one control element which provides for the replication, transcription and translation of a coding sequence encoded therein. Not all of the control elements need always be present as long as the coding sequence is capable of being replicated, transcribed and/or translated in an appropriate host cell.
  • expression control elements include sequences for transcription initiation and/or termination, promoter and/or enhancer sequences, efficient RNA processing signals such as splicing and polyadenylation signals, sequences that stabilize cytoplasmic mRNA, sequences that enhance translation efficacy (e.g., Kozak consensus sequence), sequences that enhance protein stability, and/or sequences that enhance protein processing and/or secretion.
  • AAV particles for use in therapeutics and/or diagnostics comprise a virus that has been distilled or reduced to the minimum components necessary for transduction of a nucleic acid payload or cargo of interest.
  • AAV particles are engineered as vehicles for specific delivery while lacking the deleterious replication and/or integration features found in wild-type viruses.
  • AAV vectors of the present invention may be produced recombinantly and may be based on adeno-associated virus (AAV) parent or reference sequences.
  • AAV adeno-associated virus
  • vector is any molecule or moiety which transports, transduces or otherwise acts as a carrier of a heterologous molecule such as the nucleic acids described herein.
  • scAAV self-complementary AAV
  • scAAV viral genomes contain DNA strands which anneal together to form double stranded DNA. By skipping second strand synthesis, scAAVs allow for rapid expression in the cell.
  • the AAV particle of the present invention is an scAAV.
  • the AAV particle of the present invention is an ssAAV.
  • Methods for producing and/or modifying AAV particles are disclosed in the art such as pseudotyped AAV vectors (PCT Patent Publication Nos. WO200028004; WO200123001; WO2004112727; WO 2005005610 and WO 2005072364, the content of each of which is incorporated herein by reference in its entirety).
  • AAV particles may be modified to enhance the efficiency of delivery. Such modified AAV particles can be packaged efficiently and be used to successfully infect the target cells at high frequency and with minimal toxicity.
  • the capsids of the AAV particles are engineered according to the methods described in US Publication Number US 20130195801, the contents of which are incorporated herein by reference in their entirety.
  • the AAV particles comprising a payload region encoding the polypeptides of the invention may be introduced into mammalian cells.
  • AAV particles of the present invention may comprise or be derived from any natural or recombinant AAV serotype.
  • the AAV particles may utilize or be based on a serotype selected from any of the following AAV1, AAV2, AAV2G9, AAV3, AAV3a, AAV3b, AAV3-3, AAV4, AAV4-4, AAV5, AAV6, AAV6.1, AAV6.2, AAV6.1.2, AAV7, AAV7.2, AAV8, AAV9, AAV9.11, AAV9.13, AAV9.16, AAV9.24, AAV9.45, AAV9.47, AAV9.61, AAV9.68, AAV9.84, AAV9.9, AAV10, AAV11, AAV 12, AAV16.3, AAV24.1, AAV27.3, AAV42.12, AAV42-lb, AAV42-2, AAV42-3a, AAV42-3b, AAV42-4, AAV42-5a, AAV42-5b,
  • AAVhu.29R AAVhu.31, AAVhu.32, AAVhu.34, AAVhu.35, AAVhu.37, AAVhu.39,
  • AAVF11/HSC11 AAVF12/HSC12, AAVF13/HSC13, AAVF14/HSC14, AAVF15/HSC15, AAVF16/HSC16, AAVF17/HSC17, AAVF2/HSC2, AAVF3/HSC3, AAVF4/HSC4,
  • the AAV serotype may be, or have, a sequence as described in United States Publication No. US20030138772, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV1 (SEQ ID NO: 6 and 64 of
  • US20030138772) AAV2 (SEQ ID NO: 7 and 70 of US20030138772), AAV3 (SEQ ID NO: 8 and 71 of US20030138772), AAV4 (SEQ ID NO: 63 of US20030138772), AAV5 (SEQ ID NO: 114 of US20030138772), AAV6 (SEQ ID NO: 65 of US20030138772), AAV7 (SEQ ID NO: 1- 3 of US20030138772), AAV8 (SEQ ID NO: 4 and 95 of US20030138772), AAV9 (SEQ ID NO: 5 and 100 of US20030138772), AAV10 (SEQ ID NO: 117 of US20030138772), AAV11 (SEQ ID NO: 118 of US20030138772), AAV 12 (SEQ ID NO: 119 of US20030138772), AAVrhlO (amino acids 1 to 738 of SEQ ID NO: 81 of US20030138772), AAV16.3
  • the AAV serotype may be, or have, a sequence as described in United States Publication No. US20150159173, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV2 (SEQ ID NO: 7 and 23 of
  • US20150159173) AAV8 (SEQ ID NO: 15 and 31 of US20150159173), hu.13 (SEQ ID NO: 16 and 32 of US20150159173), hu.26 (SEQ ID NO: 17 and 33 of US20150159173), hu.37 (SEQ ID NO: 18 and 34 of US20150159173), hu.53 (SEQ ID NO: 19 and 35 of US20150159173), rh.43 (SEQ ID NO: 21 and 37 of US20150159173), rh2 (SEQ ID NO: 39 of US20150159173), rh.37 (SEQ ID NO: 40 of US20150159173), rh.64 (SEQ ID NO: 43 of US20150159173), rh.48 (SEQ ID NO: 44 of US20150159173), ch.5 (SEQ ID NO 46 of US20150159173), rh.67 (SEQ ID NO: 47 of US20150159173),
  • the AAV serotype may be, or have, a sequence as described in United States Patent No. US 7198951, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV9 (SEQ ID NO: 1-3 of US 7198951), AAV2 (SEQ ID NO: 4 of US 7198951), AAVl (SEQ ID NO: 5 of US 7198951), AAV3 (SEQ ID NO: 6 of US 7198951), and AAV8 (SEQ ID NO: 7 of US7198951).
  • AAV9 SEQ ID NO: 1-3 of US 7198951
  • AAV2 SEQ ID NO: 4 of US 7198951
  • AAVl SEQ ID NO: 5 of US 7198951
  • AAV3 SEQ ID NO: 6 of US 7198951
  • AAV8 SEQ ID NO: 7 of US7198951.
  • the AAV serotype may be, or have, a mutation in the AAV9 sequence as described by N Pulichla et al. (Molecular Therapy 19(6): 1070-1078 (2011), herein incorporated by reference in its entirety), such as but not limited to, AAV9.9, AAV9.11, AAV9.13, AAV9.16, AAV9.24, AAV9.45, AAV9.47, AAV9.61, AAV9.68, AAV9.84.
  • the AAV serotype may be, or have, a sequence as described in United States Patent No. US 6156303, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV3B (SEQ ID NO: 1 and 10 of US 6156303), AAV6 (SEQ ID NO: 2, 7 and 11 of US 6156303), AAV2 (SEQ ID NO: 3 and 8 of US 6156303), AAV3A (SEQ ID NO: 4 and 9, of US 6156303), or derivatives thereof.
  • AAV3B SEQ ID NO: 1 and 10 of US 6156303
  • AAV6 SEQ ID NO: 2, 7 and 11 of US 6156303
  • AAV2 SEQ ID NO: 3 and 8 of US 6156303
  • AAV3A SEQ ID NO: 4 and 9, of US 6156303
  • the AAV serotype may be, or have, a sequence as described in United States Publication No. US20140359799, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV8 (SEQ ID NO: 1 of
  • the serotype may be AAVDJ (or AAV-DJ) or a variant thereof, such as AAVDJ8 (or AAV-DJ8), as described by Grimm et al. (Journal of Virology 82(12): 5887-5911 (2008), herein incorporated by reference in its entirety).
  • the amino acid sequence of AAVDJ8 may comprise two or more mutations in order to remove the heparin binding domain (HBD).
  • HBD heparin binding domain
  • 7,588,772 may comprise two mutations: (1) R587Q where arginine (R; Arg) at amino acid 587 is changed to glutamine (Q; Gin) and (2) R590T where arginine (R; Arg) at amino acid 590 is changed to threonine (T; Thr).
  • K406R where lysine (K; Lys) at amino acid 406 is changed to arginine (R; Arg)
  • R587Q where arginine (R; Arg) at amino acid 587 is changed to glutamine (Q; Gin)
  • R590T where arginine (R; Arg) at amino acid 590 is changed to threonine (T; Thr).
  • the AAV serotype may be, or have, a sequence of AAV4 as described in International Publication No. WO 1998011244, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to AAV4 (SEQ ID NO: 1-20 of WO1998011244).
  • the AAV serotype may be, or have, a mutation in the AAV2 sequence to generate AAV2G9 as described in International Publication No. WO2014144229 and herein incorporated by reference in its entirety.
  • the AAV serotype may be, or have, a sequence as described in International Publication No. WO2005033321, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to AAV3-3 (SEQ ID NO: 217 of
  • WO2005033321 AAV1 (SEQ ID NO: 219 and 202 of WO2005033321), AAV106.1/hu.37 (SEQ ID No: 10 of WO2005033321), AAV114.3/hu.40 (SEQ ID No: 11 of WO2005033321), AAV127.2/hu.41 (SEQ ID NO:6 and 8 of WO2005033321), AAV128.3/hu.44 (SEQ ID No: 81 of WO2005033321), AAV130.4/hu.48 (SEQ ID NO: 78 of WO2005033321), AAV145.1/hu.53 (SEQ ID No: 176 and 177 of WO2005033321), AAV145.6/hu.56 (SEQ ID NO: 168 and 192 of WO2005033321), AAV16.12/hu. l l (SEQ ID NO: 153 and 57 of WO2005033321),
  • AAV16.8/hu. lO (SEQ ID NO: : 156 and 56 of WO2005033321), AAV161.10/hu.60 (SEQ ID No: 170 of WO2005033321), AAV161.6/hu.61 (SEQ ID No: 174 of WO2005033321), AAV1- 7/rh.48 (SEQ ID NO: 32 of WO2005033321), AAVl-8/rh.49 (SEQ ID NOs: 103 and 25 of WO2005033321), AAV2 (SEQ ID NO: 211 and 221 of WO2005033321), AAV2-15/rh.62 (SEQ ID No: 33 and 114 of WO2005033321), AAV2-3/rh.61 (SEQ ID NO: 21 of WO2005033321), AAV2-4/rh.50 (SEQ ID No: 23 and 108 of WO2005033321), AAV2-5/rh.51 (SEQ ID NO: 104 and 22 of
  • AAV3.1/hu.9 (SEQ ID NO: 155 and 58 of WO2005033321), AAV3-1 l/rh.53 (SEQ ID NO: 186 and 176 of WO2005033321), AAV3-3 (SEQ ID NO: 200 of WO2005033321), AAV33.12/hu. l7 (SEQ ID NO:4 of WO2005033321), AAV33.4/hu. l5 (SEQ ID No: 50 of WO2005033321), AAV33.8/hu.
  • WO2005033321 WO2005033321
  • AAV6 SEQ ID NO: 203 and 220 of WO2005033321
  • AAV7 SEQ ID NO: 222 and 213 of WO2005033321
  • AAV7.3/hu.7 SEQ ID No: 55 of WO2005033321
  • AAV8 SEQ ID NO: 223 and 214 of WO2005033321
  • AAVH-l/hu. l SEQ ID No: 46 of
  • WO2005033321 AAVH-5/hu.3 (SEQ ID No: 44 of WO2005033321), AAVhu. l (SEQ ID NO: 144 of WO2005033321), AAVhu. lO (SEQ ID NO: 156 of WO2005033321), AAVhu. l l (SEQ ID NO: 153 of WO2005033321), AAVhu.12 (WO2005033321 SEQ ID NO: 59), AAVhu.13 (SEQ ID NO: 129 of WO2005033321), AAVhu. l4/AAV9 (SEQ ID NO: 123 and 3 of
  • WO2005033321 AAVhu.15 (SEQ ID NO: 147 of WO2005033321), AAVhu.16 (SEQ ID NO: 148 of WO2005033321), AAVhu.17 (SEQ ID NO: 83 of WO2005033321), AAVhu.18 (SEQ ID NO: 149 of WO2005033321), AAVhu.19 (SEQ ID NO: 133 of WO2005033321), AAVhu.2 (SEQ ID NO: 143 of WO2005033321), AAVhu.20 (SEQ ID NO: 134 of WO2005033321), AAVhu.21 (SEQ ID NO: 135 of WO2005033321), AAVhu.22 (SEQ ID NO: 138 of
  • WO2005033321 WO2005033321
  • AAVhu.23.2 SEQ ID NO: 137 of WO2005033321
  • AAVhu.24 SEQ ID NO: 136 of WO2005033321
  • AAVhu.25 SEQ ID NO: 146 of WO2005033321
  • AAVhu.27 SEQ ID NO: 140 of WO2005033321
  • AAVhu.29 SEQ ID NO: 132 of WO2005033321
  • AAVhu.3 SEQ ID NO: 145 of WO2005033321
  • AAVhu.31 SEQ ID NO: 121 of
  • WO2005033321 WO2005033321
  • AAVhu.32 SEQ ID NO: 122 of WO2005033321
  • AAVhu.34 SEQ ID NO: 125 of WO2005033321
  • AAVhu.35 SEQ ID NO: 164 of WO2005033321
  • AAVhu.37 SEQ ID NO: 88 of WO2005033321
  • AAVhu.39 SEQ ID NO: 102 of WO2005033321
  • AAVhu.4 SEQ ID NO: 141 of WO2005033321
  • AAVhu.40 SEQ ID NO: 87 of WO2005033321
  • AAVhu.41 SEQ ID NO: 91 of WO2005033321
  • AAVhu.42 SEQ ID NO: 85 of
  • WO2005033321 AAVhu.43 (SEQ ID NO: 160 of WO2005033321), AAVhu.44 (SEQ ID NO: 144 of WO2005033321), AAVhu.45 (SEQ ID NO: 127 of WO2005033321), AAVhu.46 (SEQ ID NO: 159 of WO2005033321), AAVhu.47 (SEQ ID NO: 128 of WO2005033321), AAVhu.48 (SEQ ID NO: 157 of WO2005033321), AAVhu.49 (SEQ ID NO: 189 of WO2005033321), AAVhu.51 (SEQ ID NO: 190 of WO2005033321), AAVhu.52 (SEQ ID NO: 191 of
  • WO2005033321 WO2005033321
  • AAVpi. l WO2005033321 SEQ ID NO: 28
  • AAVpi.2 WO2005033321 SEQ ID NO: 30
  • AAVpi.3 WO2005033321 SEQ ID NO: 29
  • AAVrh.38 SEQ ID NO: 86 of WO2005033321
  • AAVrh.40 SEQ ID NO: 92 of WO2005033321
  • AAVrh.43 SEQ ID NO: 163 of WO2005033321
  • AAVrh.44 WO2005033321 SEQ ID NO: 34
  • WO2005033321 WO2005033321
  • AAVrh.52 SEQ ID NO: 96 of WO2005033321
  • AAVrh.53 SEQ ID NO: 97 of WO2005033321
  • AAVrh.55 WO2005033321 SEQ ID NO: 37
  • AAVrh.56 SEQ ID NO: 152 of WO2005033321
  • AAVrh.57 SEQ ID NO: 105 of WO2005033321
  • AAVrh.58 SEQ ID NO: 106 of WO2005033321
  • AAVrh.59 WO2005033321 SEQ ID NO: 42
  • AAVrh.60 WO2005033321 SEQ ID NO: 31
  • AAVrh.61 SEQ ID NO: 107 of WO2005033321
  • AAVrh.62 (SEQ ID NO: 114 of WO2005033321), AAVrh.64 (SEQ ID NO: 99 of
  • WO2005033321 AAVrh.65 (WO2005033321 SEQ ID NO: 35), AAVrh.68 (WO2005033321 SEQ ID NO: 16), AAVrh.69 (WO2005033321 SEQ ID NO: 39), AAVrh.70 (WO2005033321 SEQ ID NO: 20), AAVrh.72 (WO2005033321 SEQ ID NO: 9), or variants thereof including, but not limited to, AAVcy.2, AAVcy.3, AAVcy.4, AAVcy.5, AAVcy.6, AAVrh.12, AAVrh.17, AAVrh.18, AAVrh.19, AAVrh.21, AAVrh.22, AAVrh.23, AAVrh.24, AAVrh.25, AAVrh.25/42 15, AAVrh.31, AAVrh.32, AAVrh.33, AAVrh.34, AAVrh.35, AAVrh.
  • Non limiting examples of variants include SEQ ID NO: 13, 15, 17, 19, 24, 36, 40, 45, 47, 48, 51-54, 60-62, 64-77, 79, 80, 82, 89, 90, 93-95, 98, 100, 101, 109-113, 118-120, 124, 126, 131, 139, 142, 151,154, 158, 161, 162, 165-183, 202, 204-212, 215, 219, 224-236, of
  • the AAV serotype may be, or have, a sequence as described in International Publication No. WO2015168666, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAVrh8R (SEQ ID NO: 9 of
  • WO2015168666 AAVrh8R A586R mutant (SEQ ID NO: 10 of WO2015168666), AAVrh8R R533A mutant (SEQ ID NO: 11 of WO2015168666), or variants thereof.
  • the AAV serotype may be, or have, a sequence as described in United States Patent No. US9233131, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAVhEl .1 ( SEQ ID NO:44 of US9233131), AAVhErl .5 (SEQ ID NO:45 of US9233131), AAVhER1.14 (SEQ ID NO:46 of US9233131), AAVhErl .8 (SEQ ID NO:47 of US9233131), AAVhErl .16 (SEQ ID NO:48 of US9233131), AAVhErl .18 (SEQ ID NO:49 of US9233131), AAVhErl .35 (SEQ ID NO:50 of US9233131), AAVhErl .7 (SEQ ID NO:51 of US9233131), AAVhErl .36 (SEQ ID NO:52 of US9233131), AAVhEr2.29 (SEQ ID NO:40 of US9233
  • the AAV serotype may be, or have, a sequence as described in United States Patent Publication No. US20150376607, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV-PAEC (SEQ ID NO: l of US20150376607), AAV-LKOl (SEQ ID NO:2 of US20150376607), AAV-LK02 (SEQ ID NO:3 of US20150376607), AAV-LK03 (SEQ ID NO:4 of US20150376607), AAV-LK04 (SEQ ID NO:5 of US20150376607), AAV-LK05 (SEQ ID NO:6 of US20150376607), AAV- LK06 (SEQ ID NO:7 of US20150376607), AAV-LK07 (SEQ ID NO:8 of US20150376607), AAV-LK08 (SEQ ID NO:9 of US20150376607), AAV-LK09 (SEQ
  • AAV-LK10 SEQ ID NO: 11 of US20150376607), AAV-LK11 (SEQ ID NO: 12 of US20150376607), AAV-LK12 (SEQ ID NO: 13 of US20150376607), AAV-LK13 (SEQ ID NO: 14 of US20150376607), AAV-LK14 (SEQ ID NO: 15 of US20150376607), AAV- LK15 (SEQ ID NO: 16 of US20150376607), AAV-LK16 (SEQ ID NO: 17 of US20150376607), AAV-LK17 (SEQ ID NO: 18 of US20150376607), AAV-LK18 (SEQ ID NO: 19 of
  • US20150376607 AAV-LK19 (SEQ ID NO:20 of US20150376607), AAV-PAEC2 (SEQ ID NO:21 of US20150376607), AAV-PAEC4 (SEQ ID NO:22 of US20150376607), AAV-PAEC6 (SEQ ID NO:23 of US20150376607), AAV-PAEC 7 (SEQ ID NO:24 of US20150376607), AAV-PAEC 8 (SEQ ID NO:25 of US20150376607), AAV-PAECl 1 (SEQ ID NO:26 of US20150376607), AAV-PAEC 12 (SEQ ID NO:27, of US20150376607), or variants thereof.
  • the AAV serotype may be, or have, a sequence as described in United States Patent No. US9163261, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV-2-pre-miRNA-101 (SEQ ID NO: 1
  • the AAV serotype may be, or have, a sequence as described in United States Patent Publication No. US20150376240, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV-8h (SEQ ID NO: 6 of US20150376240), AAV-8b (SEQ ID NO: 5 of US20150376240), AAV-h (SEQ ID NO: 2 of US20150376240), AAV-b (SEQ ID NO: 1 of US20150376240), or variants thereof.
  • AAV-8h SEQ ID NO: 6 of US20150376240
  • AAV-8b SEQ ID NO: 5 of US20150376240
  • AAV-h SEQ ID NO: 2 of US20150376240
  • AAV-b SEQ ID NO: 1 of US20150376240
  • the AAV serotype may be, or have, a sequence as described in United States Patent Publication No. US20160017295, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV SM 10-2 (SEQ ID NO: 22 of US20160017295), AAV Shuffle 100-1 (SEQ ID NO: 23 of US20160017295), AAV Shuffle 100-3 (SEQ ID NO: 24 of US20160017295), AAV Shuffle 100-7 (SEQ ID NO: 25 of US20160017295), AAV Shuffle 10-2 (SEQ ID NO: 34 of US20160017295), AAV Shuffle 10-6 (SEQ ID NO: 35 of US20160017295), AAV Shuffle 10-8 (SEQ ID NO: 36 of US20160017295), AAV Shuffle 100-2 (SEQ ID NO: 37 of US20160017295), AAV SM 10-1 (SEQ ID NO: 38 of US20160017295), AAV SM 10-8 (SEQ ID NO:
  • the AAV serotype may be, or have, a sequence as described in United States Patent Publication No. US20150238550, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, BNP61 AAV (SEQ ID NO: 1 of US20150238550), BNP62 AAV (SEQ ID NO: 3 of US20150238550), BNP63 AAV (SEQ ID NO: 4 of US20150238550), or variants thereof.
  • the AAV serotype may be or may have a sequence as described in United States Patent Publication No. US20150315612, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAVrh.50 (SEQ ID NO: 108 of US20150315612), AAVrh.43 (SEQ ID NO: 163 of US20150315612), AAVrh.62 (SEQ ID NO : 114 of US20150315612), AAVrh.48 (SEQ ID NO : 115 of US20150315612), AAVhu. l9 (SEQ ID NO: 133 of US20150315612), AAVhu. l l (SEQ ID NO: 153 of
  • AAV54.5/hu.23 (SEQ ID No: 60 of US20150315612), AAV54.2/hu.22 (SEQ ID No: 67 of US20150315612), AAV54.7/hu.24 (SEQ ID No: 66 of US20150315612), AAV54.1/hu.21 (SEQ ID No: 65 of US20150315612), AAV54.4R/hu.27 (SEQ ID No: 64 of US20150315612), AAV46.2/hu.28 (SEQ ID No: 68 of US20150315612), AAV46.6/hu.29 (SEQ ID No: 69 of US20150315612), AAV128.1/hu.43 (SEQ ID No: 80 of US20150315612), or variants thereof.
  • the AAV serotype may be, or have, a sequence as described in International Publication No. WO2015121501, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, true type AAV (ttAAV) (SEQ ID NO: 2 of WO2015121501), "UPenn AAV10” (SEQ ID NO: 8 of WO2015121501), “Japanese AAV10” (SEQ ID NO: 9 of WO2015121501), or variants thereof.
  • true type AAV ttAAV
  • UPenn AAV10 SEQ ID NO: 8 of WO2015121501
  • Japanese AAV10 Japanese AAV10
  • AAV capsid serotype selection or use may be from a variety of species.
  • the AAV may be an avian AAV (AAAV).
  • the AAAV serotype may be, or have, a sequence as described in United States Patent No. US 9238800, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAAV (SEQ ID NO: 1, 2, 4, 6, 8, 10, 12, and 14 of US 9,238,800), or variants thereof.
  • the AAV may be a bovine AAV (BAAV).
  • BAAV serotype may be, or have, a sequence as described in United States Patent No. US 9,193,769, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, BAAV (SEQ ID NO: 1 and 6 of US 9193769), or variants thereof.
  • BAAV serotype may be or have a sequence as described in United States Patent No. US7427396, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, BAAV (SEQ ID NO: 5 and 6 of US7427396), or variants thereof.
  • the AAV may be a caprine AAV.
  • the caprine AAV serotype may be, or have, a sequence as described in United States Patent No. US7427396, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, caprine AAV (SEQ ID NO: 3 of US7427396), or variants thereof.
  • the AAV may be engineered as a hybrid AAV from two or more parental serotypes.
  • the AAV may be AAV2G9 which comprises sequences from AAV2 and AAV9.
  • the AAV2G9 AAV serotype may be, or have, a sequence as described in United States Patent Publication No. US20160017005, the contents of which are herein incorporated by reference in its entirety.
  • the AAV may be a serotype generated by the AAV9 capsid library with mutations in amino acids 390-627 (VP1 numbering) as described by Pulichla et al. (Molecular Therapy 19(6): 1070-1078 (2011), the contents of which are herein incorporated by reference in their entirety.
  • the serotype and corresponding nucleotide and amino acid substitutions may be, but is not limited to, AAV9.1 (G1594C; D532H), AAV6.2 (T1418A and T1436X; V473D and I479K), AAV9.3 (T1238A; F413Y), AAV9.4 (T1250C and A1617T;
  • AAV9.5 A1235G, A1314T, A1642G, C1760T; Q412R, T548A, A587V), AAV9.6 (T1231A; F411I), AAV9.9 (G1203A, G1785T; W595C), AAV9.10 (A1500G, T1676C; M559T), AAV9.11 (A1425T, A1702C, A1769T; T568P, Q590L), AAV9.13 (A1369C, A1720T; N457H, T574S), AAV9.14 (T1340A, T1362C, T1560C, G1713A; L447H), AAV9.16 (A1775T; Q592L), AAV9.24 (T1507C, T1521G; W503R), AAV9.26 (A1337G, A1769C; Y446C, Q590P), AAV9.33 (A1667C;
  • the AAV serotype may be, or have, a sequence as described in International Publication No. WO2016049230, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to AAVF1/HSC1 (SEQ ID NO: 2 and 20 of WO2016049230), AAVF2/HSC2 (SEQ ID NO: 3 and 21 of WO2016049230), AAVF3/HSC3 (SEQ ID NO: 5 and 22 of WO2016049230), AAVF4/HSC4 (SEQ ID NO: 6 and 23 of
  • WO2016049230 AAVF5/HSC5 (SEQ ID NO: 11 and 25 of WO2016049230), AAVF6/HSC6 (SEQ ID NO: 7 and 24 of WO2016049230), AAVF7/HSC7 (SEQ ID NO: 8 and 27 of
  • WO2016049230 AAVF8/HSC8 (SEQ ID NO: 9 and 28 of WO2016049230), AAVF9/HSC9 (SEQ ID NO: 10 and 29 of WO2016049230), AAVF11/HSCl 1 (SEQ ID NO: 4 and 26 of WO2016049230), AAVF12/HSC12 (SEQ ID NO: 12 and 30 of WO2016049230),
  • the AAV serotype may be, or have, a sequence as described in United States Patent No. US 8734809, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV CBr-El (SEQ ID NO: 13 and 87 of
  • the AAV serotype may be, or have, a sequence as described in International Publication No. WO2016065001, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to AAV CHt-P2 (SEQ ID NO: 1 and 51 of WO2016065001), AAV CHt-P5 (SEQ ID NO: 2 and 52 of WO2016065001), AAV CHt-P9 (SEQ ID NO: 3 and 53 of WO2016065001), AAV CBr-7.1 (SEQ ID NO: 4 and 54 of
  • WO2016065001 AAV CBr-7.2 (SEQ ID NO: 5 and 55 of WO2016065001), AAV CBr-7.3 (SEQ ID NO: 6 and 56 of WO2016065001), AAV CBr-7.4 (SEQ ID NO: 7 and 57 of
  • WO2016065001 AAV CBr-7.5 (SEQ ID NO: 8 and 58 of WO2016065001), AAV CBr-7.7 (SEQ ID NO: 9 and 59 of WO2016065001), AAV CBr-7.8 (SEQ ID NO: 10 and 60 of
  • WO2016065001 AAV CBr-7.10 (SEQ ID NO: 11 and 61 of WO2016065001), AAV CKd-N3 (SEQ ID NO: 12 and 62 of WO2016065001), AAV CKd-N4 (SEQ ID NO: 13 and 63 of WO2016065001), AAV CKd-N9 (SEQ ID NO: 14 and 64 of WO2016065001), AAV CLv-L4 (SEQ ID NO: 15 and 65 of WO2016065001), AAV CLv-L5 (SEQ ID NO: 16 and 66 of WO2016065001), AAV CLv-L6 (SEQ ID NO: 17 and 67 of WO2016065001), AAV CLv-Kl (SEQ ID NO: 18 and 68 of WO2016065001), AAV CLv-K3 (SEQ ID NO: 19 and 69 of WO2016065001), AAV CLv-K6 (SEQ ID NO: 20 and 70 of WO201606
  • the AAV may be a serotype selected from any of those found in Table 1.
  • the AAV may comprise a sequence, fragment or variant thereof, of the sequences in Table 1.
  • the AAV may be encoded by a sequence, fragment or variant as described in Table 1.
  • AAV1 2 US20160017295 SEQ ID NO: 1US20030138772 SEQ ID NO: 64, US20150159173
  • AAV2 11 US20030138772 SEQ ID NO: 70, US20150159173 SEQ ID NO: 23, US20150315612
  • AAV3 32 US20030138772 SEQ ID NO: 71, US20150159173 SEQ ID NO: 28, US20160017295
  • AAV7 106 US20030138772 SEQ ID NO: 2, US20150159173 SEQ ID NO: 30, US20150315612
  • AAV8 114 US20030138772 SEQ ID NO: 95, US20140359799 SEQ ID NO: 1, US20150159173
  • AAAV 537 US9238800 SEQ ID NO: 10 (Avian AAV)
  • AAAV 538 US9238800 SEQ ID NO: 15 (Avian AAV)
  • AAV CSp-4 642 US8734809 SEQ ID NO: 50
  • AAV CSp- 808 WO2016065001 SEQ ID NO: 41 8.5
  • AAV CBr- 828 WO2016065001 SEQ ID NO: 61 7.10
  • AAV CHt- 852 WO2016065001 SEQ ID NO: 85 6.6
  • AAV CSp- 858 WO2016065001 SEQ ID NO: 91
  • AAV3B 865 WO2016065001 SEQ ID NO: 98
  • the AAV serotype may be, or may have a sequence as described in International Patent Publication WO2015038958, the contents of which are herein
  • AAV9 SEQ ID NO: 2 and 11 of WO2015038958 or SEQ ID NO: 127 and 126 respectively herein
  • PHP.B SEQ ID NO: 8 and 9 of WO2015038958, herein SEQ ID NO: 868 and 869
  • G2B-13 SEQ ID NO: 12 of WO2015038958, herein SEQ ID NO: 870
  • G2B-26 SEQ ID NO: 13 of WO2015038958, herein SEQ ID NO: 868 and 869
  • THl .1-32 SEQ ID NO: 14 of WO2015038958, herein SEQ ID NO: 871
  • THl .1-35 SEQ ID NO: 15 of WO2015038958, herein SEQ ID NO: 872) or variants thereof.
  • WO2015038958 may be inserted into any parent AAV serotype, such as, but not limited to, AAV9 (SEQ ID NO: 126 for the DNA sequence and SEQ ID NO: 127 for the amino acid sequence).
  • AAV9 SEQ ID NO: 126 for the DNA sequence and SEQ ID NO: 127 for the amino acid sequence.
  • the amino acid insert is inserted between amino acids 586-592 of the parent AAV (e.g., AAV9).
  • the amino acid insert is inserted between amino acids 588-589 of the parent AAV sequence.
  • the amino acid insert may be, but is not limited to, any of the following amino acid sequences, TLAVPFK (SEQ ID NO: 1 of WO2015038958; herein SEQ ID NO: 873), KFPVALT (SEQ ID NO: 3 of WO2015038958; herein SEQ ID NO: 874), LAVPFK (SEQ ID NO: 31 of WO2015038958; herein SEQ ID NO: 875), AVPFK (SEQ ID NO: 32 of WO2015038958; herein SEQ ID NO: 876), VPFK (SEQ ID NO: 33 of WO2015038958; herein SEQ ID NO: 877), TLAVPF (SEQ ID NO: 34 of
  • WO2015038958 herein SEQ ID NO: 878
  • TLAVP SEQ ID NO: 35 of WO2015038958; herein SEQ ID NO: 879
  • TLAV SEQ ID NO: 36 of WO2015038958; herein SEQ ID NO: 880
  • SVSKPFL SEQ ID NO: 28 of WO2015038958; herein SEQ ID NO: 881
  • FTLTTPK SEQ ID NO: 29 of WO2015038958; herein SEQ ID NO: 882
  • MNATKNV SEQ ID NO: 30 of WO2015038958; herein SEQ ID NO: 883)
  • QSSQTPR SEQ ID NO: 54 of WO2015038958; herein SEQ ID NO: 884
  • ILGTGTS SEQ ID NO: 55 of WO2015038958; herein SEQ ID NO: 885
  • TRTNPEA SEQ ID NO: 56 of WO2015038958; herein SEQ ID NO: 886
  • NGGTSSS
  • ACTTTGGCGGTGCCTTTTAAG (SEQ ID NO: 24 and 49 of WO2015038958; herein SEQ ID NO: 890), AGTGTGAGTAAGCCTTTTTTG (SEQ ID NO: 25 of WO2015038958; herein SEQ ID NO: 891), TTTACGTTGACGACGCCTAAG (SEQ ID NO: 26 of WO2015038958; herein SEQ ID NO: 892), ATGA ATGC T AC GA AGA ATGTG (SEQ ID NO: 27 of WO2015038958; herein SEQ ID NO: 893), CAGTCGTCGCAGACGCCTAGG (SEQ ID NO: 48 of
  • WO2015038958 herein SEQ ID NO: 894
  • ATTCTGGGGACTGGTACTTCG SEQ ID NO: 50 and 52 of WO2015038958; herein SEQ ID NO: 895
  • ACGCGGACTAATCCTGAGGCT SEQ ID NO: 51 of WO2015038958; herein SEQ ID NO: 896
  • AATGGGGGGACTAGTAGTTCT SEQ ID NO: 53 of WO2015038958; herein SEQ ID NO: 897
  • the AAV serotype may be engineered to comprise at least one AAV capsid CD8+ T-cell epitope for AAV2 such as, but not limited to, SADNNNSEY (SEQ ID NO: 899), LIDQYLYYL (SEQ ID NO: 900), VPQYGYLTL (SEQ ID NO: 901), TTSTRTWAL (SEQ ID NO: 902), YHLNGRDSL (SEQ ID NO: 903), SQAVGRSSF (SEQ ID NO: 904), VPANPSTTF (SEQ ID NO: 905), FPQSGVLIF (SEQ ID NO: 906), YFDFNRFHCHF SPRD (SEQ ID NO: 907), VGNSSGNWHCDSTWM (SEQ ID NO: 908), QFSQAGASDIRDQSR (SEQ ID NO: 909), GA SDIRQ SRNWLP (SEQ ID NO: 910) and GNRQAATADVNTQGV (SEQ ID NO: 911
  • SADNNNSEY
  • the AAV serotype may be engineered to comprise at least one AAV capsid CD8+ T-cell epitope for AAV1 such as, but not limited to, LDRLMNPLI (SEQ ID NO: 912), TTSTRTWAL (SEQ ID NO: 902), and QPAKKRLNF (SEQ ID NO: 913)).
  • AAV capsid CD8+ T-cell epitope for AAV1 such as, but not limited to, LDRLMNPLI (SEQ ID NO: 912), TTSTRTWAL (SEQ ID NO: 902), and QPAKKRLNF (SEQ ID NO: 913)).
  • the AAV serotype may be, or may have a sequence as described in International Patent Publication WO2017100671, the contents of which are herein
  • AAV9 SEQ ID NO: 45 of WO2017100671, herein SEQ ID NO: 1420
  • PHP.N SEQ ID NO: 46 of WO2017100671, herein SEQ ID NO: 1418
  • PHP.S SEQ ID NO: 47 of WO2017100671, herein SEQ ID NO: 1419
  • WO2017100671 may be inserted into any parent AAV serotype, such as, but not limited to, AAV9 (SEQ ID NO: 127 or SEQ ID NO: 1420).
  • AAV9 SEQ ID NO: 127 or SEQ ID NO: 1420.
  • the amino acid insert is inserted between amino acids 586-592 of the parent AAV (e.g., AAV9).
  • the amino acid insert is inserted between amino acids 588-589 of the parent AAV sequence.
  • the amino acid insert may be, but is not limited to, any of the following amino acid sequences, AQTLAVPFKAQ (SEQ ID NO: 1 of WO2017100671; herein SEQ ID NO: 1804), AQSVSKPFLAQ (SEQ ID NO: 2 of WO2017100671; herein SEQ ID NO: 1805), AQFTLTTPKAQ (SEQ ID NO: 3 in the sequence listing of WO2017100671; herein SEQ ID NO: 1806), DGTLAVPFKAQ (SEQ ID NO: 4 in the sequence listing of WO2017100671; herein SEQ ID NO: 1807), ESTLAVPFKAQ (SEQ ID NO: 5 of WO2017100671; herein SEQ ID NO: 1808), GGTLAVPFKAQ (SEQ ID NO: 6 of WO2017100671; herein SEQ ID NO: 1809), AQTLATPFKAQ (SEQ ID NO: 7 and 33 of WO2017100671; herein SEQ ID NO: 18
  • DGTLATPFKAQ (SEQ ID NO: 9 of WO2017100671; herein SEQ ID NO: 1812),
  • GGTLATPFKAQ (SEQ ID NO: 10 of WO2017100671; herein SEQ ID NO: 1813),
  • QGTLAVPFKAQ (SEQ ID NO: 16 of WO2017100671; herein SEQ ID NO: 1819),
  • NQTLAVPFKAQ (SEQ ID NO: 17 of WO2017100671; herein SEQ ID NO: 1820),
  • EGSLAVPFKAQ (SEQ ID NO: 18 of WO2017100671; herein SEQ ID NO: 1821),
  • DSTLAVPFKAQ (SEQ ID NO: 21 in Table 1 of WO2017100671; herein SEQ ID NO: 1824), AVTLAVPFKAQ (SEQ ID NO: 22 of WO2017100671; herein SEQ ID NO: 1825),
  • AQTLPQPFKAQ (SEQ ID NO: 24 and 32 of WO2017100671; herein SEQ ID NO: 1827), AQTLSQPFKAQ (SEQ ID NO: 25 of WO2017100671; herein SEQ ID NO: 1828),
  • AQTLTMPFKAQ (SEQ ID NO: 27, and 34 of WO2017100671 and SEQ ID NO: 35 in the sequence listing of WO2017100671; herein SEQ ID NO: 1830), AQTLTTPFKAQ (SEQ ID NO: 28 of WO2017100671; herein SEQ ID NO: 1831), AQYTLSQGWAQ (SEQ ID NO: 29 of WO2017100671; herein SEQ ID NO: 1832), AQMNATKNVAQ (SEQ ID NO: 30 of
  • WO2017100671 herein SEQ ID NO: 1834
  • AQTLTAPFKAQ SEQ ID NO: 35 in Table 1 of WO2017100671; herein SEQ ID NO: 1835
  • AQTLSKPFKAQ SEQ ID NO: 36 of
  • WO2017100671 herein SEQ ID NO: 1836
  • QAVRTSL SEQ ID NO: 37 of WO2017100671; herein SEQ ID NO: 1837
  • YTLSQGW SEQ ID NO: 38 of WO2017100671; herein SEQ ID NO: 888
  • LAKERLS SEQ ID NO: 39 of WO2017100671; herein SEQ ID NO: 1838
  • TLAVPFK (SEQ ID NO: 40 in the sequence listing of WO2017100671; herein SEQ ID NO: 873), SVSKPFL (SEQ ID NO: 41 of WO2017100671; herein SEQ ID NO: 881), FTLTTPK (SEQ ID NO: 42 of WO2017100671; herein SEQ ID NO: 882), MNSTKNV (SEQ ID NO: 43 of WO2017100671; herein SEQ ID NO: 1839), VSGGHHS (SEQ ID NO: 44 of WO2017100671; herein SEQ ID NO: 1840), SAQTLAVPFKAQAQ (SEQ ID NO: 48 of WO2017100671; herein SEQ ID NO: 1841), SXXXLAVPFKAQAQ (SEQ ID NO: 49 of WO2017100671 wherein X may be any amino acid; herein SEQ ID NO: 1842), SAQXXXVPFKAQAQ (SEQ ID NO: 50 of WO2017100671 where
  • SAQTLXXXFKAQAQ (SEQ ID NO: 51 of WO2017100671 wherein X may be any amino acid; herein SEQ ID NO: 1844), SAQTLAVXXXAQAQ (SEQ ID NO: 52 of WO2017100671 wherein X may be any amino acid; herein SEQ ID NO: 1845), SAQTLAVPFXXXAQ (SEQ ID NO: 53 of WO2017100671 wherein X may be any amino acid; herein SEQ ID NO: 1846), TNHQSAQ (SEQ ID NO: 65 of WO2017100671; herein SEQ ID NO: 1847), AQAQTGW (SEQ ID NO: 66 of WO2017100671; herein SEQ ID NO: 1848), DGTLATPFK (SEQ ID NO: 67 of WO2017100671; herein SEQ ID NO: 1849), DGTLATPFKXX (SEQ ID NO: 68 of
  • WO2017100671 wherein X may be any amino acid; herein SEQ ID NO: 1850), LAVPFKAQ (SEQ ID NO: 80 of WO2017100671; herein SEQ ID NO: 1851), VPFKAQ (SEQ ID NO: 81 of WO2017100671; herein SEQ ID NO: 1852), FKAQ (SEQ ID NO: 82 of WO2017100671; herein SEQ ID NO: 1853), AQTLAV (SEQ ID NO: 83 of WO2017100671; herein SEQ ID NO: 1854), AQTLAVPF (SEQ ID NO: 84 of WO2017100671; herein SEQ ID NO: 1855), QAVR (SEQ ID NO: 85 of WO2017100671; herein SEQ ID NO: 1856), AVRT (SEQ ID NO: 86 of
  • WO2017100671 herein SEQ ID NO: 1857
  • VRTS SEQ ID NO: 87 of WO2017100671; herein SEQ ID NO: 1858
  • RTSL SEQ ID NO: 88 of WO2017100671; herein SEQ ID NO: 1859
  • QAVRT SEQ ID NO: 89 of WO2017100671; herein SEQ ID NO: 1860
  • AVRTS SEQ ID NO: 90 of WO2017100671; herein SEQ ID NO: 1861
  • VRTSL SEQ ID NO: 91 of
  • WO2017100671 herein SEQ ID NO: 1862
  • QAVRT S SEQ ID NO: 92 of WO2017100671; herein SEQ ID NO: 1863
  • AVRTSL SEQ ID NO: 93 of WO2017100671; herein SEQ ID NO: 1864
  • Non-limiting examples of nucleotide sequences that may encode the amino acid inserts include the following, GATGGGACTTTGGCGGTGCCTTTTAAGGCACAG (SEQ ID NO: 54 of WO2017100671; herein SEQ ID NO: 1865), GATGGGACGTTGGCGGTGCCTTTTAAGGCACAG (SEQ ID NO: 55 of WO2017100671; herein SEQ ID NO: 1866), CAGGCGGTTAGGACGTCTTTG (SEQ ID NO: 56 of
  • WO2017100671 herein SEQ ID NO: 1867
  • CAGGTCTTCACGGACTCAGACTATCAG SEQ ID NO: 57 and 78 of WO2017100671; herein SEQ ID NO: 1868
  • GGAAGTATTCCTTGGTTTTGAACCCA SEQ ID NO: 60 of WO2017100671; herein SEQ ID NO: 1871
  • GGTCGCGGTTCTTGTTTGTGGAT SEQ ID NO: 61 of WO2017100671; herein SEQ ID NO: 1872
  • CGACCTTGAAGCGCATGAACTCCT SEQ ID NO: 62 of
  • N may be A, C, T, or G; herein SEQ ID NO: 1878), ACTTTGGCGGTGCCTTTTAAG (SEQ ID NO: 74 of WO2017100671; herein SEQ ID NO: 890), AGTGTGAGTAAGCCTTTTTTG (SEQ ID NO: 75 of WO2017100671; herein SEQ ID NO: 891), TTTACGTTGACGACGCCTAAG (SEQ ID NO: 76 of WO2017100671; herein SEQ ID NO: 892),
  • the AAV serotype may be, or may have a sequence as described in United States Patent No.
  • US 9624274 the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV1 (SEQ ID NO: 181 of US9624274), AAV6 (SEQ ID NO: 182 of US9624274), AAV2 (SEQ ID NO: 183 of US9624274), AAV3b (SEQ ID NO: 184 of US9624274), AAV7 (SEQ ID NO: 185 of US9624274), AAV8 (SEQ ID NO: 186 of US9624274), AAV10 (SEQ ID NO: 187 of US9624274), AAV4 (SEQ ID NO: 188 of US9624274), AAV11 (SEQ ID NO: 189 of US9624274), bAAV (SEQ ID NO: 190 of US9624274), AAV5 (SEQ ID NO: 191 of US9624274), GPV (SEQ ID NO: 192 of US9624274; herein SEQ ID NO:
  • any of the structural protein inserts described in US 962427 may be inserted into, but not limited to, 1-453 and 1-587 of any parent AAV serotype, such as, but not limited to, AAV2 (SEQ ID NO: 183 of US9624274).
  • the amino acid insert may be, but is not limited to, any of the following amino acid sequences, VNLTWSRASG (SEQ ID NO: 50 of US9624274; herein SEQ ID NO: 1880), EFCINHRGYWVCGD (SEQ ID NO:55 of US9624274; herein SEQ ID NO: 1881), EDGQVMDVDLS (SEQ ID NO: 85 of US9624274; herein SEQ ID NO: 1882), EKQRNGTLT (SEQ ID NO: 86 of US9624274; herein SEQ ID NO: 1883), TYQCRVTHPHLPRALMR (SEQ ID NO: 87 of US9624274; herein SEQ ID NO: 1884), RHSTTQPRKTKGSG (SEQ ID NO: 88 of US9624274; herein SEQ ID NO: 1885),
  • DSNPRGVSAYLSR (SEQ ID NO: 89 of US9624274; herein SEQ ID NO: 1886),
  • TITCLWDLAPSK (SEQ ID NO: 90 of US9624274; herein SEQ ID NO: 1887), KTKGSGFFVF (SEQ ID NO: 91 of US9624274; herein SEQ ID NO: 1888), THPHLPRALMRS (SEQ ID NO: 92 of US9624274; herein SEQ ID NO: 1889), GETYQCRVTHPHLPRALMRSTTK (SEQ ID NO: 93 of US9624274; herein SEQ ID NO: 1890), LPRALMRS (SEQ ID NO: 94 of
  • US9624274 herein SEQ ID NO: 1891
  • INHRGYWV SEQ ID NO: 95 of US9624274; herein SEQ ID NO: 1892
  • CDAGSVRTNAPD SEQ ID NO: 60 of US9624274; herein SEQ ID NO: 1893
  • AKAVSNLTESRSESLQS SEQ ID NO: 96 of US9624274; herein SEQ ID NO: 1894
  • SLTGDEFKKVLET SEQ ID NO: 97 of US9624274; herein SEQ ID NO: 1895
  • REAVAYRFEED SEQ ID NO: 98 of US9624274; herein SEQ ID NO: 1896
  • INPEIITLDG SEQ ID NO: 99 of US9624274; herein SEQ ID NO: 1897
  • DISVTGAPVITATYL SEQ ID NO: 100 of US9624274; herein SEQ ID NO: 1898
  • DISVTGAPVITA SEQ ID NO: 101 of US9624274; herein SEQ ID NO: 1899
  • PKTVSNLTESSSESVQS SEQ ID NO: 102 of US9624274; herein SEQ ID NO: 1900
  • SLMGDEFKAVLET SEQ ID NO: 103 of US9624274; herein SEQ ID NO: 1901
  • QHSVAYTFEED SEQ ID NO: 104 of US9624274; herein SEQ ID NO: 1902
  • INPEIITRDG SEQ ID NO: 105 of US9624274; herein SEQ ID NO: 1903
  • DISLTGDPVITA SEQ ID NO: 107 of US9624274; herein SEQ ID NO: 1905
  • DQSIDFEIDSA SEQ ID NO: 108 of US9624274; herein SEQ ID NO: 1906
  • KNVSEDLPLPTF SPTLLGD S SEQ ID NO: 109 of US9624274; herein SEQ ID NO: 1907
  • KNVSEDLPLPT SEQ ID NO: 110 of US9624274; herein SEQ ID NO: 1908
  • CD S GRVRTD APD SEQ ID NO: 111 of US9624274; herein SEQ ID NO: 1909
  • FPEHLLVDFLQSLS SEQ ID NO: 112 of US9624274; herein SEQ ID NO: 1910
  • DAEFRHDSG SEQ ID NO: 65 of US9624274; herein SEQ ID NO: 65 of US9624274; herein SEQ ID NO:
  • SSRTPSDKPVAHWANPQAE (SEQ ID NO: 116 of US9624274; herein SEQ ID NO: 1915), SRTPSDKPVAHWANP (SEQ ID NO: 117 of US9624274; herein SEQ ID NO: 1916),
  • SSRTPSDKP (SEQ ID NO: 118 of US9624274; herein SEQ ID NO: 1917),
  • NADGNVDYHMNSVP (SEQ ID NO: 119 of US9624274; herein SEQ ID NO: 1918),
  • RSFKEFLQ S SLRALRQ (SEQ ID NO: 121 of US9624274; herein SEQ ID NO: 1920);
  • FKEFLQSSLRA (SEQ ID NO: 122 of US9624274; herein SEQ ID NO: 1921), or
  • QMWAPQWGPD (SEQ ID NO: 123 of US9624274; herein SEQ ID NO: 1922).
  • the AAV serotype may be, or may have a sequence as described in United States Patent No. US 9475845, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV capsid proteins comprising modification of one or more amino acids at amino acid positions 585 to 590 of the native AAV2 capsid protein.
  • the modification may result in, but not limited to, the amino acid sequence RGNRQA (SEQ ID NO: 3 of US9475845; herein SEQ ID NO: 1923), SSSTDP (SEQ ID NO: 4 of US9475845; herein SEQ ID NO: 1924), SSNTAP (SEQ ID NO: 5 of US9475845; herein SEQ ID NO: 1925), SNSNLP (SEQ ID NO: 6 of US9475845; herein SEQ ID NO: 1926), SSTTAP (SEQ ID NO: 7 of US9475845; herein SEQ ID NO: 1927), AANTAA (SEQ ID NO: 8 of US9475845; herein SEQ ID NO: 1928), QQNTAP (SEQ ID NO: 9 of US9475845; herein SEQ ID NO: 1929), SAQAQA (SEQ ID NO: 10 of US9475845; herein SEQ ID NO: 1930), QANTGP (SEQ ID NO: 11 of US9475845; herein SEQ
  • US9475845 herein SEQ ID NO: 1937
  • SIVGLP SEQ ID NO: 18 of US9475845; herein SEQ ID NO: 1938
  • AASTAA SEQ ID NO: 19, and 27 of US9475845; herein SEQ ID NO: 1939
  • SQNTTA SEQ ID NO: 21 of US9475845; herein SEQ ID NO: 1940
  • QQDTAP SEQ ID NO: 22 of US9475845; herein SEQ ID NO: 1941
  • QTNTGP SEQ ID NO: 23 of US9475845; herein SEQ ID NO: 1942
  • QTNGAP SEQ ID NO: 24 of US9475845; herein SEQ ID NO: 1943
  • QQNAAP SEQ ID NO: 25 of US9475845; herein SEQ ID NO: 1944
  • AANTQA SEQ ID NO: 26 of US9475845; herein SEQ ID NO: 1945).
  • the amino acid modification is a substitution at amino acid positions 262 through 265 in the native AAV2 capsid protein or the corresponding position in the capsid protein of another AAV with a targeting sequence.
  • the targeting sequence may be, but is not limited to, any of the amino acid sequences, NGRAHA (SEQ ID NO: 38 of US9475845; herein SEQ ID NO: 1946), QPEHSST (SEQ ID NO: 39 and 50 of US9475845; herein SEQ ID NO: 1947), VNTANST (SEQ ID NO: 40 of US9475845; herein SEQ ID NO: 1948), HGPMQKS (SEQ ID NO: 41 of US9475845; herein SEQ ID NO: 1949), PHKPPLA (SEQ ID NO: 42 of US9475845; herein SEQ ID NO: 1950), n NNEMW (SEQ ID NO: 43 of US9475845; herein SEQ ID NO: 1951), RNLDTPM (SEQ ID NO: 44 of US9475845
  • GYRDGYAGPILYN (SEQ ID NO: 74 of US9475845; herein SEQ ID NO: 1981), XXXYXXX (SEQ ID NO: 75 of US9475845; herein SEQ ID NO: 1982), YXNW (SEQ ID NO: 76 of US9475845; herein SEQ ID NO: 1983), RPLPPLP (SEQ ID NO: 77 of US9475845; herein SEQ ID NO: 1984), APPLPPR (SEQ ID NO: 78 of US9475845; herein SEQ ID NO: 1985),
  • DVFYPYPYASGS (SEQ ID NO: 79 of US9475845; herein SEQ ID NO: 1986), MYWYPY (SEQ ID NO: 80 of US9475845; herein SEQ ID NO: 1987), DITWDQLWDLMK (SEQ ID NO: 81 of US9475845; herein SEQ ID NO: 1988), CWDDXWLC (SEQ ID NO: 82 of US9475845; herein SEQ ID NO: 1989), EWCEYLGGYLRCYA (SEQ ID NO: 83 of US9475845; herein SEQ ID NO: 1990), YXCXXGPXTWXCXP (SEQ ID NO: 84 of US9475845; herein SEQ ID NO: 1991), IEGPTLRQWLAARA (SEQ ID NO: 85 of US9475845; herein SEQ ID NO: 1992), LWXXX (SEQ ID NO: 86 of US9475845; herein SEQ ID NO:
  • CTVALPGGYVRVC (SEQ ID NO: 114 of US9475845; herein SEQ ID NO: 2020),
  • CVAYCIEHHCWTC (SEQ ID NO: 116 of US9475845; herein SEQ ID NO: 2021),
  • CVFAHNYDYLVC (SEQ ID NO: 117 of US9475845; herein SEQ ID NO: 2022),
  • CVFTSNYAFC (SEQ ID NO: 118 of US9475845; herein SEQ ID NO: 2023), VHSPNKK (SEQ ID NO: 119 of US9475845; herein SEQ ID NO: 2024), CRGDGWC (SEQ ID NO: 120 of US9475845; herein SEQ ID NO: 2025), XRGCDX (SEQ ID NO: 121 of US9475845; herein SEQ ID NO: 2026), PXXX (SEQ ID NO: 122 of US9475845; herein SEQ ID NO: 2027), SGKGPRQITAL (SEQ ID NO: 124 of US9475845; herein SEQ ID NO: 2028),
  • AAAAAAAAAXXXXX (SEQ ID NO: 125 of US9475845; herein SEQ ID NO: 2029), VYMSPF (SEQ ID NO: 126 of US9475845; herein SEQ ID NO: 2030), ATWLPPR (SEQ ID NO: 127 of US9475845; herein SEQ ID NO: 2031), HTMYYHHYQHHL (SEQ ID NO: 128 of US9475845; herein SEQ ID NO: 2032), SE VGCRAGPLQ WLCEK YF G (SEQ ID NO: 129 of US9475845; herein SEQ ID NO: 2033), CGLLPVGRPDRNVWRWLC (SEQ ID NO: 130 of US9475845; herein SEQ ID NO: 2034), CKGQCDRFKGLPWEC (SEQ ID NO: 131 of US9475845; herein SEQ ID NO: 2035), SGRSA (SEQ ID NO: 132 of US9475845; herein S
  • AEPMPHSLNFSQYLWYT SEQ ID NO: 134 of US9475845; herein SEQ ID NO: 2038
  • WAYXSP SEQ ID NO: 135 of US9475845; herein SEQ ID NO: 2039
  • IELLQAR SEQ ID NO: 136 of US9475845; herein SEQ ID NO: 2040
  • AYTKC SRQWRTCMTTH SEQ ID NO: 137 of US9475845; herein SEQ ID NO: 2041
  • PQNSKIPGPTFLDPH SEQ ID NO: 138 of US9475845; herein SEQ ID NO: 2042
  • SMEPALPDWWWKMFK SEQ ID NO: 139 of US9475845; herein SEQ ID NO: 2043
  • ANTPCGPYTHDCPVKR SEQ ID NO: 140 of US9475845; herein SEQ ID NO: 2044
  • TACHQHVRMVRP SEQ ID NO: 141 of US9475
  • CXXTXXXGXGC (SEQ ID NO: 146 of US9475845; herein SEQ ID NO: 2050), CPIEDRPMC (SEQ ID NO: 147 of US9475845; herein SEQ ID NO: 2051), HEWSYLAPYPWF (SEQ ID NO: 148 of US9475845; herein SEQ ID NO: 2052), MCPKHPLGC (SEQ ID NO: 149 of
  • US9475845 herein SEQ ID NO: 2054
  • SAKTAVSQRVWLPSHRGGEP SEQ ID NO: 151 of US9475845; herein SEQ ID NO: 2055
  • KSREHVNNSACPSKRITAAL SEQ ID NO: 152 of US9475845; herein SEQ ID NO: 2056
  • EGFR SEQ ID NO: 153 of US9475845; herein SEQ ID NO: 2057
  • AGLGVR SEQ ID NO: 154 of US9475845; herein SEQ ID NO: 2058
  • GTRQGHTMRLGVSDG (SEQ ID NO: 155 of US9475845; herein SEQ ID NO: 2059),
  • SMSIARL SEQ ID NO: 157 of US9475845; herein SEQ ID NO: 2061
  • HTFEPGV SEQ ID NO: 158 of US9475845; herein SEQ ID NO: 2062
  • NTSLKRISNKRIRRK SEQ ID NO: 159 of US9475845; herein SEQ ID NO: 2063
  • LRIKRKRRKRKKTRK SEQ ID NO: 160 of
  • the AAV serotype may be, or may have a sequence as described in United States Publication No. US 20160369298, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, site-specific mutated capsid protein of AAV2 (SEQ ID NO: 97 of US 20160369298; herein SEQ ID NO: 2065) or variants thereof, wherein the specific site is at least one site selected from sites R447, G453, S578, N587, N587+1, S662 of VP1 or fragment thereof.
  • any of the mutated sequences described in US 20160369298, may be or may have, but not limited to, any of the following sequences SDSGASN (SEQ ID NO: 1 and SEQ ID NO: 231 of US20160369298; herein SEQ ID NO: 2066), SPSGASN (SEQ ID NO: 2 of
  • YYL SRTNTRS GIMTK S SLMF S Q AGA (SEQ ID NO: 23 of US20160369298; herein SEQ ID NO: 2088), YYL SRTNTK SGRKTL SNL SF S Q AGA (SEQ ID NO: 24 of US20160369298; herein SEQ ID NO: 2089), YYL SRTNDGSGP VTP SKLRF SQRGA (SEQ ID NO: 25 of US20160369298; herein SEQ ID NO: 2090), YYLSRTNAASGHATHSDLKFSQPGA (SEQ ID NO: 26 of US20160369298; herein SEQ ID NO: 2091),
  • YYL SRTNGQ AGSLTM SELGF S Q VGA (SEQ ID NO: 27 of US20160369298; herein SEQ ID NO: 2092), YYLSRTNSTGGNQTTSQLLFSQLSA (SEQ ID NO: 28 of US20160369298;
  • US20160369298 herein SEQ ID NO: 2153), SQSGASN (SEQ ID NO: 89 and SEQ ID NO: 241 of US20160369298; herein SEQ ID NO: 2154), NNGSQA (SEQ ID NO: 90 of US20160369298; herein SEQ ID NO: 2155), YYLSRTNTPSGTTTWSRLQFSQAGA (SEQ ID NO: 91 of US20160369298; herein SEQ ID NO: 2156), SKTSADNNNSEYSWTG (SEQ ID NO: 92 of US20160369298; herein SEQ ID NO: 2157), HKDDEEKF (SEQ ID NO: 93, 209, 214, 219, 224, 234, 239, and 244 of US20160369298; herein SEQ ID NO: 2158), KQGSEKTNVDIEEV (SEQ ID NO: 94 of US20160369298; herein SEQ ID NO: 2159), QRGNNQAATADV
  • SASGASNYNTPSGTTTQSRLQFSTSADNNNSEFSWPGATTYH (SEQ ID NO: 109 of US20160369298; herein SEQ ID NO: 2165),
  • SKTDGENNNSDFS (SEQ ID NO: 213 and SEQ ID NO: 248 of US20160369298; herein SEQ ID NO: 2193), KQGAAADDVEIDGV (SEQ ID NO: 215 and SEQ ID NO: 250 of
  • YFLSRTNDASGSDTKSTLLFSQAG (SEQ ID NO: 222 of US20160369298; herein SEQ ID NO: 2199), STTPSENNNSEYS (SEQ ID NO: 223 of US20160369298; herein SEQ ID NO: 2200), SAAGATN (SEQ ID NO: 226 and SEQ ID NO: 251 of US20160369298; herein SEQ ID NO: 2201), YFLSRTNGEAGSATLSELRFSQAG (SEQ ID NO: 227 of US20160369298; herein SEQ ID NO: 2202), HGDDADRF (SEQ ID NO: 229 and SEQ ID NO: 254 of US20160369298; herein SEQ ID NO: 2203), KQGAEKSDVEVDRV (SEQ ID NO: 230 and SEQ ID NO: 255 of US20160369298; herein SEQ ID NO: 2204), KQD S GGDNIDID Q V (SEQ ID NO: 235 of US
  • US20160369298 herein SEQ ID NO: 2207
  • KEDGGGSDVAIDEV SEQ ID NO: 240 of US20160369298; herein SEQ ID NO: 2208
  • SNAGASN SEQ ID NO: 246 of US20160369298; herein SEQ ID NO: 2209
  • YFLSRTNGEAGSATLSELRFSQPG SEQ ID NO: 252 of US20160369298; herein SEQ ID NO: 2210.
  • nucleotide sequences that may encode the amino acid mutated sites include the following,
  • AGCVVMDCAGGARSCASCAAC SEQ ID NO: 97 of US20160369298; herein SEQ ID NO: 2211
  • AACRACRRSMRSMAGGCA SEQ ID NO: 98 of US20160369298; herein SEQ ID NO: 2212
  • CACRRGGACRRCRMSRRSARSTTT SEQ ID NO: 99 of US20160369298; herein SEQ ID NO: 2213
  • AAGSAARRCRSCRVSRVARVCRATRYCGMSNHCRVMVRSGTC (SEQ ID NO: 102 of US20160369298; herein SEQ ID NO: 2216),
  • CAGVVSVVSMRSRVCVNSGCAGCTDHCVVSRNSGTCVMSACA (SEQ ID NO: 103 of US20160369298; herein SEQ ID NO: 2217),
  • AACTWCRVSVASMVSVHSDDTGTGSWSTKSACT SEQ ID NO: 104 of US20160369298; herein SEQ ID NO: 2218
  • TTGTTGAACATCACCACGTGACGCACGTTC SEQ ID NO: 256 of US20160369298; herein SEQ ID NO: 2219
  • TCCCCGTGGTTCTACTACATAATGTGGCCG SEQ ID NO: 257 of US20160369298; herein SEQ ID NO: 2220
  • TTCCACACTCCGTTTTGGATAATGTTGAAC SEQ ID NO: 258 of US20160369298; herein SEQ ID NO: 2221
  • AGGGACATCCCCAGCTCCATGCTGTGGTCG SEQ ID NO: 259 of US20160369298; herein SEQ ID NO: 2222
  • AGTACCATGTACACCCACTCTCCCAGTGCC (SEQ ID NO: 262 of US20160369298; herein SEQ ID NO: 2225), ATATGGACGTTCATGCTGATCACCATACCG (SEQ ID NO: 263 of US20160369298; herein SEQ ID NO: 2226), AGCAGGAGCTCCTTGGCCTCAGCGTGCGAG (SEQ ID NO: 264 of US20160369298; herein SEQ ID NO: 2227),
  • ACAAGCAGCTTCACTATGACAACCACTGAC SEQ ID NO: 265 of US20160369298; herein SEQ ID NO: 2228
  • the AAV serotype may comprise an ocular cell targeting peptide as described in International Patent Publication WO2016134375, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to SEQ ID NO: 9, and SEQ ID NO: 10 of WO2016134375.
  • any of the ocular cell targeting peptides or amino acids described in WO2016134375 may be inserted into any parent AAV serotype, such as, but not limited to, AAV2 (SEQ ID NO:8 of WO2016134375; herein SEQ ID NO: 2234), or AAV9 (SEQ ID NO: 11 of WO2016134375; herein SEQ ID NO: 2235).
  • modifications such as insertions are made in AAV2 proteins at P34-A35, T138-A139, A139- P140, G453- T454, N587-R588, and/or R588-Q589.
  • insertions are made at D384, G385, 1560, T561, N562, E563, E564, E565, N704, and/or Y705 of AAV9.
  • the ocular cell targeting peptide may be, but is not limited to, any of the following amino acid sequences, GSTPPPM (SEQ ID NO: 1 of WO2016134375; herein SEQ ID NO: 2236), or GETRAPL (SEQ ID NO: 4 of WO2016134375; herein SEQ ID NO: 2237).
  • the AAV serotype may be modified as described in the United States Publication US 20170145405 the contents of which are herein incorporated by reference in their entirety.
  • AAV serotypes may include, modified AAV2(e.g., modifications at Y444F, Y500F, Y730F and/or S662V), modified AAV3 (e.g., modifications at Y705F, Y731F and/or T492V), and modified AAV6 (e.g., modifications at S663 V and/or T492V).
  • the AAV serotype may be modified as described in the International Publication WO2017083722 the contents of which are herein incorporated by reference in their entirety.
  • AAV serotypes may include, AAV1 (Y705+731F+T492V), AAV2 (Y444+500+730F+T491V), AAV3 (Y705+731F), AAV5, AAV 5(Y436+693+719F), AAV6 (VP3 variant Y705F/Y731F/T492V), AAV8 (Y733F), AAV9, AAV9 (VP3 variant Y731F), and AAV10 (Y733F).
  • the AAV serotype may comprise, as described in International Patent Publication WO2017015102, the contents of which are herein incorporated by reference in their entirety, an engineered epitope comprising the amino acids SPAKFA (SEQ ID NO: 24 of WO2017015102; herein SEQ ID NO: 2238) or NKDKLN (SEQ ID NO:2 of WO2017015102; herein SEQ ID NO: 2239).
  • the epitope may be inserted in the region of amino acids 665 to 670 based on the numbering of the VP1 capsid of AAV8 (SEQ ID NO: 3 of WO2017015102) and/or residues 664 to 668 of AAV3B (SEQ ID NO:3).
  • the AAV serotype may be, or may have a sequence as described in International Patent Publication WO2017058892, the contents of which are herein
  • AAV variants with capsid proteins that may comprise a substitution at one or more (e.g., 2, 3, 4, 5, 6, or 7) of amino acid residues 262-268, 370- 379, 451 -459, 472-473, 493-500, 528-534, 547-552, 588- 597, 709-710, 716-722 of AAV1, in any combination, or the equivalent amino acid residues in AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV 12, AAVrh8, AAVrhlO, AAVrh32.33, bovine AAV or avian AAV.
  • AAV variants with capsid proteins that may comprise a substitution at one or more (e.g., 2, 3, 4, 5, 6, or 7) of amino acid residues 262-268, 370- 379, 451 -459, 472-473, 493-500, 528-534, 547-552, 588- 597, 709-7
  • the amino acid substitution may be, but is not limited to, any of the amino acid sequences described in WO2017058892.
  • the AAV may comprise an amino acid substitution at residues 256L, 258K, 259Q, 261 S, 263 A, 264S, 265T, 266G, 272H, 385S, 386Q, S472R, V473D, N500E 547S, 709A, 7 ION, 716D, 717N, 718N, 720L, A456T, Q457T, N458Q, K459S, T492S, K493A, S586R, S587G, S588N, T589R and/or 722T of AAVl (SEQ ID NO: 1 of WO2017058892) in any combination, 244N, 246Q, 248R, 249E, 2501, 25 IK, 252S, 253G, 254S, 255V, 256D, 263 Y,
  • the AAV may include a sequence of amino acids at positions 155, 156 and 157 of VPl or at positions 17, 18, 19 and 20 of VP2, as described in International Publication No. WO 2017066764, the contents of which are herein incorporated by reference in their entirety.
  • sequences of amino acid may be, but not limited to, N-S-S, S-X-S, S-S-Y, N- X-S, N-S-Y, S-X-Y and N-X-Y, where N, X and Y are, but not limited to, independently non- serine, or non-threonine amino acids, wherein the AAV may be, but not limited to AAVl, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAVl 1 and AAV12.
  • the AAV may include a deletion of at least one amino acid at positions 156, 157 or 158 of VPl or at positions 19, 20 or 21 of VP2, wherein the AAV may be, but not limited to AAVl, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAVl 1 and AAV12.
  • peptides for inclusion in an AAV serotype may be identified using the methods described by Hui et al. (Molecular Therapy - Methods & Clinical
  • the procedure includes isolating human splenocytes, restimulating the splenocytes in vitro using individual peptides spanning the amino acid sequence of the AAV capsid protein, IFN-gamma ELISpot with the individual peptides used for the in vitro restimulation, bioinformatics analysis to determine the HLA restriction of 15-mers identified by IFN-gamma ELISpot, identification of candidate reactive 9-mer epitopes for a given HLA allele, synthesis candidate 9-mers, second IFN-gamma ELISpot screening of splenocytes from subjects carrying the HLA alleles to which identified AAV epitopes are predicted to bind, determine the AAV capsid-reactive CD8+ T cell epitopes and determine the frequency of subjects reacting to a given AAV epitope.
  • the AAV may be a serotype generated by Cre-recombinati on- based AAV targeted evolution (CREATE) as described by Deverman et al., (Nature
  • AAV serotypes generated in this manner have improved CNS transduction and/or neuronal and astrocytic tropism, as compared to other AAV serotypes.
  • the AAV serotype may be PHP.B, PHP.B2, PHP.B3, PHP. A, G2A12, G2A15.
  • these AAV serotypes may be AAV9 (SEQ ID NO: 126 and 127) derivatives with a 7-amino acid insert between amino acids 588-589.
  • Non- limiting examples of these 7-amino acid inserts include TLAVPFK (SEQ ID NO: 873),
  • SVSKPFL (SEQ ID NO: 1249), FTLTTPK (SEQ ID NO: 882), YTLSQGW (SEQ ID NO: 888), QAVRTSL (SEQ ID NO: 914) and/or LAKERLS (SEQ ID NO: 915).
  • the AAV serotype may be as described in Jackson et al (Frontiers in Molecular Neuroscience 9: 154 (2016)), the contents of which are herein incorporated by reference in their entirety.
  • the AAV serotype is PHP.B or AAV9.
  • the AAV serotype is paired with a synapsin promoter to enhance neuronal transduction, as compared to when more ubiquitous promoters are used (i.e., CBA or CMV).
  • peptides for inclusion in an AAV serotype may be identified by isolating human splenocytes, restimulating the splenocytes in vitro using individual peptides spanning the amino acid sequence of the AAV capsid protein, IFN-gamma ELISpot with the individual peptides used for the in vitro restimulation, bioinformatics analysis to determine the given allele restriction of 15-mers identified by IFN-gamma ELISpot, identification of candidate reactive 9-mer epitopes for a given allele, synthesis candidate 9-mers, second IFN-gamma ELISpot screening of splenocytes from subjects carrying the specific alleles to which identified AAV epitopes are predicted to bind, determine the AAV capsid-reactive CD8+ T cell epitopes and determine the frequency of subjects reacting to a given AAV epitope.
  • AAV particles comprising a modulatory polynucleotide encoding the siRNA molecules may be prepared or derived from various serotypes of AAVs, including, but not limited to, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV9.47, AAV9(hul4), AAV10, AAVl l, AAV 12, AAVrh8, AAVrhlO, AAV-DJ8 and AAV-DJ.
  • different serotypes of AAVs may be mixed together or with other types of viruses to produce chimeric AAV particles.
  • the AAV particle is derived from the AAV9 serotype.
  • an AAV particle comprises a viral genome with a payload region.
  • the viral genome may comprise the components as shown in FIG. 1.
  • the payload region 110 is located within the viral genome 100.
  • At the 5' and/or the 3' end of the viral genome 100 there may be at least one inverted terminal repeat (ITR) 120.
  • ITR inverted terminal repeat
  • the payload region may comprise at least one modulatory polynucleotide.
  • the viral genome 100 may comprise the components as shown in FIG. 2.
  • the payload region 110 is located within the viral genome 100.
  • At the 5' and/or the 3' end of the viral genome 100 there may be at least one inverted terminal repeat (ITR) 120.
  • ITR inverted terminal repeat
  • a promoter region 130 Between the 5' ITR 120 and the payload region 110, there may be a promoter region 130.
  • the payload region may comprise at least one modulatory polynucleotide.
  • the viral genome 100 may comprise the components as shown in FIG. 3. At the 5' and/or the 3' end of the viral genome 100 there may be at least one inverted terminal repeat (ITR) 120. Within the viral genome 100, there may be an enhancer region 150, a promoter region 130, an intron region 140, and a payload region 110. In one embodiment, the payload region may comprise at least one modulatory polynucleotide.
  • ITR inverted terminal repeat
  • the viral genome 100 may comprise the components as shown in FIG. 4. At the 5' and/or the 3' end of the viral genome 100 there may be at least one inverted terminal repeat (ITR) 120. Within the viral genome 100, there may be an enhancer region 150, a promoter region 130, an intron region 140, a payload region 110, and a polyadenylation signal sequence region 160. In one embodiment, the payload region may comprise at least one modulatory polynucleotide.
  • ITR inverted terminal repeat
  • the viral genome 100 may comprise the components as shown in FIG. 5. At the 5' and/or the 3' end of the viral genome 100 there may be at least one inverted terminal repeat (ITR) 120. Within the viral genome 100, there may be at least one MCS region 170, an enhancer region 150, a promoter region 130, an intron region 140, a payload region 110, and a polyadenylation signal sequence region 160. In one embodiment, the payload region may comprise at least one modulatory polynucleotide.
  • ITR inverted terminal repeat
  • the viral genome 100 may comprise the components as shown in FIG. 6. At the 5' and/or the 3' end of the viral genome 100 there may be at least one inverted terminal repeat (ITR) 120. Within the viral genome 100, there may be at least one MCS region 170, an enhancer region 150, a promoter region 130, at least one exon region 180, at least one intron region 140, a payload region 110, and a polyadenylation signal sequence region 160. In one embodiment, the payload region may comprise at least one modulatory polynucleotide.
  • ITR inverted terminal repeat
  • the viral genome 100 may comprise the components as shown in FIG. 7 and 8. Within the viral genome 100, there may be at least one promoter region 130, and a payload region 110. In one embodiment, the payload region may comprise at least one modulatory polynucleotide.
  • the viral genome 100 may comprise the components as shown in FIG. 9. Within the viral genome 100, there may be at least one promoter region 130, a payload region 110, and a polyadenylation signal sequence region 160. In one embodiment, the payload region may comprise at least one modulatory polynucleotide.
  • the viral genome which comprises a payload described herein may be single stranded or double stranded viral genome.
  • the size of the viral genome may be small, medium, large or the maximum size.
  • the viral genome may comprise a promoter and a poly A tail.
  • the viral genome which comprises a payload described herein may be a small single stranded viral genome.
  • a small single stranded viral genome may be 2.7 to 3.5 kb in size such as about 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, and 3.5 kb in size.
  • the small single stranded viral genome may be 3.2 kb in size.
  • the viral genome may comprise a promoter and a poly A tail.
  • the viral genome which comprises a payload described herein may be a small double stranded viral genome.
  • a small double stranded viral genome may be 1.3 to 1.7 kb in size such as about 1.3, 1.4, 1.5, 1.6, and 1.7 kb in size.
  • the small double stranded viral genome may be 1.6 kb in size.
  • the viral genome may comprise a promoter and a poly A tail.
  • the viral genome which comprises a payload described herein may a medium single stranded viral genome.
  • a medium single stranded viral genome may be 3.6 to 4.3 kb in size such as about 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2 and 4.3 kb in size.
  • the medium single stranded viral genome may be 4.0 kb in size.
  • the viral genome may comprise a promoter and a poly A tail.
  • the viral genome which comprises a payload described herein may be a medium double stranded viral genome.
  • a medium double stranded viral genome may be 1.8 to 2.1 kb in size such as about 1.8, 1.9, 2.0, and 2.1 kb in size.
  • the medium double stranded viral genome may be 2.0 kb in size.
  • the viral genome may comprise a promoter and a poly A tail.
  • the viral genome which comprises a payload described herein may be a large single stranded viral genome.
  • a large single stranded viral genome may be 4.4 to 6.0 kb in size such as about 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 and 6.0 kb in size.
  • the large single stranded viral genome may be 4.7 kb in size.
  • the large single stranded viral genome may be 4.8 kb in size.
  • the large single stranded viral genome may be 6.0 kb in size.
  • the viral genome may comprise a promoter and a polyA tail.
  • the viral genome which comprises a payload described herein may be a large double stranded viral genome.
  • a large double stranded viral genome may be 2.2 to 3.0 kb in size such as about 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 and 3.0 kb in size.
  • the large double stranded viral genome may be 2.4 kb in size.
  • the viral genome may comprise a promoter and a poly A tail.
  • ITRs Inverted Terminal Repeats
  • the AAV particles of the present invention comprise a viral genome with at least one ITR region and a payload region.
  • the viral genome has two ITRs. These two ITRs flank the payload region at the 5' and 3' ends.
  • the ITRs function as origins of replication comprising recognition sites for replication.
  • ITRs comprise sequence regions which can be complementary and symmetrically arranged.
  • ITRs incorporated into viral genomes of the invention may be comprised of naturally occurring polynucleotide sequences or recombinantly derived polynucleotide sequences.
  • the ITRs may be derived from the same serotype as the capsid, selected from any of the serotypes listed in Table 1, or a derivative thereof.
  • the ITR may be of a different serotype from the capsid.
  • the AAV particle has more than one ITR.
  • the AAV particle has a viral genome comprising two ITRs.
  • the ITRs are of the same serotype as one another.
  • the ITRs are of different serotypes.
  • Non-limiting examples include zero, one or both of the ITRs having the same serotype as the capsid.
  • both ITRs of the viral genome of the AAV particle are AAV2 ITRs.
  • each ITR may be about 100 to about 150 nucleotides in length.
  • An ITR may be about 100-105 nucleotides in length, 106-110 nucleotides in length, 111-115 nucleotides in length, 116-120 nucleotides in length, 121-125 nucleotides in length, 126-130 nucleotides in length, 131-135 nucleotides in length, 136-140 nucleotides in length, 141-145 nucleotides in length or 146-150 nucleotides in length.
  • the ITRs are 140-142 nucleotides in length.
  • Non limiting examples of ITR length are 102, 140, 141, 142, 145 nucleotides in length, and those having at least 95% identity thereto.
  • the AAV particle comprises a nucleic acid sequence encoding an siRNA molecule which may be located near the 5' end of the flip ITR in an expression vector. In another embodiment, the AAV particle comprises a nucleic acid sequence encoding an siRNA molecule may be located near the 3' end of the flip ITR in an expression vector. In yet another embodiment, the AAV particle comprises a nucleic acid sequence encoding an siRNA molecule may be located near the 5' end of the flop ITR in an expression vector. In yet another
  • the AAV particle comprises a nucleic acid sequence encoding an siRNA molecule may be located near the 3' end of the flop ITR in an expression vector. In one embodiment, the AAV particle comprises a nucleic acid sequence encoding an siRNA molecule may be located between the 5' end of the flip ITR and the 3' end of the flop ITR in an expression vector.
  • the AAV particle comprises a nucleic acid sequence encoding an siRNA molecule may be located between (e.g., half-way between the 5' end of the flip ITR and 3' end of the flop ITR or the 3' end of the flop ITR and the 5' end of the flip ITR), the 3' end of the flip ITR and the 5' end of the flip ITR in an expression vector.
  • the AAV particle comprises a nucleic acid sequence encoding an siRNA molecule may be located within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more than 30 nucleotides downstream from the 5' or 3' end of an ITR (e.g., Flip or Flop ITR) in an expression vector.
  • an ITR e.g., Flip or Flop ITR
  • the AAV particle comprises a nucleic acid sequence encoding an siRNA molecule may be located within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more than 30 nucleotides upstream from the 5' or 3' end of an ITR (e.g., Flip or Flop ITR) in an expression vector.
  • an ITR e.g., Flip or Flop ITR
  • the AAV particle comprises a nucleic acid sequence encoding an siRNA molecule may be located within 1-5, 1-10, 1-15, 1-20, 1-25, 1-30, 5-10, 5-15, 5-20, 5-25, 5-30, 10-15, 10-20, 10-25, 10-30, 15-20, 15-25, 15-30, 20-25, 20-30 or 25-30 nucleotides downstream from the 5' or 3' end of an ITR (e.g., Flip or Flop ITR) in an expression vector.
  • an ITR e.g., Flip or Flop ITR
  • the AAV particle comprises a nucleic acid sequence encoding an siRNA molecule may be located within 1-5, 1-10, 1-15, 1-20, 1-25, 1-30, 5-10, 5-15, 5-20, 5-25, 5-30, 10-15, 10-20, 10-25, 10-30, 15-20, 15-25, 15-30, 20-25, 20-30 or 25-30 upstream from the 5' or 3' end of an ITR (e.g., Flip or Flop ITR) in an expression vector.
  • an ITR e.g., Flip or Flop ITR
  • the AAV particle comprises a nucleic acid sequence encoding an siRNA molecule may be located within the first 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25% or more than 25% of the nucleotides upstream from the 5' or 3' end of an ITR (e.g., Flip or Flop ITR) in an expression vector.
  • an ITR e.g., Flip or Flop ITR
  • the AAV particle comprises a nucleic acid sequence encoding an siRNA molecule may be located with the first 1-5%, 1-10%, 1-15%, 1-20%, 1-25%, 5-10%, 5-15%, 5-20%, 5-25%, 10-15%, 10-20%, 10-25%, 15-20%, 15- 25%, or 20-25% downstream from the 5' or 3' end of an ITR (e.g., Flip or Flop ITR) in an expression vector.
  • an ITR e.g., Flip or Flop ITR
  • the payload region of the viral genome comprises at least one element to enhance the transgene target specificity and expression (See e.g., Powell et al. Viral Expression Cassette Elements to Enhance Transgene Target Specificity and Expression in Gene Therapy, 2015; the contents of which are herein incorporated by reference in its entirety).
  • elements to enhance the transgene target specificity and expression include promoters, endogenous miRNAs, post-transcriptional regulatory elements (PREs),
  • Poly A polyadenylation signal sequences and upstream enhancers (USEs), CMV enhancers and introns.
  • a person skilled in the art may recognize that expression of the polypeptides of the invention in a target cell may require a specific promoter, including but not limited to, a promoter that is species specific, inducible, tissue-specific, or cell cycle-specific (Parr et al., Nat. Med.3 : ⁇ ⁇ 45-9 (1997); the contents of which are herein incorporated by reference in their entirety).
  • the promoter is deemed to be efficient when it drives expression of the polypeptide(s) encoded in the payload region of the viral genome of the AAV particle.
  • the promoter is a promoter deemed to be efficient to drive the expression of the modulatory polynucleotide. [00143] In one embodiment, the promoter is a promoter deemed to be efficient when it drives expression in the cell being targeted.
  • the promoter drives expression of the payload for a period of time in targeted tissues.
  • Expression driven by a promoter may be for a period of 1 hour, 2, hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 3 weeks, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 13 months, 14 months, 15 months, 16 months, 17 months, 18
  • Expression may be for 1-5 hours, 1-12 hours, 1-2 days, 1-5 days, 1-2 weeks, 1-3 weeks, 1-4 weeks, 1-2 months, 1-4 months, 1-6 months, 2-6 months, 3-6 months, 3-9 months, 4-8 months, 6-12 months, 1-2 years, 1-5 years, 2-5 years, 3-6 years, 3-8 years, 4-8 years or 5-10 years.
  • the promoter drives expression of the payload for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 13 years, 14 years, 15 years, 16 years, 17 years, 18 years, 19 years, 20 years, 21 years, 22 years, 23 years, 24 years, 25 years, 26 years, 27 years, 28 years, 29 years, 30 years, 31 years, 32 years, 33 years, 34 years, 35 years, 36 years, 37 years, 38 years, 39 years, 40 years, 41 years, 42 years, 43 years, 44 years, 45 years, 46 years, 47 years, 48 years, 49 years, 50 years, 55 years, 60 years, 65 years, or more than 65 years.
  • Promoters may be naturally occurring or non-naturally occurring.
  • Non-limiting examples of promoters include viral promoters, plant promoters and mammalian promoters.
  • the promoters may be human promoters.
  • the promoter may be truncated.

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