WO2023196576A2 - Méthodes et compositions pour détecter ou traiter des maladies neurologiques et des malignités hématologiques - Google Patents
Méthodes et compositions pour détecter ou traiter des maladies neurologiques et des malignités hématologiques Download PDFInfo
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Definitions
- Targeted protein degradation is a new therapeutic modality for eliminating pathological proteins from cells by modifying them with ubiquitin chains and subsequent disposal (UPS, Bard et al., 2018).
- Target engagement by an E3 ligase is a complex process orchestrated by a system of enzymes leading to ubiquitination of the target protein and degradation via the proteasome. Degradation via the proteasome is only one of many possible outcomes of ubiquitin tagged substrates depending on the ubiquitin family member, SUMO, or other proteins utilized for tagging (Oh et al, 2018).
- target specificities and selectivity of biological E3 ligases towards its substrates, post-translational modifications, accessory proteins of the ubiquitin system, changes in intracellular localization of the proteins, or their expression in specific tissues (or at particular stages of development or disease) add additional layers of complexity.
- Current approaches are not amenable for detecting the dynamic state of ubiquitination of a protein in the complex cellular environment, nor observing the type of ubiquitin conjugated to a protein of interest, since the fate of the protein, and the cell, depends upon the timing, type, and subcellular localization of ubiquitinated proteins.
- E3 ligases are encoded in the human genome provides. Yet the clinical applications of TPD have centered mainly around 2 E3 ligases, primarily in the disease area of cancer, employing the 2 leading platforms for TPD - PROTACs and molecular glues. Although the generation of VHL- and CRBN- based PROTAC molecules as research tools has become routine, their preclinical and clinical development can still pose challenges (Bekes et aL, 2022). Co-opting more E3 ligases for targeted protein degradation (TPD) has been suggested as a path forwards and additional ligandable E3 ligase candidates have been enabled by structural and/or validated substrate information, but progress in finding and harnessing them for TPD has been slow.
- TPD targeted protein degradation
- E3 ligases recognize their substrates via amino acid signatures in their primary sequence - termed motifs, which may be contiguous or not along the sequence of the substrate protein. (Duan and Pagano, 2021). Unfortunately, however, not many motifs have been described in the literature. There is a need for finding motifs in E3 ligases as well as the substrates which they engage, which can help understand the functional complexity, or the degradation network of the E3 ligase, map the substrates into distinct pathways, study the effects of mutations which may affect E3 ligase-target interactions or detect how different E3 ligases may collaborate in the cells.
- motif information can help greatly for expanding the TPD toolbox by providing a choice of targets paired with a biological E3 ligase, and as desired and appropriate, the ability to degrade a cohort of proteins with a single E3 ligase, rather than in singles.
- an approach for inducing polyubiquitination of proteins by overexpressing peptides in cell cultures is described.
- Each of several peptides gave rise to a characteristic pattern of polyubiquitinated proteins, and targeted distinct sets of proteins.
- Differential mass spectrometry of the ubiquitin-conjugated proteins with one peptide, VB-009 identified proteins predominantly having roles in RNA metabolism, including some that are frequently mutated in Amyotropic Lateral Sclerosis, Fronto-Temporal Dementia, and myelodysplastic syndrome. The applications of the approach for identifying and targeting specific proteins are discussed.
- peptides were designed for targeting proteins based on their ability to induce polyubiquitination when overexpressed in HEK293T cells.
- peptides to target 3 distinct functional classes of proteins were used in singles: 1) 4 members of a family of enzymes (VB-001 through VB-004); 2) MAPK1 (VB012) or TRIM28, an E3 ligase; or 3) 5 additional ligandable E3 ligases (VB-009-11 and VB-013-015).
- each of the peptides When overexpressed in HEK293T cells and detected by western blotting with an anti-ubiquitin antibody, each of the peptides induced polyubiquitination of multiple proteins, producing a smear of proteins larger than 100 kd. As shown in Fig. 2, the smear of ubiquitin-conjugated proteins was pronouncedly larger and brighter in peptide-treated cells over control (pCMV vector), indicating the presence of multiple ubiquitin conjugated proteins in each sample expressing a peptide. Moreover, each peptide produced a characteristic pattern of bands within the smear suggesting that there may be some specificity as to which proteins reside in the polyubiquitinated fractions.
- the proteins targeted by VB-002 and VB-003 produced significantly larger smears, which likely stems from their co-chaperone function, and may involve extensive interactions with other proteins and/or E3 ligase substrates.
- this invention discloses that the polyubiquitinating property can be localized to such small regions as 25 - 30 amino acids which differentiates this invention from the prior art, and that the number of peptides which consistently showed polyubiquitination suggests a common theme or principle, which needs to be elucidated.
- the peptides cause dysregulation of process of delivering the polyubiquitinated proteins to the proteasome for degradation, which might explain their accumulation in cells.
- polyubiquitin-conjugated proteins do not normally accumulate in healthy cells to the extent observed by this invention, being rapidly transported to the proteasome for degradation, since the peptide induced polyubiquitinated proteins are stable.
- the peptides of this invention are termed, PINTACs, [Proteasome Inhibiting Targeting Construct],
- the accumulation of polyubiquitinated proteins are purified and characterized.
- the reagents and information from this aspect can be developed as a tool for use in drug discovery research or therapeutic applications, such as, TPD.
- these observations indicate a role for PINTACs in ubiquitin modification of substrates, a strategy for targeting E3 ligases or other proteins involved in UPS by designing appropriate PINTACs, and developing assays. To realize those opportunities, it is critical to determine the fidelity of ubiquitination induced by the peptides or whether distinct sets of proteins are targeted in this manner by each PINTAC, regardless of whether the ubiquitinated proteins are the natural substrates (or not) of the E3 ligase targeted by the PINTAC.
- a PINTAC to differentially target an E3 ligase and/or its substrate.
- Two PINTACs were designed, one directed to MAPK1, (VB-012, 42 kd native size) and the other to the Sumo/E3 ligase, TRIM28 (VB-016), which likely targets MAPK1 for degradation (VB-015) in HEK293T cells (unpublished).
- TRIM28 Sumo/E3 ligase
- TRIM28 TRIM28
- the two PINTACs produced an identical pattern of ubiquitinated MAPK1, with discrete bands larger than 100 kd.
- there was a near complete disappearance of the native MAPK1 protein indicating extensive ubiquitin conjugation of the MAPK1 protein in these cells.
- TRIM28 was not significantly altered nor ubiquitinated, or many other proteins tested (as shown in Fig. 3b), and which are related to MAPK1 function, were not conjugated with ubiquitin, thereby indicating specific targeting of MAPK1.
- PIK3CD showed a band of slightly lower mobility with VB-012, which is likely not a ubiquitinated form but may be an alternatively spliced isoform.
- the VB015 sample showed a large smear of high molecular weight proteins when detected with an anti-ubiquitin antibody, as in Fig. lc, indicating the presence of multiple proteins in this fraction.
- each of the PINTACs possesses the ability to induce polyubiquitination.
- a PINTAC directed to the substrate of an E3 ligase in this case MAPK1
- MAPK1 predominantly modified the substrate
- a PINTAC directed to an E3 ligase (such as TRIM28) modified multiple proteins via ubiquitination, including exhibiting specificity towards its substrate, MAPK1. While the mechanism(s) by which the polyubiquitination occurs are unclear; it seems likely that the peptides interfere with protein interactions between the E3 ligase and its substrate, which might also explain why the substrates are not delivered to the proteasome after conjugation with ubiquitin chains.
- three different E3 ligases were targeted by designing 5 PINTACs (VB-009, -010, -Oil, -013 and -014).
- Polyubiquitinated proteins from the transfected HEK293T cells were observed as a smear of high molecular weight proteins as described above (not shown).
- the samples were further characterized by western blotting with a panel of antibodies to detect specific proteins, and, by challenging the transfected cells with a panel of compounds to observe any alterations to the composition of polyubiquitinated proteins.
- MAPK1 was not detectable in the same supernatants, indicating that the column fractionation completely removed MAPK1, unconjugated MEK1/2, and generally, proteins of less than 100 kda in size. Importantly, the process also showed more direct proof of ubiquitin conjugation of MEK1/2 by the PINTACs mentioned above.
- PINTAC expressing HEK293T cells were treated with lenalidomide, which is actively being applied in the clinic as a molecular glue, and is particularly effective in multiple myeloma.
- CRBN target cereblon
- CRBN target cereblon
- lenalidomide markedly decreased polyubiquitination by the MAPK1 PINTAC, VB-012, and also VB-015, but enhanced the effect with VB-009 and VB-010, both of which are designed to target the same E3 ligase (not cereblon).
- PINTACs polyubiquitinate many substrates, which is highly advantageous since they can be applied for targeting CRL E3 ligase subunits, cullins, or other essential proteins necessary for their function.
- this approach can help apply the combined effects of the PINTACs and lenalidomide in the clinic for obtaining greater selectivity towards neotargets, finding new ones, or overcoming drug resistance in multiple myeloma, such as, aberrant Wnt signaling (van Andel et al, 2019).
- the mechanism by which VB-009 and VB-010 polyubiquitination is enhanced by lenalidomide may suggest crosstalk between the E3 ligase targeted by the PINTACs with CRL4 E3 ligase complex, thereby enabling the mechanism to be fully understood.
- the stimulation of ubiquitination provided by PINTAC treatments substantially increases their relative amounts, and enables their detection in the polyubiquitinated fraction over the cellular background.
- the 100 kd supernatants from VB-011 PINTAC and two additional control PINTACs (directed to other E3 ligases) treatments were subjected to differential mass spectrometry.
- a total of 3,084 proteins were identified across the three samples, represented by 37,593 peptides from VB-011 sample, and 32,065 and 5,599 peptides, respectively, for two control samples.
- the mass spectrometry data from VB-011 sample was queried for proteins with a native molecular weight under 100 kd, represented by at least 20 peptides per protein, and, with the number of peptides being in 2-fold excess (or higher) when compared with at least one of the control samples (evidence of stimulation). Such proteins were considered specifically polyubiquitinated with VB-011 expression and selected for further analysis. This identified 40 proteins which were substantially enriched in the VB-011 sample. Consistent with the western blot data in Fig. 4, MEK1 and MEK2 were identified in the mass spectrometry data from VB-011 and VB-011, but not in the control sample which did not detect MEK1/2 by western blotting.
- a number of proteins involved in the ubiquitination process were also enriched with VB-011. These include the E2 enzymes, UBE2D2, UBE2K, and UBE2V2, all of which are known interactors of the intended E3 ligase target of VB-011.
- UBA1, RPS27A, SAE1, and the ubiquitin fold containing protein, GABARAPL2 were highly enriched, and UBL4A was represented.
- the deubiquitinases, OTUD6b and UCHL1 were enriched in VB-011 sample compared to the control samples.
- RNA binding property By way of example only, and in a non-limiting manner, and as shown in Table 1, 18 proteins possessed either an RNA binding property or were components of the splicing or translation machinery. 5 additional proteins have the property of associating with DNA. Curiously, 15 proteins are known to associate with Stress granules (SGs), which are cytosolic membraneless organelles involved in RNA metabolism, post-transcriptional regulation, and translational control [Reviewed in: Youn et al, 2019], Believed to form through phase separation enabled by a combination of interactions among different molecular entities, SGs exhibit a very large number of inter-molecular interactions, including, RNA-RNA interactions (Van Treeck and Parker, 2018), protein-protein interactions, and RNA-protein interactions.
- SGs Stress granules
- RNA binding proteins are being investigated as candidates in both diseases (Olney, N.T et al, 2017). Besides FUS, low levels of TDP43, EWSR1, and SMN1 were identified in the VB-011 samples, as well.
- Tar-binding protein TDP43
- FUS EWS R A Binding Protein 1
- EWSR1 EWSR1
- TAF15 hnRNPAl
- hnRNPA2Bl ATXN2
- TIA1 TAF15
- hnRNPAl hnRNPA2Bl
- ATXN2 ATXN2
- TIA1 TAF15
- hnRNPAl hnRNPA2Bl
- ATXN2 ATXN2
- TIA1 TAF15
- hnRNPAl hnRNPA2Bl
- ATXN2 ATXN2
- TDP-43 is depleted from the nucleus and found as hyperphosphorylated, aggregated cytoplasmic inclusions in ⁇ 97% of ALS and ⁇ 50% of FTD patients (Giordana et al., 2010). Most of the ALS associated mutations appear in the exon 6 of the TARDBP, representing the C-terminal glycine-rich region of TDP-43.
- N-terminal mutations are rare, but the missense mutations A90V and D169G are causative in ALS as well as FTD.
- splicing factor genes are mutated in myeloid malignancies.
- LUC7L2, SRSF2, and U2AF1 are among the proteins mutated at frequencies ranging between 40% and 85% in different subtypes of myelodysplastic syndrome (MDS) (Visconte et al, 2019). Mutations in U2AF1 at codon S34 and Q.157 are found in about 11% of patients with MDS.
- MDS myelodysplastic syndrome
- Mutations in U2AF1 at codon S34 and Q.157 are found in about 11% of patients with MDS.
- the expression of the L166P mutated form of PARK7 leads to enhanced degradation through the ubiquitin-proteasome system.
- E3 ligases recognize their targets through specific motifs referred to as degrons, which may either be a stretch of linear amino acids (physical degrons), or comprised of discontinuous sequences brought in close proximity by the folding of the protein (structural degrons).
- degrons have been identified in some E3 ligases, such as, SCF FBXL17 , APC/C, SCF bTrCP , and SPOP (reviewed in: Jevtic et al, 2021).
- the substrate proteins contain conserved sequences, or motifs, which are recognized by the cognate E3 ligase for target engagement prior to ubiquitination.
- degrons may require posttranslational modifications, such as phosphorylation (Winston et al., 1999), acetylation (Shemorry et al., 2013), hydroxylation (Ivan et aL, 2001; Jaakkola et aL, 2001), ADP ribosylation (Zhang et aL, 2011), or arginylation (Yoo et al., 2018), or be inactivated by oxidation (Manford et aL, 2020).
- posttranslational modifications such as phosphorylation (Winston et al., 1999), acetylation (Shemorry et al., 2013), hydroxylation (Ivan et aL, 2001; Jaakkola et aL, 2001), ADP ribosylation (Zhang et aL, 2011), or arginylation (Yoo et al., 2018), or be inactivated by oxidation (Manford et
- E3 ligases a variety of approaches have been effectively employed for identifying motifs in E3 ligases, including, protein interactions (House, 2003; Venables, 2004; and Buchwald, 2013), structural studies (Santel li et al, 2005), and miRNA knockdown (Murphy Schafer et al, 2020) with the E3 ligase Siahl.
- the polyubiquitinated proteins reported here represent a signature of the action by one or more E3 ligases within the complex cellular environment, wherein accessory factors, protein modifications, proximity, protein network alterations or other factors may determine the range or substrate specificities. Therefore, the protein sequences were aligned using COBALT and refined to shorter stretches of "'100 amino acids which exhibited maximal homology.
- Group 1 possesses an RNA binding property and RRM domains in their structure [FUS, RBM26, EIF4B, EIF4H, EIF5A, SRSF1, and SRSF6], however, the regions of maximal sequence homology among these proteins did not consistently map to the RRM domains. Disclosures in the art suggest that the Group 1 signature may possess biological function.
- FUS homology region For instance, several of the amino acids in FUS homology region are located within the nuclear localization signal (NLS) and are frequently mutated in Amyotropic Lateral Sclerosis (ALS) [Deng and Jankovich], The GRG triplet (residues 486-488), DRG (502 to 505), G (507), S (513), and RP (524-525) amino acids share homologies with other proteins in Group 1 [Chong et al].
- Some clinically significant FUS mutations are truncated at G466X, R495X,and G456vfsx, or may alter the secondary structure of the motif (G472X, or R521G, R521L, R521C).
- the Group 2 signature sequence was not as striking as that of Group 1, but were generally rich in charged or modifiable amino acids (K, R, Q, N, or T) with interspersed serine, glycine or alanine, and may constitute a structural degron.
- the amino acid region of PARK7 (DJ-1) exhibiting homology with other members of this group is known from literature to be mutated which cause autosomal recessive forms of Parkinson's disease (PD).
- A107, E113, and P158, are frequently mutated in PD, and 1105, L116, L122 and T154 are located within the (Hering et al, 2004) homologous regions of Group 2.
- Previously studies of the E64D variant in fibroblasts from a patient bearing the homozygous mutation showed that levels of the protein are decreased.
- the E163K mutation reduces the stability of the protein in vitro, and the P158del variant is unstable when expressed in cells.
- this group also includes HMGB2 and HMGB3 which were identified in the sample, but not included in the homology search on account of the high level of sequence conservation with HMGB1.
- This group also comprises FABP5, wherein the G114R and N124S polymorphisms have been implicated in schizophrenia and autism (Shimamoto et al, 2014).
- the Group 3 signature sequence exhibited a high degree of sequence conservation, and may involve a peroxiredoxin fold.
- the remaining homology groups also consisted of at least one protein mutated (or possessing a causative polymorphism) in hematological or neurological diseases. This includes the S34 and Q.157 mutations in U2AF1 found in about 11% of patients with myelodysplastic syndrome. The significance of these mutations in relation to any biological activity of the homologies identified in this study needs to be fully understood, particularly in the context of the ubiquitin proteasome system function.
- the PINTAC was directed to a single E3 ligase.
- the typical protein interaction motif is around 6-12 amino acids in length or shorter. So, the PINTACs may contain a few tandem or overlapping motifs in their sequence (currently 30 amino acids), each with the ability of recruiting distinct sets of proteins. Additional proteins, such as ubiquitin accessory factors or chaperones may partially determine interaction specificity, and may have recruited some proteins. G3BP2, DNAJC8, TBCA, SUGT1, STIP1, or U2AF1 are likely candidates and additional proteins which were not found to be ubiquitinated in this study may also be involved.
- RNA binding proteins and chaperones were identified in this study but are not presented here since they did not meet the selection threshold of at least 20 peptides represented in the mass spectrometry data. Optimization of PINTAC sequence, deeper sequencing of the polyubiquitinated fraction with mass spectrometry, computational analysis of the candidate motifs, and comparisons of the ubiquitinated fraction across more samples (directed towards different E3 ligases) may aid their identification, as well as the search for motifs.
- this invention discloses a biomarker set of proteins comprising, FUS, RBM26, EIF4B, EIF4H, SRSF1, SRSF6, SART1, PARK7, PSPC1, FABP5, HMGB1, FUBP3, HMGB2, HMGB3, SERPB1, AK2, PRDX1, PLRG1, PRDX2, DNAJC8, HDGF, STIP1, SRSF2, HDGFL2, PITHD1, CFL1, THRAP3, U2AF1, SF1, DEK, LM NA, LUC7L2, and LUC7L3.
- this invention discloses a method of measuring a biomarker in a sample comprising the steps of: providing a test sample, measuring at least one biomarker in the test, the biomarker selected from the group consisting of: FUS, RBM26, EIF4B, EIF4H, SRSF1, SRSF6, SART1, PARK7, PSPC1, FABP5, HMGB1, FUBP3, HMGB2, HMGB3, SERPB1, AK2, PRDX1, PLRG1, PRDX2, DNAJC8, HDGF, STIP1, SRSF2, HDGFL2, PITHD1, CFL1, THRAP3, U2AF1, SF1, DEK, LMNA, LUC7L2, and LUC7L3, and determining the amount of said biomarker in said test sample.
- the biomarker selected from the group consisting of: FUS, RBM26, EIF4B, EIF4H, SRSF1, SRSF6, SART1, PARK7, PSPC1, FABP5, HMGB1, FUBP3,
- this invention describes a method of detecting a disease in human subject comprising providing a test sample from said human subject suspected of having disease, measuring at least one biomarker in the test sample, the biomarker selected from the group consisting of: FUS, RBM26, EIF4B, EIF4H, SRSF1, SRSF6, SART1, PARK7, PSPC1, FABP5, HMGB1, FUBP3, HMGB2, HMGB3, SERPB1, AK2, PRDX1, PLRG1, PRDX2, DNAJC8, HDGF, STIP1, SRSF2, HDGFL2, PITHD1, CFL1, THRAP3, U2AF1, SF1, DEK, LMNA, LUC7L2, and LUC7L3, comparing the amount of said at least one biomarker in a control sample not having disease, determining a change in the amount of at least one biomarker in the test sample as compared with the control sample, thereby detecting disease in said human subject.
- the biomarker selected from the group consisting of: F
- this invention discloses a method wherein the disease is amyotrophic lateral sclerosis, fronto-temporal dementia, myelodysplastic syndrome, a hematological malignancy, or multiple myeloma.
- the control sample is derived from a healthy subject.
- this invention discloses a method wherein said change in the amount of a biomarker involves an increase in the amount of said at least one biomarker compared with the level of the same protein from said control sample.
- this invention discloses a method wherein said change involves a decrease in the amount of said at least one biomarker compared with the level of the same protein from said control sample.
- this invention discloses a method of inducing polyubiquitination of a protein comprising, providing a sample comprising of cells, treating said sample with a composition selected from the group consisting of: lenalidomide, panobinostat, JQ1, pomalidomide, a benzophosphonic acid analog, ibrutinib, valrubicin, verapamil, and rapamycin.
- this invention discloses a method wherein said step of detecting comprises detecting polyubiquitination of at least one protein from the group consisting of: FUS, RBM26, EIF4B, EIF4H, SRSF1, SRSF6, SART1, PARK7, PSPC1, FABP5, HMGB1, FUBP3, HMGB2, HMGB3, SERPB1, AK2, PRDX1, PLRG1, PRDX2, DNAJC8, HDGF, STIP1, SRSF2, HDGFL2, PITHD1, CFL1, THRAP3, U2AF1, SF1, DEK, LMNA, LUC7L2, and LUC7L3.
- this invention discloses an additional step of comparing the polyubiquitination of said at least one protein between a test sample from a human subject suspected of having disease and a control sample from a healthy subject.
- the disease is amyotrophic lateral sclerosis, fronto-temporal dementia, myelodysplastic syndrome, a hematological malignancy, or multiple myeloma.
- this invention discloses a method of treating a human subject suspected of having disease, the method comprising, administering to said human subject an effective dose of a first composition comprising at least one of the substances selected from the group consisting of: lenalidomide, panobinostat, JQ1, pomalidomide, a benzophosphonic acid analog, ibrutinib, valrubicin, verapamil, and rapamycin.
- this invention discloses a method comprising administering to said human subject a second composition comprising at least one of the proteins selected from the group consisting of: FUS, RBM26, EIF4B, EIF4H, SRSF1, SRSF6, SART1, PARK7, PSPC1, FABP5, HMGB1, FUBP3, HMGB2, HMGB3, SERPB1, AK2, PRDX1, PLRG1, PRDX2, DNAJC8, HDGF, STIP1, SRSF2, HDGFL2, PITHD1, CFL1, THRAP3, U2AF1, SF1, DEK, LMNA, LUC7L2, and LUC7L3, and fragments thereof.
- a second composition comprising at least one of the proteins selected from the group consisting of: FUS, RBM26, EIF4B, EIF4H, SRSF1, SRSF6, SART1, PARK7, PSPC1, FABP5, HMGB1, FUBP3, HMGB2, HMGB3, SERPB1, AK2, PRDX1,
- the disease is amyotrophic lateral sclerosis, fronto-temporal dementia, myelodysplastic syndrome, a hematological malignancy, or multiple myeloma.
- this invention discloses methods of determining the relative amounts of the biomarkers of this invention wherein said step of determining comprises detecting or quantitating any of said biomarkers by western blotting, ELISA, competitive ELISA, immunoprecipitation, mass spectrometry, or protein interaction.
- Methods of quantifying proteins in biological samples are known to those of skill in the art.
- western blot or ELISAs assays involve the use of antibodies which recognize proteins of interest and are also used for quantifying the protein from biological samples.
- this invention utilizes proteins or fragments thereof for competing binding of the analyte (protein of interest) in ELISA formats.
- This invention describes the sequences of some proteins and peptides derived therefrom, as shown in the sequence listing. Any of the proteins or peptides can be used for practicing this invention.
- SEQ ID1 describes a peptidic region of the protein FUS.
- the method for using SEQ. ID1 for competitive is herein described, as an example.
- the quantification of FUS from a biological sample proceeds via the following steps.
- An interacting protein of this invention, such as RNF8, is suffixed to a solid support.
- FUS protein in the sample is captured by contacting with the solid support under conditions favoring formation of a complex between FUS and the matrix-associated RNF8 protein. This interaction can be abrogated, diminished, or abolished by next incubating with effective amounts of a peptide comprising SEQ ID1, via competition with the FUS-RNF8 protein interaction.
- the sample can be preincubated with the peptide of SEQ ID1 prior to contacting with the solid matrix to observe diminishing of signal intensity.
- the amount of FUS associated with the solid matrix can be detected by next incubating with an antibody to FUS, which contains a detectable label or tag. Such labels or tags have been described in the art and are in routine use.
- either the FUS protein or the peptide of SEQ ID1 harbors a mutation, in which case the degree of association with the matrix associated RNF8 protein, and hence the detected signal intensity can vary.
- the signal will be higher than that observed by using a wild type FUS protein if the mutant FUS protein associates more strongly with RNF8.
- the signal can be lower if the mutation reduces the binding intensity (affinity) with RNF8, or may abolish it completely.
- the amino acid sequence of the peptide representing SEQ ID1 can be made to harbor mutations. The extent of inhibition of the mutant peptide can be determined according to the methods of this invention.
- this invention discloses the step of detecting by ELISA comprises capturing any one of said biomarkers with a substance capable of interacting with said biomarker wherein said capturing substance is affixed to a solid matrix.
- the capturing substance is selected from the group consisting of: an antibody, an interacting peptide, an interacting protein, an E3 ligase protein, a SUMO ligase protein, RNA, DNA, a ubiquitin interacting protein, a heat shock protein, a ubiquitin, and a protein of interest.
- the capturing substance can be any which has affinity for a biomarker of this invention, or may form a complex with one of the capturing substances.
- the capturing substance can be a nucleic acid (RNA or DNA), a chaperone protein, such as a heat shock protein, a ubiquitin binding protein, or any member of the ubiquitin proteasome system in humans.
- the capture proteins have an affinity for associating with the biomarker of this invention, and such interaction may also occur in vivo. Accordingly, this invention describes methods for forming a complex of two or more members of said group of capturing substances with said at least one biomarker.
- the interacting protein is selected from the group consisting of: UBA52, PHB1, PDLIM1, NPM1, HSP9, RNF2, and RNF8.
- this invention discloses a step of forming a complex which comprises at least two capturing proteins selected from the group consisting of: UBA52, PHB1, PDLIM1, NPM1, HSP9, RNF2, and RNF8.
- a binding event may involve the simultaneous contacting of the analyte or biomarker of this invention by two or more proteins so as to form a complex involving at least 3 proteins, including the biomarker.
- the binding event is detected by the methods of this invention via associating with of one or both of the interacting proteins in the complex.
- this invention describes a method wherein at least one member of said group of proteins comprising a capture proteins, capture peptides, or interacting proteins is or are affixed to a solid matrix.
- a multiplicity of capture proteins, capture peptides, or interacting proteins can be affixed to the solid support, such as in microarrays or ELISA plates, as is well known to those of skill in the art.
- this invention discloses methods for characterizing a sample from a human subject for the presence of disease. In a non-limiting and exemplary fashion, this invention compares the interaction of disease candidate proteins with the capture proteins or their fragments.
- the capture protein fragments are the likely sites of interaction necessary for complex formation according to this invention, and may represent motifs.
- the presence of disease is evaluated according to this invention by comparing the amounts of complexes formed with the analyte or biomarker in the diseased sample with the same protein in a control sample from a healthy individual.
- the disease is amyotrophic lateral sclerosis, fronto-temporal dementia, myelodysplastic syndrome, a hematological malignancy, or multiple myeloma.
- this invention provides a method wherein the step of determining comprises, providing a sample from a human subject suspected of having disease, providing a control sample from a human subject not having disease, providing a solid matrix comprising at least one of UBA52, PHB1, PDLIMl, NPM1, HSP9, RNF2, or RNF8 proteins, or fragments thereof, affixed to said matrix, incubating said sample from human subject suspected of having disease under conditions favoring formation of a complex of said at least one biomarker with the at least one affixed protein from step (c), washing the solid matrix to remove unbound materials, incubating with a detection reagent, wherein said reagent detects the association of said biomarker with the solid matrix, or components thereon, generating a signal showing association of the said biomarker with the solid matrix, repeating steps c through f with control sample in step (b), generating a signal, comparing signals from steps (g) and (i), thereby determining the relative levels of said biomarker in disease or
- this invention discloses a method of determining wherein any of the recited proteins further comprises a detectable tag selected from the group consisting of: a biotin tag, a fluorescent tag, or a moiety emitting light in the infrared range.
- a detectable tag selected from the group consisting of: a biotin tag, a fluorescent tag, or a moiety emitting light in the infrared range.
- step of competitive ELISA comprises the steps of: providing a sample from a human subject suspected of having disease, providing a control sample from a human subject not having disease, providing a solid matrix comprising at least one of UBA52, PHB1, PDLIMl, NPM1, HSP9, RNF2, or RNF8 proteins, or fragments thereof, affixed to said matrix, incubating said sample from human subject suspected of having disease under conditions favoring formation of a complex of said at least one biomarker with the at least one affixed protein from step (c), washing the solid matrix to remove unbound materials, incubating with a detection reagent, wherein said reagent detects the association of said biomarker with the solid matrix, or components thereon, generating a signal showing association of the said biomarker with the solid matrix, following step (b) or (c), incubating said matrix with a competing peptide bearing the sequence as in any one of SEQ.
- the disease is amyotrophic lateral sclerosis, fronto-temporal dementia, myelodysplastic syndrome, a hematological malignancy, or multiple myeloma.
- Amyloid precursor protein accumulates in aggresomes in response to proteasome inhibitor. Neurochemistry International. 60:533-542.
- RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling. Nat Cell Biol. 13:623-9. Yoo, YD et al 2018. N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis. Proc. Natl. Acad. Sci. USA 115: E2716-E2724. Manford AG, et al., 2020. A Cellular Mechanism to Detect and Alleviate Reductive Stress. Cell. 183:46-61. House, CM, et al., 2003. A binding motif for Siah ubiquitin ligase. Proc. Natl. Acad. Sci.
- SIAH1 targets the alternative splicing factor T-STAR for degradation by the proteasome, Human Molecular Genetics, 13: 1525-1534. Buchwald, M., et al., (2013).
- SIAH ubiquitin ligases target the nonreceptor tyrosine kinase ACK1 for ubiquitinylation and proteasomal degradation. Oncogene 32, 4913-4920. Santelli, E et al., (2005). Structural Analysis of Siahl-Siah-interacting Protein Interactions and Insights into the Assembly of an E3 Ligase Multiprotein Complex. J. Biol.
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Abstract
La présente invention divulgue des méthodes de diagnostic et des compositions pour traiter un sujet humain suspecté d'être atteint d'une maladie neurologique ou hématologique. L'invention divulgue également des protéines qui servent de biomarqueurs efficaces pour confirmer l'état pathologique, ainsi que pour suivre des variations de leurs quantités avec une progression ou une rémission de maladie lors d'un traitement avec des médicaments.
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