Methods of inhibiting hsp90ab1 for the treatment of degenerative ocular diseases

Abstract

The present invention provides compositions, e.g., pharmaceutical compositions, which include a recombinant adeno-associated viral (AAV) expression construct, AAV vectors, AAV particles, and methods of treating a subject having a degenerative ocular disorder, e.g., retinitis pigmentosa.

Description

[0001]117823-35920 METHODS OF INHIBITING HSP90AB1 FOR THE TREATMENT OF DEGENERATIVE OCULAR DISEASES RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No.63 / 527150, filed on July 17, 2023, the entire contents of which are incorporated herein by reference. This application is related to U.S. Patent Application No.18 / 017093, filed on January 20, 2023, PCT Application No. PCT / US2021 / 042697, filed on July 22, 2021, U.S. Provisional Application No.63 / 137911, filed on January 15, 2021, and U.S. Provisional Application No. 63 / 055413, filed on July 23, 2020. The entire contents of each of the foregoing applications are incorporated herein by reference. GOVERNMENT FUNDING This invention was made with government support under EY030951 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND OF THE INVENTION Retinitis pigmentosa (RP) is a disease of the eye that presents with progressive degeneration of rod and cone photoreceptors, the light-sensing cells of the retina (Hartong DT, et al. (2006) Lancet 368(9549):1795–1809). The disease can result from mutations in any of over 60 different genes and is the most common inherited form of blindness in the world, affecting an estimated 1 in 4000 individuals (Daiger SP, et al. (2013) Clin Genet 84(2):132–141; Berson EL (1996) Proc Natl Acad Sci U S A 93(10):4526–8; Haim M (2002) Acta Ophthalmol Scand Suppl (233):1–34). One approach to treat this disease is gene therapy, e.g. using adeno-associated vectors (AAVs) to deliver a wild-type allele to complement a mutated gene (Ali RR, et al. (1996) Hum Mol Genet 5(5):591–4; Murata T, et al. (1997) Ophthalmic Res 29(5):242–251). While this approach has proven successful in other conditions, even leading to the approval of a gene therapy for RPE65-associated Leber’s congenital amaurosis (Maguire AM, et al. (2008) N Engl J Med 358(21):2240–2248), it is difficult to implement for the majority of RP patients, given the extensive heterogeneity of genetic lesions (Daiger SP, et al. (2013) Clin Genet 84(2):132–141). A broadly applicable gene therapy that is agnostic to the genetic lesion would provide a treatment option for a greater number of RP patients. Presently, there is no effective therapy of any kind for RP, and despite more than a dozen randomized clinical trials to date, none have been able to demonstrate an improvement in visual function (Sacchetti M, et al.2015) J Ophthalmol 2015:737053). In patients with RP, there is an initial loss of rods, the photoreceptors that mediate vision in dim light. Clinically, this results in the first manifestation of RP, poor or no night vision, which 1 ME149103561v.1 117823-35920 usually occurs between birth and adolescence (Hartong DT, et al. (2006) Lancet 368(9549):1795– 1809). Daylight vision in RP is largely normal for decades, but eventually deteriorates beginning when most of the rods have died. This is due to dysfunction, and then death, of the cone photoreceptors, which are essential for high acuity and color vision. Loss of cone function is the major source of morbidity in the disease (Hartong DT, et al. (2006) Lancet 368(9549):1795–1809). Importantly, while the vast majority of genes implicated in RP are expressed in rods, few actually exhibit expression in cones, suggesting the existence of one or more common mechanisms by which diverse mutations in rods trigger non-autonomous cone degeneration (Narayan DS, et al. (2016) Acta Ophthalmol 94(8):748–754; Wang W, et al. (2016) Cell Rep 15(2):372–85; Komeima K, et al. (2006) Proc Natl Acad Sci U S A 103(30):11300–5). Attempts to elucidate these mechanisms have been made with the goal of developing therapies for RP that preserve cone vision regardless of the underlying mutation (Punzo C, et al. (2009) Nat Neurosci 12(1):44–52; Xiong W, et al. (2015) J Clin Invest 125(4):1433–1445; Venkatesh A, et al. (2015) J Clin Invest 125(4):1446–58; Aït-Ali N, et al. (2015) Cell 161(4):817–832; Murakami Y, et al. (2012) Proc Natl Acad Sci 109(36):14598–14603). Accordingly, there is a need in the art for therapies to treat and prevent vision loss that results from degenerative retinal diseases, such as RP. SUMMARYOF THE INVENTION The present invention provides compositions and methods which include inhibiting the expression of a gene, Hsp90ab1, alone or in combination with compositions and methods for inhibiting TXNIP, to provide survival benefits for cone photoreceptors in retinitis pigmentosa (RP) disease. Accordingly, in one aspect the present invention provides a composition, comprising an adeno-associated virus (AAV) expression cassette, the expression cassette comprising a promoter and a nucleic acid molecule encoding a thioredoxin-interacting 5 protein (TXNIP) variant protein, wherein the nucleic acid molecule is selected from the group consisting of (a) a nucleic acid molecule encoding amino acid residues 149-397 of a C247S variant TXNIP, or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 149-397 of the C247S variant TXNIP; (b) a nucleic acid molecule encoding amino acid residues 149-397 of a C247S .LL351.352AA variant TXNIP, or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 149-397 of the a C247S .LL351.352AA variant TXNIP; (c) a nucleic acid molecule encoding amino acid residues 1-228 of TXNIP, or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 2 ME149103561v.1 117823-35920 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 1-228 of TXNIP; (d) a nucleic acid molecule encoding amino acid residues 1-301 of TXNIP, or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 1-301 of TXNIP; (e) a nucleic acid molecule encoding amino acid residues 1-320 of TXNIP, or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 1-320 of TXNIP; or (f) a nucleic acid molecule encoding amino acid residues 255-397 of TXNIP, or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 255-397 of TXNIP. In one embodiment, the promoter is a ubiquitous promoter. In one embodiment, the promoter is an ocular specific promoter. In one embidoment, the promoter is a photoreceptor specific (PR-specific) promoter. In one embodiment, the PR-specific promoter is a human red opsin (hRedO) promoter. In one embodiment, the PR-specific promoter is a human bestrophin 1 (hBest1) promoter. In another aspect, the present invention provides a composition, comprising an adeno- associated virus (AAV) expression cassette, the expression cassette comprising a photoreceptor- specific (PR- specific) promoter and a short hairpin RNA (shRNA) targeting heat shock protein 90 alpha family class B member 1 (HSP90AB1). In one embodiment, the PR-specific promoter is a human red opsin (hRedO) promoter. In one embodiment, the expression cassette is present in a vector. In one embodiment, the vector is an AAV vector. In one embodiment, the vector is an AAV vector selected from the group consisting of AAV2, AAV 8, AAV2 / 5, and AAV 2 / 8. The present invention also provides an AAV vector particle comprising a composition of the invention and isolated cells comprising an AAV particle of of the invention, as well as a pharmaceutical composition comprising the AAV composition of or the particle of the invention. In one aspect, the present invention provides a method for prolonging the viability of a photoreceptor cell compromised by a degenerative ocular disorder, comprising contacting said cell with the composition of the invention, the AAV viral particle of the invention, or the pharmaceutical composition of of the invention, thereby prolonging the viability of the photoreceptor cell compromised by the degenerative ocular disorder. 3 ME149103561v.1 117823-35920 In another aspect, the present invention provides a method for treating or preventing a degenerative ocular disorder in a subject, comprising administering to said subject a therapeutically effective amount of any one or more of a composition of the invention, the AAV viral particle of of the invention, or the pharmaceutical composition of of the invention, thereby treating or preventing said degenerative ocular disorder. In yet another aspect, the present invention provides a method for delaying loss of functional vision in a subject having a degenerative ocular disorder, comprising administering to said subject a therapeutically effective amount of the composition of of the invention, the AAV viral particle of of the invention, or the pharmaceutical composition of of the invention, thereby treating or preventing said degenerative ocular disorder. In one embodiment, the degenerative ocular disorder is associated with decreased viability of cone cells and / or decreased viability of rod cells. In one embodiment, the degenerative ocular disorder is selected from the group consisting of retinitis pigmentosa, age related macular degeneration, cone rod dystrophy, and rod cone dystrophy. In one embodiment, the degenerative ocular disorder is a genetic disorder. In one embodiment, the degenerative ocular disorder is not associated with blood vessel leakage and / or growth. In one embodiment, the degenerative ocular disorder is retinitis pigmentosa. In another aspect, the present invention provides a method for treating or preventing retinitis pigmentosa in a subject, comprising administering to the subject a therapeutically effective amount of the composition of of the invention, the AAV viral particle of of the invention, or the pharmaceutical composition of of the invention, thereby treating or preventing retinitis pigmentosa in said subject. The promoter may be a ubiquitous promoter, an ocular specicific promoter, or a PR-specific promoter. In one embodiment, the PR-specific promoter is a human red opsin (hRedO) promoter. In one embodiment, the PR-specific promoter is a human bestrophin 1 (hBest1) promoter. In one embodiment, the method further comprises administering to the subject a therapeutically effective amount of a composition comprising an adeno-associated virus (AAV) expression cassette, the expression cassette comprising a promoter and a short hairpin RNA (shRNA) targeting heat shock protein 90 alpha family class B member 1 (HSP90AB1). The promoter may be a ubiquitous promoter, an ocular specicific promoter, or a PR-specific promoter. In one embodiment, the PR-specific promoter is a human red opsin (hRedO) promoter. In one aspect, the present invention provides a method for prolonging the viability of a photoreceptor cell compromised by a degenerative ocular disorder, comprising contacting said cell with a composition, comprising an adeno-associated virus (AAV) expression cassette, the expression cassette comprising a promoter and a short hairpin RNA (shRNA) targeting heat shock protein 90 4 ME149103561v.1 117823-35920 alpha family class B member 1 (HSP90AB1), thereby prolonging the viability of the photoreceptor cell compromised by the degenerative ocular disorder. The promoter may be a ubiquitous promoter, an ocular specicific promoter, or a PR-specific promoter. In another aspect, the present invention provides a method for treating or preventing a degenerative ocular disorder in a subject, comprising administering to said subject a therapeutically effective amount of a composition, comprising an adeno-associated virus (AAV) expression cassette, the expression cassette comprising a promoter and a short hairpin RNA (shRNA) targeting heat shock protein 90 alpha family class B member 1 (HSP90AB1), thereby treating or preventing said degenerative ocular disorder. The promoter may be a ubiquitous promoter, an ocular specicific promoter, or a PR-specific promoter. In yet another aspect, the present invention provides a method for delaying loss of functional vision in a subject having a degenerative ocular disorder, comprising administering to said subject a therapeutically effective amount of a composition, comprising an adeno-associated virus (AAV) expression cassette, the expression cassette comprising a promoter and a short hairpin RNA (shRNA) targeting heat shock protein 90 alpha family class B member 1 (HSP90AB1), thereby treating or preventing said degenerative ocular disorder. The promoter may be a ubiquitous promoter, an ocular specicific promoter, or a PR-specific promoter. In one embodiment, the PR-specific promoter is a human red opsin (hRedO) promoter. In one embodiment, the PR-specific promoter is a human bestrophin 1 (hBest1) promoter. In one embodiment, the degenerative ocular disorder is associated with decreased viability of cone cells and / or decreased viability of rod cells. In one embodiment, the degenerative ocular disorder is selected from the group consisting of retinitis pigmentosa, age related macular degeneration, cone rod dystrophy, and rod cone dystrophy. In one embodiment, the degenerative ocular disorder is a genetic disorder. In one embodiment, the degenerative ocular disorder is not associated with blood vessel leakage and / or growth. In one embodiment, the degenerative ocular disorder is retinitis pigmentosa. In one aspect, the present invention provides a method for treating or preventing retinitis pigmentosa in a subject, comprising administering to the subject a therapeutically effective amount of a composition, comprising an adeno-associated virus (AAV) expression cassette, the expression cassette comprising a promoter and a short hairpin RNA (shRNA) targeting heat shock protein 90 alpha family class B member 1 (HSP90AB1). The promoter may be a ubiquitous promoter, an ocular specicific promoter, or a PR-specific promoter. 5 ME149103561v.1 117823-35920 In one embodiment, the PR-specific promoter is a human red opsin (hRedO) promoter. In one embodiment, the method further comprises administering to the subject a therapeutically effective amount of a composition, comprising an adeno-associated virus (AAV) expression cassette, the expression cassette comprising a promoter and a nucleic acid molecule encoding a C247S variant thioredoxin-interacting 5 protein (TXNIP). The promoter may be a ubiquitous promoter, an ocular specicific promoter, or a PR-specific promoter. In one embodiment, the PR-specific promoter is a human red opsin (hRedO) promoter. In one embodiment, the PR-specific promoter is a human bestrophin 1 (hBest1) promoter. Other features and advantages of the invention will be apparent from the following detailed description and claims. BRIEF DESCRIPTION OF THE DRAWINGS Figures 1A-1D depict the effect of Arrdc4 on cone survival in retinitis pigmentosa (RP) mice. Figure 1A. Amino acid sequences of mouse TXNIP and mouse ARRDC4. In the full length alignment (421 amino acid), Identity: 172 / 421, 40.86%; Similarity: 246 / 421, 58.43%; Gaps: 28 / 421, 6.65%. Color code: identical, black; similar, blue; not similar, red. Figure 1B. Predicted 3D protein structures of mouse TXNIP and mouse ARRDC4 by artificial intelligence (AI) algorithm AlphaFold-2. Abbreviations: Arr N-, N-terminal arrestin domain; Arr C-, C-terminal arrestin domain. Figure 1C. Representative P50 rd1 flat-mounted retinas after P0 subretinal infection with AAV8-RO1.7-Arrdc4 (1 × 109 vg / eye), plus AAV8-RedO-H2BGFP (2.5 × 108 vg / eye), or control eyes infected with AAV8-RedO-H2BGFP, 2.5 × 108 vg / eye alone. Figure 1D. Quantification of H2BGFP-positive cones within the center of P50 rd1 retinas transduced with Arrdc4, and control (same as in C). The number in the round brackets ‘()’ indicates the number of retinas within each group. Error bar: standard deviation. **** p< or <<0.0001. RedO: red opsin promoter; RO1.7: a 1.7kb version of red opsin promoter. AAV: adeno- associated virus. Figures 2A-2G depict Txnip deletions expressed only within RPE cells: effects on GLUT1 removal and cone survival. Figure 2A. Glucose transporter 1 (GLUT1) expression in P20 wildtype eyes infected with control (AAV8-RedO-H2BGFP, 2.5 × 108 vg / eye), or a Txnip allele (2.5 × 108 vg / eye) plus RedO- H2BGFP (2.5 × 108 vg / eye), as indicated in each panel. Txnip deletions are detailed in Figure 4. Magenta: GLUT1; green: RedO-H2BGFP for infection tracing; gray: DAPI. 6 ME149103561v.1 117823-35920 Figures 2B, 2D, 2F. Representative P50 rd1 flat-mounted retinas after P0 infection with one of seven different Txnip alleles expressed only within the RPE, as indicated in the figure, or control eyes infected with AAV8-RedO-H2BGFP, 2.5 × 108 vg / eye alone. Figures 2C, 2E, 2G. Quantification of H2BGFP-positive cones within the center of P50 rd1 retinas transduced with indicated vectors, as shown in B, D, F. The number in the round brackets ‘()’ indicates the number of retinas within each group. Error bar: standard deviation. Figure 2C. Txnip.CS: C-terminal portion of Txnip.C247S; C.Txnip.CS.LLAA: C-terminal portion of Txnip.C247S.LL351 and 352AA; nt.Txnip.CS320: no tail Txnip (1-320aa). NS: not significant, p>0.05, *p<0.05, **p<0.01, **** p< or <<0.0001. Best1: Best1 promoter. Figure 2 Supplement depicts the predicted protein-protein interaction of TXNIP and GLUT1 by an algorithm based on AlphaFold-2. Figures 3A-3C depict the tests of Txnip alleles on cone survival. Figure 3A. Representative P50 rd1 flat-mounted retinas after P0 infection with one of 5 different Txnip alleles (AAV8-RedO- N.Txnip / C.Txnip.C247S / nt.Txnip.C247S1- 301 / nt.Txnip.C247S1-320 or AAV8-CMV-Txnip.C247S, ≈1 × 109 vg / eye, plus AAV8-RedO- H2BGFP, 2.5 × 108 vg / eye), or control eyes infected with AAV8-RedO-H2BGFP, 2.5 × 108 vg / eye alone. Figures 3B, 3C. Quantification of H2BGFP-positive cones within the center of P50 rd1 retinas transduced with AAV8-RedO- N.Txnip / C.Txnip.C247S / nt.Txnip.C247S1- 301 / nt.Txnip.C247S1-320 or AAV8-CMV-Txnip.C247S, and control (same as in A). The number in the round brackets ‘()’ indicates the number of retinas within each group. Error bar: standard deviation. NS: not significant, **** p< or <<0.0001. Figure 4 is a summary of various alleles of TXNIP in this and previous study (Xue et al. 2021). "RPE GLUT1 Removal" refers to the amount of GLUT1 immunohistochemical signal following expression in the RPE using the Best1 promoter. "Cone Rescue: Expression in RPE" refers to cone rescue following expression only in the RPE using the Best1 promoter. "Cone Rescue: Expression in Cones" is due to expression only in cone photoreceptors using the RedO promoter. Abbreviations: Y (x%): Yes with x% increase compared to AAV-H2BGFP control; N: No; I: Impaired ability to remove GLUT1; NT: Not tested. N.Txnip, N-terminal portion of TXNIP; C.TXNIP.C247S, C-terminal portion of TXNIP.C247S mutant allele; sC.TXNIP: a shorter version of C-terminal portion of TXNIP; nt.Txnip.C247S, no tail version TXNIP.C247S mutant allele; Arrestin N-, N-terminal arrestin domain; Arrestin C-, C-terminal arrestin domain; PPxY, a motif where P is proline, x is any amino acid and Y is tyrosine. Figures 5A-5H depict the effect of knockdown of Hsp90ab1 in RP cones in vivo. Figure 5A. AAV8-RO1.7-Hsp90ab1-FLAG (1 × 109 vg / eye) co-injected with shNC (non- targeting shRNA control, AAV8-RedO-shRNA, 1 × 109 vg / eye) or co-injected with Hsp90ab1 7 ME149103561v.1 117823-35920 shRNAs #a, #b, #c (AAV8-RedO-shRNA, 1 × 109 vg / eye) in P20 wt retina, all also injected with AAV8-RedO-H2BGFP (2.5 × 108 vg / eye) to track the infection. Magenta: anti-FLAG; green: anti- GFP; gray: DAPI. Right panel: Figure 5B. The quantification of FLAG intensity from multiple fields of inner segment regions in A. The number in the square brackets ‘[]’ indicates the number of images taken from regions of interest of one retina, in each condition. Figure 5C. Representative P50 rd1 flat-mounted retinas injected with shNC, shHsp90ab1(#a), shHsp90ab1(#b), or shHsp90ab1(#c) (AAV8-RedO-shRNAs, 1 × 109 vg / eye, plus AAV8-RedO- H2BGFP, 2.5 × 108 vg / eye). Figure 5D. Quantification of H2BGFP-positive cones within the center of P50 rd1 retinas transduced with shNC, shHsp90ab1(#a, #b, #c) (same as in C). Figure 5E. Representative P50 rd1 flat-mounted retinas with H2BGFP (gray)-labeled cones transduced with Txnip.C247S or Txnip.C247S + shHsp90ab1 (AAV8-RedO-Txnip.C247S, 1 × 109 vg / eye; AAV8-RO1.7-shHsp90ab1(#a or #c), 1 × 109 vg / eye; plus AAV8-RedO-H2BGFP, 2.5 × 108 vg / eye). Figure 5F. Quantification of H2BGFP-positive cones within the center of P50 rd1 retinas transduced with Txnip.C247S or Txnip.C247S + shHsp90ab1 (same as in E). Figure 5G. Representative P50 Parp1- / - rd1 flat-mounted retinas with H2BGFP (gray)-labeled cones transduced with shNC (non-targeting shRNA control, AAV8-RedO-shRNA, 1 × 109 vg / eye; plus AAV8-RedO-H2BGFP, 2.5 × 108 vg / eye) or shHsp90ab1 (AAV8-RedO-shRNA #a or #c, 1 × 109 vg / eye; plus AAV8-RedO-H2BGFP, 2.5 × 108 vg / eye). Figure 5H. Quantification of H2BGFP-positive cones within the center of P50 Parp1- / - rd1 retinas transduced with shNC or shHsp90ab1 (same as in G). Error bar: standard deviation. NS: not significant, p>0.05, *p<0.05, **p<0.01, ***p<0.001 **** p< or <<0.0001. Figures 5A Supplement – 5B Supplement depict the predicted 3D protein structures of HSP90AB1 and PARP1. Figure 5A Supplement. Predicted 3D protein structures of HSP90AB1 by AI algorithm AlphaFold-2 from two angles of view. Figure 5B Supplement. Predicted 3D protein structures of PARP1 by AI algorithm AlphaFold-2 from two angles of view. DETAILED DESCRIPTION OF THE INVENTION The present invention provides compositions and methods which include inhibiting the expression of a gene, Hsp90ab1, alone or in combination with compositions and methods for inhibiting TXNIP, to provide survival benefits for cone photoreceptors in retinitis pigmentosa (RP) disease. 8 ME149103561v.1 117823-35920 Various aspects of the invention are described in further detail in the following subsections: I. Definitions As used herein, each of the following terms has the meaning associated with it in this section. The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element, e.g., a plurality of elements. The term "including" is used herein to mean, and is used interchangeably with, the phrase "including but not limited to". The term "or" is used herein to mean, and is used interchangeably with, the term "and / or," unless context clearly indicates otherwise. As used herein, the term "nucleic acid molecule" is intended to include DNA molecules (e.g., cDNA or genomic DNA) and RNA molecules (e.g., mRNA) and analogs of the DNA or RNA generated using nucleotide analogs. The nucleic acid molecule can be single-stranded or double- stranded, but preferably is double-stranded DNA. A nucleic acid molecule used in the methods of the present invention can be isolated using standard molecular biology techniques. Using all or portion of a nucleic acid sequence of interest as a hybridization probe, nucleic acid molecules can be isolated using standard hybridization and cloning techniques (e.g., as described in Sambrook, J., Fritsh, E. F., and Maniatis, T. Molecular Cloning. A Laboratory Manual.2nd, ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989). An "isolated" nucleic acid molecule is one which is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid. For example, with regards to genomic DNA, the term "isolated" includes nucleic acid molecules which are separated from the chromosome with which the genomic DNA is naturally associated. Preferably, an "isolated" nucleic acid molecule is free of sequences which naturally flank the nucleic acid molecule (i.e., sequences located at the 5' and 3' ends of the nucleic acid molecule) in the genomic DNA of the organism from which the nucleic acid molecule is derived. A nucleic acid molecule for use in the methods of the invention can also be isolated by the polymerase chain reaction (PCR) using synthetic oligonucleotide primers designed based upon the sequence of a nucleic acid molecule of interest. A nucleic acid molecule used in the methods of the invention can be amplified using cDNA, mRNA or, alternatively, genomic DNA as a template and appropriate oligonucleotide primers according to standard PCR amplification techniques. Furthermore, oligonucleotides corresponding to nucleotide sequences of interest can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer. The nucleic acids for use in the methods of the invention can also be prepared, e.g., by standard recombinant DNA techniques. A nucleic acid of the invention can also be chemically 9 ME149103561v.1 117823-35920 synthesized using standard techniques. Various methods of chemically synthesizing polydeoxynucleotides are known, including solid-phase synthesis which has been automated in commercially available DNA synthesizers (See e.g., Itakura et al. U.S. Patent No.4,598,049; Caruthers et al. U.S. Patent No.4,458,066; and Itakura U.S. Patent Nos.4,401,796 and 4,373,071, incorporated by reference herein). As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA loop into which additional DNA segments may be ligated. Another type of vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes or nucleic acid molecules to which they are operatively linked and are referred to as “expression vectors” or "recombinant expression vectors.”. Nucleic acid sequences necessary for expression in prokaryotes usually include a promoter, an operator (optional), and a ribosome binding site, often along with other sequences. Eukaryotic cells are known to utilize promoters, enhancers, and termination and polyadenylation signals. In some embodiments, "expression vectors" are used in order to permit pseudotyping of the viral envelope proteins. Expression vectors are often in the form of plasmids. In the present specification, "plasmid" and "vector" may be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses, adeno-associated viruses, lentiviruses), which serve equivalent functions. The recombinant expression vectors of the invention comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, which is operatively linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, “operably linked” is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner which allows for expression of the nucleotide sequence (e.g., in an in vitro transcription / translation system or in a host cell when the vector is introduced into the host cell). The term “regulatory sequence” is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel; Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990). Regulatory sequences include those which direct constitutive expression of a nucleotide sequence in many types of host cells, those which 10 ME149103561v.1 117823-35920 are constitutively active, those which are inducible, and those which direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). The expression vectors of the invention can be introduced into host cells to thereby produce proteins or portions thereof, including fusion proteins or portions thereof, encoded by nucleic acids as described herein. The terms "transformation," "transfection," and “transduction” refer to introduction of a nucleic acid, e.g., a viral vector, into a recipient cell. As used herein, the term "subject” includes warm-blooded animals, preferably mammals, including humans. In a preferred embodiment, the subject is a primate. In an even more preferred embodiment, the primate is a human. As used herein, the various forms of the term "modulate" are intended to include stimulation (e.g., increasing or upregulating a particular response or activity) and inhibition (e.g., decreasing or downregulating a particular response or activity). As used herein, the term "contacting" (i.e., contacting a cell with an agent) is intended to include incubating the agent and the cell together in vitro (e.g., adding the agent to cells in culture) or administering the agent to a subject such that the agent and cells of the subject are contacted in vivo. The term "contacting" is not intended to include exposure of cells to an agent that may occur naturally in a subject (i.e., exposure that may occur as a result of a natural physiological process). As used herein, the term “administering” to a subject includes dispensing, delivering or applying a composition of the invention to a subject by any suitable route for delivery of the composition to the desired location in the subject, including delivery by intraocular administration or intravenous administration. Alternatively or in combination, delivery is by the topical, parenteral or oral route, intracerebral injection, intramuscular injection, subcutaneous / intradermal injection, intravenous injection, buccal administration, transdermal delivery and administration by the rectal, colonic, vaginal, intranasal or respiratory tract route. As used herein, the term “degenerative ocular disorder” refers generally to a disorder of the retina. In one embodiment, the degenerative ocular disorder is associated with death, of cone cells, and / or rod cells. Moreover, in a particular embodiment, a degenerative ocular disorder is not associated with blood vessel leakage and / or growth, for example, as is the case with diabetic retinopathy, but, instead is characterized primarily by reduced viability of cone cells and / or rod cells. In certain embodiments, the degenerative ocular disorder is a genetic or inherited disorder. In a particular embodiment, the degenerative ocular disorder is retinitis pigmentosa. In another embodiment, the degenerative ocular disorder is age-related macular degeneration. In another embodiment, the degenerative ocular disorder is cone-rod dystrophy. In another embodiment, the degenerative ocular disorder is rod-cone dystrophy. In other embodiments, the degenerative ocular disorder is not associated with blood vessel leakage and / or growth. In certain embodiments, the degenerative ocular disorder is not associated with diabetes and / or diabetic retinopathy. In further 11 ME149103561v.1 117823-35920 embodiments, the degenerative ocular disorder is not NARP (neuropathy, ataxia, and retinitis pigmentosa). In yet further embodiments, the degenerative ocular disorder is not a neurological disorder. In certain embodiments, thedegenerative ocular disorder is not a disorder that is associated with a compromised optic nerve and / or disorders of the brain. In the foregoing embodiments, the degenerative ocular disorder is associated with a compromised photoreceptor cell, and is not a neurological disorder. As used herein, the term “retinitis pigmentosa” or “RP” is known in the art and encompasses a disparate group of genetic disorders of rods and cones. Retinitis pigmentosa generally refers to retinal degeneration often characterized by the following manifestations: night blindness, progressive loss of peripheral vision, eventually leading to total blindness; ophthalmoscopic changes consist in dark mosaic-like retinal pigmentation, attenuation of the retinal vessels, waxy pallor of the optic disc, and in the advanced forms, macular degeneration. In some cases there can be a lack of pigmentation. Retinitis pigmentosa can be associated to degenerative opacity of the vitreous body, and cataract. Family history is prominent in retinitis pigmentosa; the pattern of inheritance may be autosomal recessive, autosomal dominant, or X-linked; the autosomal recessive form is the most common and can occur sporadically. As used herein, the terms “Cone-Rod Dystrophy” or “CRD” and “Rod-Cone Dystrophy” or “RCD” refer to art recognized inherited progressive diseases that cause deterioration of the cone and rod photoreceptor cells and often result in blindness. CRD is characterized by reduced viability or death of cone cells followed by reduced viability or death of rod cells. By contrast, RCD is characterized by reduced viability or death of rod cells followed by reduced viability or death of cone cells. As used herein, the term "age-related macular degeneration" also referred to as “macular degeneration” or “AMD”, refers to the art recognized pathological condition which causes blindness amongst elderly individuals. Age related macular degeneration includes both wet and dry forms of AMD. The dry form of AMD, which accounts for about 90 percent of all cases, is also known as atrophic, nonexudative, or drusenoid (age-related) macular degeneration. With the dry form of AMD, drusen typically accumulate in the retinal pigment epithelium (RPE) tissue beneath / within the Bruch's membrane. Vision loss can then occur when drusen interfere with the function of photoreceptors in the macula. The dry form of AMD results in the gradual loss of vision over many years. The dry form of AMD can lead to the wet form of AMD. The wet form of AMD, also known as exudative or neovascular (age-related) macular degeneration, can progress rapidly and cause severe damage to central vision. The macular dystrophies include Stargardt Disease, also known as Stargardt Macular Dystrophy or Fundus Flavimaculatus, which is the most frequently encountered juvenile onset form of macular dystrophy. “Preventing” or “prevention” refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a patient that may 12 ME149103561v.1 117823-35920 be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease). As used herein, the terms “treating” or “treatment” refer to a beneficial or desired result including, but not limited to, alleviation or amelioration of one or more symptoms, diminishing the extent of infection, stabilized (i.e., not worsening) state of infection, amelioration or palliation of the infectious state, whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival in the absence of treatment. Various additional aspects of the methods of the invention are described in further detail in the following subsections. II. COMPOSITIONS OF THE INVENTION The present invention provides adeno-associated viral (AAV) expression cassettes, AAV expression cassetes present in AAV vectors, and AAV vectors comprising a recombinant viral genome which include an expression cassette. Accordingly, in one aspect the present invention provides compositions comprising an adeno- associated virus (AAV) expression cassette, the expression cassette comprising a promoter and a nucleic acid molecule encoding a thioredoxin-interacting 5 protein (TXNIP) variant protein. The nucleic acid molecule may be selected from the group consisting of (a) a nucleic acid molecule encoding amino acid residues 149-397 of a C247S variant TXNIP, or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 149-397 of the C247S variant TXNIP; (b) a nucleic acid molecule encoding amino acid residues 149-397 of a a C247S .LL351.352AA variant TXNIP, or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 149-397 of the a C247S.LL351.352AA variant TXNIP; (c) a nucleic acid molecule encoding amino acid residues 1-228 of TXNIP, or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 1-228 of TXNIP; (d) a nucleic acid molecule encoding amino acid residues 1-301 of TXNIP, or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 1-301 of TXNIP; 13 ME149103561v.1 117823-35920 (e) a nucleic acid molecule encoding amino acid residues 1-320 of TXNIP, or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 1-320 of TXNIP; or (f) a nucleic acid molecule encoding amino acid residues 255-397 of TXNIP, or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 255-397 of TXNIP. In some embodiments, the promoter is a ubiquitous promoter. In some embodiments, the promoter is an ocular specicific promoter. In some embodiments, the promoter is a photoreceptor- specific (PR- specific) promoter. In some embodiments, the promoter is a cone-specific promoter. In some embodiments, the cone-specific promoter is a human red opsin (RedO) promoter. In some embodiements, the promoter is a retinal pigment epithelium (RPE)-specifc promoter. In some embodiments, the RPE-specific promoter is human bestrophin 1 (hBest1). In another aspect, the present invention provides compositions comprising an adeno- associated virus (AAV) expression cassette, the expression cassette comprising a promoter and a short hairpin RNA (shRNA) targeting heat shock protein 90 alpha family class B member 1 (HSP90AB1). In some embodiments, the promoter is a ubiquitous promoter. In some embodiments, the promoter is an ocular specicific promoter. In some embodiments, the promoter is a photoreceptor- specific (PR- specific) promoter. In some embodiments, the promoter is a cone-specific promoter. In some embodiments, the cone-specific promoter is a human red opsin (RedO) promoter. In some embodiments, the expression cassettes of the invention further comprise an intron, such as an intron between the promoter and the nucleic acid molecule encoding TXNIP. The invention provides a short hairpin ribonucleic acid molecule (shRNA) and polynucleotides comprising same, that can be used to knock down (e.g., inhibit expression of) HSP90AB1. In one embodiment, the polynucleotide further comprises an expression control sequence, in one embodiment, the polynucleotide is a vector, such as, for example, a viral vector. In one embodiment, the expression control sequence comprises a 5’ long terminal repeat (LTR) upstream of the shRNA and a 3" LTR downstream of the shRNA. In some embodiments of the invention,the expression cassettes of the invention further comprise expression control sequences including, but not limited to, appropriate transcription sequences (i.e. initiation, termination, and enhancer), efficient RNA processing signals (e.g. splicing and polyadenylation (polyA) signals), sequences that stabilize cytoplasmic mRNA, sequences that code for a transcriptional enhancer, sequences that code for a posttranscriptional enhancer, sequences 14 ME149103561v.1 117823-35920 that enhance translation efficiency (i.e. Kozak consensus sequence), sequences that enhance protein stability, and when desired, sequences that enhance secretion of the encoded product. The terms "adeno-associated virus", "AAV virus", "AAV virion", "AAV viral particle", and "AAV particle", as used interchangeably herein, refer to a viral particle composed of at least one AAV capsid protein (preferably by all of the capsid proteins of a particular AAV serotype) and an encapsidated polynucleotide AAV genome. If the particle comprises a heterologous polynucleotide (i.e. a polynucleotide other than a wild-type AAV genome such as a transgene to be delivered to a mammalian cell) flanked by the AAV inverted terminal repeats (ITRs), it is typically referred to as an "AAV vector particle.” AAV viruses belonging to the genus Dependovirus of the Parvoviridae family and, as used herein, include any serotype of the over 100 serotypes of AAV viruses known. In general, serotypes of AAV viruses have genomic sequences with a significant homology at the level of amino acids and nucleic acids, provide an identical series of genetic functions, produce virions that are essentially equivalent in physical and functional terms, and replicate and assemble through practically identical mechanisms. The AAV genome is approximately 4.7 kilobases long and is composed of single-stranded deoxyribonucleic acid (ssDNA) which may be either positive- or negative-sensed. The genome comprises inverted terminal repeats (ITRs) at both ends of the DNA strand, and two open reading frames (ORFs): rep and cap. The rep frame is made of four overlapping genes encoding Rep proteins required for the AAV life cycle. The cap frame contains overlapping nucleotide sequences of capsid proteins: VP1, VP2 and VP3, which interact together to form a capsid of an icosahedral symmetry. See Carter B, Adeno-associated virus and adeno- associated virus vectors for gene delivery, Lassie D, et ah, Eds., "Gene Therapy: Therapeutic Mechanisms and Strategies" (Marcel Dekker, Inc., New York, NY, US, 2000) and Gao G, et al, J. Virol.2004; 78(12):6381-6388. The term "AAV vector" or “AAV construct” refers to a vector derived from an adeno- associated virus serotype, including without limitation, AAV-1, AAV-2, AAV-3, AAV-4, AAV-5, AAV6, AAV7, AAV8, and AAV9. "AAV vector" refers to a vector that includes AAV nucleotide sequences as well as heterologous nucleotide sequences. AAV vectors require only the 145 base terminal repeats in cis to generate virus. All other viral sequences are dispensable and may be supplied in trans (Muzyczka (1992) Curr. Topics Microbiol. Immunol.158:97-129). Typically, the rAAV vector genome will only retain the inverted terminal repeat (ITR) sequences so as to maximize the size of the transgene that can be efficiently packaged by the vector. The ITRs need not be the wild-type nucleotide sequences, and may be altered, e.g., by the insertion, deletion or substitution of nucleotides, as long as the sequences provide for functional rescue, replication and packaging. In particular embodiments, the AAV vector is an AAV2, AAV2.7m8, AAV2 / 5 or AAV2 / 8 vector. Suitable AAV vectors are described in, for example, U.S. Patent No.7,056,502 and Yan et al. (2002) J. Virology 76(5):2043-2053, the entire contents of which are incorporated herein by reference. 15 ME149103561v.1 117823-35920 Such AAV vectors can be replicated and packaged into infectious viral particles when present in a host cell that has been transfected with a vector encoding and expressing rep and cap gene products (i.e. AAV Rep and Cap proteins), and wherein the host cell has been transfected with a vector which encodes and expresses a protein from the adenovirus open reading frame E4orf6. The term "cap gene" or "AAV cap gene", as used herein, refers to a gene that encodes a Cap protein. The term "Cap protein", as used herein, refers to a polypeptide having at least one functional activity of a native AAV Cap protein (e.g. VP1, VP2, VP3). Examples of functional activities of Cap proteins (e.g. VP1, VP2, VP3) include the ability to induce formation of a capsid, facilitate accumulation of single-stranded DNA, facilitate AAV DNA packaging into capsids (i.e. encapsidation), bind to cellular receptors, and facilitate entry of the virion into host. The term "capsid", as used herein, refers to the structure in which the viral genome is packaged. A capsid consists of several oligomeric structural subunits made of proteins. For instance, AAV have an icosahedral capsid formed by the interaction of three capsid proteins: VP1, VP2 and VP3. The term "genes providing helper functions", as used herein, refers to genes encoding polypeptides which perform functions upon which AAV is dependent for replication (i.e. "helper functions"). The helper functions include those functions required for AAV replication including, without limitation, those moieties involved in activation of AAV gene transcription, stage specific AAV mRNA splicing, AAV DNA replication, synthesis of cap expression products, and AAV capsid assembly. Viral- based accessory functions can be derived from any of the known helper viruses such as adenovirus, herpesvirus (other than herpes simplex virus type-1), and vaccinia virus. Helper functions include, without limitation, adenovirus E1, E2a, VA, and E4 or herpesvirus UL5, UL8, UL52, and UL29, and herpesvirus polymerase. In one embodiemtn, a helper function does not include adenovirus E1. The term "rep gene" or "AAV rep gene", as used herein, refers to a gene that encodes a Rep protein. The term "Rep protein", as used herein, refers to a polypeptide having at least one functional activity of a native AAV Rep protein (e.g. Rep 40, 52, 68, 78). A "functional activity" of a Rep protein (e.g. Rep 40, 52, 68, 78) is any activity associated with the physiological function of the protein, including facilitating replication of DNA through recognition, binding and nicking of the AAV origin of DNA replication as well as DNA helicase activity. Additional functions include modulation of transcription from AAV (or other heterologous) promoters and site- specific integration of AAV DNA into a host chromosome. The term "adeno-associated virus ITRs" or "AAV ITRs", as used herein, refers to the inverted terminal repeats present at both ends of the DNA strand of the genome of an adeno-associated virus. The ITR sequences are required for efficient multiplication of the AAV genome. Another property of these sequences is their ability to form a hairpin. This characteristic contributes to its self-priming which allows the primase- independent synthesis of the second DNA strand. The ITRs have also 16 ME149103561v.1 117823-35920 shown to be required for efficient encapsidation of the AAV DNA combined with generation of fully assembled, deoxyribonuclease- resistant AAV particles. The term "expression cassette", as used herein, refers to a nucleic acid construct, generated recombinantly or synthetically, with a series of specified nucleic acid elements, which permit transcription of a particular nucleic acid in a target cell. The term "promoter" as used herein refers to a recognition site of a DNA strand to which the RNA polymerase binds. The promoter forms an initiation complex with RNA polymerase to initiate and drive transcriptional activity. The complex can be modified by activating sequences termed "enhancers" or inhibitory sequences termed "silencers". Suitable promoters for use in the expression cassetees of the invention may be ubiquitous promoters, such as a CMV promoter or an SV40 promoter, but are preferably tissue-specific promoters, i.e., promoters that direct expression of a nucleic acid molecule preferentially in a particular cell type. In one embodiment, a tissue-specific promoter for use in the present invention is a photoreceptor-specific (PR-specific) promoter, a promoter that drives expression which is substantially retricted to photoreceptor cells and / or retinal pigment epithelial cells . The PR-specific promoter may be a rod-specific promoter; a cone-specific promoter; or a rod- and cone-specific promoter. In one embodiment, a tissue-specific promoter for use in the present invention is a cone- specific promoter. Suitable PR-specific promoters are known in the art and include, for example, a human red opsin, a guanine nucleotide-binding protein G subunit alpha-2 (GNAT2) promoter, a human rhodopsin promoter, a human rhodopsin kinase (RK) promoter, a G protein–coupled receptor kinase 1 (GRK1) promoter. In certain embodiments, a suitable PR-specific promoter is a human red opsin (RedO) promoter. As used interchangeably herein, the terms “human RO,” “red opsin,” “RedO,” “RO,” and “hRO” refer to Opsin 1, Long Wave Sensitive, also known as Red Cone Photoreceptor Pigment, Opsin 1 (Cone Pigments), Long-Wave-Sensitive, Cone Dystrophy 5 (X-Linked), Red-Sensitive Opsin, RCP, ROP, Long-Wave-Sensitive Opsin, Color Blindness, Protan, Red Cone Opsin, COD5, CBBm, and CBP. The nucleotide sequence of the genomic region containing the hRO gene (including the region upstream of the coding region of hRO which includes the hRO promoter region) is also known and may be found in, for example, GenBank Reference Sequence NG_009105.2 (SEQ ID NO: 8, the entire contents of which is incorporated herein by reference). Suitable RedO promoters for use in the present invention include nucleic acid molecules which include nucleotides 452-2017 of SEQ ID NO:8 directly linked, i.e., containing no intervening sequences, to nucleotides 4541-5032 of SEQ ID NO:8; or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide 17 ME149103561v.1 117823-35920 sequence identity to the entire nucleotide sequence of nucleotides 452-2017 of SEQ ID NO:8 directly linked to nucleotides 4541-5032 of SEQ ID NO:8. In one embodiment, the RedO promoter comprises the nucleotide sequence of SEQ ID NO:16, or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of SEQ ID NO:16. In one embodiment, the hRedO promoter comprises nucleotides 457-2514 of SEQ ID NO:26, or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of nucleotides 457-2514 of SEQ ID NO:26. In another embodiment, the hRedO promoter comprises nucleotides 457-2514 of SEQ ID NO: 49, or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of nucleotides 457-2514 of SEQ ID NO: 49. In another embodiment, the hRedO promoter comprises the nucleotide sequence of SEQ ID NO:119, or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of SEQ ID NO:119. In one embodiment, a tissue-specific promoter for use in the present invention is a retinal pigment epithelium (RPE)-specific promoter. In certain embodiment, a suitable RPE-specific promoter is a human bestrophin 1 (hBest1) promoter. As used interchangeably herein, the terms “bestrophin 1,” “hBest1,” and “hBEST1” refer to bestrophin-1, also known as Bestrophin 1; Vitelliform Macular Dystrophy Protein 2; Best Disease; TU15B; VMD2; Vitelliform Macular Dystrophy 2; Best1V1Delta2; Bestrophin-1; BEST; RP50; ARB; and BMD refers to the gene that is highly and preferentially expressed in the RPE. There are four transcript variants of hBest, the nucleotide and amino acid sequences of which are known and may be found in, for example, GenBank Reference Sequences NM_001139443.1; NM_001300786.1; NM_001300787.1; and NM_004183.3. The nucleotide sequence of the genomic region containing the hBest1 gene (including the region upstream of the coding region of hBest1 which includes the hBest1 promoter region) is also known and may be found in, for example, GenBank Reference Sequence NG_009033.1 (SEQ ID NO:118, the entire contents of which is incorporated herein by reference). Suitable hBest1 promoters for use in the present invention include nucleic acid molecules which include nucleotides -585 to +38 of the hBest1gene, (i.e., nucleotides 4885-5507 of SEQ ID NO:118); nucleotides −154 to +38 of the hBest1 gene (i.e., nucleotides 5316-5507 of SEQ ID NO:9); or nucleotides −104 to +38 bp of the hBest1 gene (i.e., nucleotides 5366-5507 of SEQ ID NO:9), or or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 18 ME149103561v.1 117823-35920 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of nucleotides 4885-5507 of SEQ ID NO:118, nucleotides 5316-5507 of SEQ ID NO:118, or nucleotides 5366-5507 of SEQ ID NO:118. In one embodiement, an hBest1 promoter comprises nucleotides -585 to +38 of the hBest1gene, (i.e., nucleotides 4885-5507 of SEQ ID NO:118), or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of nucleotides 4885-5507 of SEQ ID NO:118. Additional nucleotide sequences of hBest1 promoters are also described in PCT Publication No. WO 2020 / 132040, the entire contents of which is incorporated herein by reference. As used herein, the term “TXNIP” refers to thioredoxin-interacting protein, a member of the alpha arrestin protein family. Thioredoxin is a thiol-oxidoreductase that is a major regulator of cellular redox signaling which protects cells from oxidative stress. TXNIP inhibits the antioxidative function of thioredoxin resulting in the accumulation of reactive oxygen species and cellular stress, and functions as a regulator of cellular metabolism and of endoplasmic reticulum (ER) stress. TXNIP is also known as Upregulated By 1,25-Dihydroxyvitamin D-3; Vitamin D3 Up-Regulated Protein 1; Thioredoxin Binding Protein 2; VDUP1; Thioredoxin-Binding Protein 2; EST01027; HHCPA78; ARRDC6; and THIF . There are two wild-type transcript variants of human TXNIP and two wild-type transcript variants of mouse TXNIP, the nucleotide and amino acid sequences of which are known and may be found in, for example, GenBank Reference Sequences NM_006472.5 and NP_006463.3; NM_001313972.1 and NP_001300901.1; NM_001009935.2 and NP_001009935.1; and NM_023719.2 and NP_076208.2. The amino acid sequences of the foregoing GenBank entries (NP_ entries) are SEQ ID Nos:1-4, respectively, and the corresponding nucleotide sequences (NM_ are SEQ ID NOs:101-104, respectively. The entire contents of each of the foregoing GenBank entries are incorporated herein by reference. As used herein, the term “a C247S variant TXNIP protein” refers to a protein, or a portion (e.g., the N-terminus or the C-terminus) of the protein in which the cysteine at amino acid residue position 247 of SEQ ID NO:1 is replaced with a serine. Based on the amino acid sequence similarities between SEQ ID Nos:1-4, one of ordinary skill in the art will readily appreciate that, as used herein, a C247S variant of SEQ ID NO:1 is equivalent to a C192S variant of SEQ ID NO:2, or a C248S variant of SEQ ID NO:3 or a C247S variant of SEQ ID NO:4. Exemplary C247S variant TXNIP amino acid sequences are provided in SEQ ID Nos:105-108. The codon for cysteine is TGT or TGC while the codon for serine is AGT or AGC. In one embodiment, the nucleic acid molecule encoding the C247S variant TXNIP comprises a nucleic acid molecule encoding amino acid residues 149-397 of a C247S variant TXNIP (e.g., a C247S variant of SEQ ID NO:3), or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity 19 ME149103561v.1 117823-35920 to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 149-397 of a C247S variant TXNIP (e.g., a C247S variant of SEQ ID NO:3). In one embodiment, the nucleic acid molecule encoding amino acid residues 1-228 of TXNIP (SEQ ID NO:3), or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 1-228 of TXNIP (SEQ ID NO:3). In one embodiment, the nucleic acid molecule encoding amino acid residues 1-301 of TXNIP (SEQ ID NO:3), or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 1-301 of TXNIP (SEQ ID NO:3). In one embodiment, the nucleic acid molecule encoding amino acid residues 1-320 of TXNIP(SEQ ID NO:3), or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 1-320 of TXNIP (SEQ ID NO:3). In one embodiment, the nucleic acid molecule encoding amino acid residues 255-397 of TXNIP (SEQ ID NO:3), or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 255-397 of TXNIP (SEQ ID NO:3) In one embodiment, the nucleic acid molecule encoding the C247S variant TXNIP comprises nucleotides 366-1541 of SEQ ID NO:111; or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of nucleotides 366-1541 of SEQ ID NO:111. In another embodiment, the nucleic acid molecule encoding the C247S variant TXNIP comprises nucleotides 162-1172 of SEQ ID NO:112, or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of nucleotides 162-1172 of SEQ ID NO:112. In yet another embodiment, the nucleic acid molecule encoding the C247S variant TXNIP comprises nucleotides 280-1473 of SEQ ID NO:113; or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of nucleotides 280-1473 of SEQ ID NO:113. In one embodiment, the nucleic acid molecule encoding the C247S variant TXNIP comprises nucleotides 280-1470 of SEQ ID NO:114, or a nucleotide sequence having about 85%, 86%, 87%, 20 ME149103561v.1 117823-35920 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of nucleotides 280-1470 of SEQ ID NO:114. In one embodiment, the nucleic acid molecule encoding the C247S variant TXNIP comprises SEQ ID NO: 120; or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of SEQ ID NO:120. The invention further encompasses nucleic acid molecules that differ, due to degeneracy of the genetic code, from the nucleotide sequence of nucleic acids encoding a C247S variant TXNIP polypeptide, and, thus, encode the same protein. As used herein, the term “a C247S. LL351.352AA variant TXNIP protein” refers to protein, or a portion (e.g., the N-terminus or the C-terminus) of the protein in which the cysteine at amino acid residue position 247 of SEQ ID NO:1 is replaced with a serine, and the leucines at amino acid residue positions 351 and 352 are replaced by alanine residues. In one embodiment, the nucleic acid molecule encoding the C247S. LL351.352AA variant TXNIP comprises a nucleic acid molecule encoding amino acid residues 149-397 of a C247S .LL351.352AA variant TXNIP (e.g., a C247S.LL351.352AA variant of SEQ ID NO:3), or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 149-397 of a C247S .LL351.352AA variant TXNIP (e.g., a C247S.LL351.352AA variant of SEQ ID NO:3). In one embodiment, the nucleic acid molecule encoding the C247S. LL351.352AA variant TXNIP comprises SEQ ID NO:115, or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of SEQ ID NO: 115. In one embodiment, the nucleic acid molecule encoding he C247S. LL351.352AA variant TXNIP comprises SEQ ID NO: 121; or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of SEQ ID NO:121. The invention further encompasses nucleic acid molecules that differ, due to degeneracy of the genetic code, from the nucleotide sequence of nucleic acids encoding a C247S. LL351.352AA variant TXNIP polypeptide, and, thus, encode the same protein. As used herein, the term “heat shock protein 90 alpha family class B member 1” or “HSP90AB1” refers to the well-known protein that is encoded by the HSP90AB1 gene. The HSP90AB1 protein is a molecular chaperone. Chaperones are proteins that bind to other proteins, thereby stabilizing them. HSP90AB1 is active as homodimer, forming a V-shaped structure. It consists of three major domains, an N-terminal domain (NTD) containing the ATP binding site; a 21 ME149103561v.1 117823-35920 middle domain, primarily responsible for substrate binding; and a C-terminal domain (CTD) which is the dimerization domain (base of the V). Between these domains, there are short charged domains. The nucleotide and amino acid sequence of the six variant nucleotide sequence of HSP90AB1 are known and may be found in, for example, GeneBank Reference Nos. NM_001271969.2, NM_001271970.2, NM_001271971.2, NM_001271972.2, NM_001371238.1, and NM_007355.4, the entire contents of each of which are incorporated herein by reference. A short hairpin RNA or small hairpin RNA (shRNA) is an artificial RNA molecule with a tight hairpin turn that silences target gene expression via RNA interference by exression in a vector. When the expression vector comprising the shRNA is transfected or transduced into cells, DICER converts the hairpin structure of in situ shRNA into in situ siRNA that then engages with RISC in an optimal way for RNAi processing and target gene silencing. shRNAs targeting HSP90AB1 to inhibit expression of HSP90AB1 for use in the compositions of the invention can be readily designed and assessed by one of ordinary skill in the art based on the known nucleotide sequence of HSP90AB1. To determine the percent identity of two amino acid sequences or of two nucleic acids, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = # of identical positions total # of positions (e.g., overlapping positions) x100). The determination of percent identity between two sequences may be accomplished using a mathematical algorithm. A non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul (1990) Proc. Natl. Acad. Sol. USA 87:2264-2268, modified as in Karlin and Altschul (1993) Proc. Nati. Accid Sci. USA 90:5873- 5877. Such an algorithm is incorporated into the BLASTN and BLASTX programs of Altschul, et al. (1990) J. Mol. Biol.215:403-410. BLAST nucleotide searches can be performed with the BLASTN program, score = 100, wordlength = 12 to obtain nucleotide sequences homologous to a nucleic acid molecules of the invention. BLAST protein searches can be performed with the BLASTP program, score — 50, wordlength = 3 to obtain amino acid sequences homologous to a protein molecules of the invention. To obtain gapped alignments for comparison purposes, a newer version of the BLAST algorithm called Gapped BLAST can be utilized as described in Altschul et al. (1997) Nucleic Acids Res 25:3389-3402, which is able to perform gapped local alignments for the programs BLASTN, BLASTP and BLASTX. 22 ME149103561v.1 117823-35920 In some embodiments, the expression cassettes of the invention further comprise an intron between the promoter and the nucleic acid molecule, e.g., encoding the C247S variant TXNIP. In some embodiments, the expression cassettes of the invention further comprise an intron between the promoter and the nucleic acid molecule encoding the C247S variant TXNIP. In some embodiments, the expression cassettes of the invention further comprise an intron between the promoter and the nucleic acid molecule encoding the C247S.LL.351.352AA variant TXNIP. In some embodiments, the expression cassettes of the invention further comprise an intron between the promoter and the nucleic acid molecule encoding the C247S.LL.351.352AA. As used herein, “an intron” refers to a non-coding nucleic acid molecule which is removed by RNA splicing during maturation of a final RNA product. In one embodiment, the intron is an SV40 intron, e.g., the intron comprises the nucleotide sequence of SEQ ID NO:20, or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleotide sequence of SEQ ID NO: 20. In yet another embodiment, the intron is a human beta-globin intron, e.g., the intron comprises the nucleotide sequence of SEQ ID NO:12, or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleotide sequence of SEQ ID NO: 12. In another embodiment, the intron is a chimeric intron. A “chimeric intron” is an artificial (or non-naturally occurring intron that enhances mRNA processing and increases expression levels of a downstream open reading frame. In some embodiments of the invention, for example, when the expression cassette a linker. Suitable linkers for co-expression of genes from a single promoter are known in the art. In one embodiment, a suitable linker comprises a nucleotide sequence encoding a 2A peptide. As used herein, a “2A peptide” refers to the art-known peptides also referred to as “self-cleaving 2A peptides” first discovered in picornaviruses. 2A peptides are short (about 20 amino acids) and produce equimolar levels of mulitple genes from the same mRNA. Exemplary nucleotide sequnces of suitable 2A peptides are provided in SEQ ID NOs:21-24. In some embodiments, the expression cassettes of the invention further comprise a post- transcriptional regulatory region. The term "post-transcriptional regulatory region", as used herein, refers to any polynucleotide that facilitates the expression, stabilization, or localization of the sequences contained in the cassette or the resulting gene product. In one embodiment, a post-transcriptional regulatory region suitable for use in the expression cassettes of the invention includes a Woodchuck hepatitis virus post-transcriptional regulatory element. 23 ME149103561v.1 117823-35920 As used herein, the term "Woodchuck hepatitis virus posttranscriptional regulatory element" or "WPRE,” refers to a DNA sequence that, when transcribed, creates a tertiary structure capable of enhancing the expression of a gene. See Lee Y, et al, Exp. Physiol.2005; 90(l):33-37 and Donello J, et al, J. Virol.1998; 72(6):5085-5092. In one embodiment, a WPRE includes the nucleotide sequence of SEQ ID NO: 10 (See, e.g., J Virol.1998 Jun; 72(6): 5085–5092), or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleotide sequence of SEQ ID NO: 10. In another embodiment, a WPRE includes the nucleotide sequence of SEQ ID NO: 11, or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleotide sequence of SEQ ID NO: 11. In another embodiment, a WPRE includes nucleotides 1868-2025 of SEQ ID NO: 39, or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of nucleotides 1868-2025 of SEQ ID NO: 39. In another embodiment, a WPRE includes nucleotides 3529-4070 of SEQ ID NO: 49, or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of nucleotides 3529-4070 of SEQ ID NO: 49. In some embodiments, the expression cassettes of the invention further comprises a polyadenylation signal. As used herein, a “polyadenylation signal” or “polyA signal,” as used herein refers to a nucleotide sequence that terminates transcription. Suitable polyadenylation signals for use in the AAV vectors of the invention are known in the art and include, for example, a bovine growth hormone polyA signal (BGH pA) or an SV40 polyadenylation signal (SV40 polyA). In one embodiment, a SV40 pA includes the nucleotide sequence of SEQ ID NO: 13, or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleotide sequence of SEQ ID NO: 13. In one embodiment, a BGH pA includes the nucleotide sequence of SEQ ID NO: 25, or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleotide sequence of SEQ ID NO: 25. In one embodiment, a BGH pA includes the nucleotide sequence of nucleotides 4270-4484 of SEQ ID NO:26, or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 24 ME149103561v.1 117823-35920 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of nucleotides 4270-4484 of SEQ ID NO:26. In one embodiment, a SV40 pA includes the nucleotide sequence of nucleotides 2026-2228 of SEQ ID NO: 39, or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of nucleotides 2026-2228 of SEQ ID NO: 39. In one embodiment, a BGH pA includes the nucleotide sequence of nucleotides 4077-4291 of SEQ ID NO: 49, or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of nucleotides 4077-4291 of SEQ ID NO: 49. In some embodiments, the expression cassettes of the invention further comprise an enhancer. The term "enhancer", as used herein, refers to a DNA sequence element to which transcription factors bind to increase gene transcription. The AAV vectors of the invention may also include cis- acting 5' and 3' inverted terminal repeat (ITR) sequences. In some embodiments, the ITR sequences are about 145 bp in length. In some embodiments, substantially the entire sequences encoding the ITRs are used in the molecule. In other embodiments, the ITRs include modifications. Procedures for modifying these ITR sequences are known in the art. See Brown T, "Gene Cloning" (Chapman & Hall, London, GB, 1995), Watson R, et al, "Recombinant DNA", 2nd Ed. (Scientific American Books, New York, NY, US, 1992), Alberts B, et al, "Molecular Biology of the Cell" (Garland Publishing Inc., New York, NY, US, 2008), Innis M, et al, Eds., "PCR Protocols. A Guide to Methods and Applications" (Academic Press Inc., San Diego, CA, US, 1990), Erlich H, Ed., "PCR Technology. Principles and Applications for DNA Amplification" (Stockton Press, New York, NY, US, 1989), Sambrook J, et al, "Molecular Cloning. A Laboratory Manual" (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, US, 1989), Bishop T, et al, "Nucleic Acid and Protein Sequence. A Practical Approach" (IRL Press, Oxford, GB, 1987), Reznikoff W, Ed., "Maximizing Gene Expression" (Butterworths Publishers, Stoneham, MA, US, 1987), Davis L, et al, "Basic Methods in Molecular Biology" (Elsevier Science Publishing Co., New York, NY, US, 1986), and Schleef M, Ed., "Plasmid for Therapy and Vaccination" (Wiley- VCH Verlag GmbH, Weinheim, DE, 2001). The AAV vectors of the invention may include ITR nucleotide sequences derived from any one of the AAV serotypes. In a preferred embodiment, the AAV vector comprises 5' and 3' AAV ITRs. In one embodiment, the 5' and 3' AAV ITRs derive from AAV2. AAV ITRs for use in the AAV vectors of the invention need not have a wild- type nucleotide sequence (See Kotin, Hum. Gene Ther., 1994, 5:793-801). As long as ITR sequences function as intended for the rescue, replication and packaging of the AAV virion, the ITRs may be altered by the insertion, deletion or substitution of nucleotides or the ITRs may be derived from any of several AAV serotypes or its mutations. 25 ME149103561v.1 117823-35920 In one embodiment, a 5’ ITR includes nucleotides 248-377 of SEQ ID NO:26; nucleotides 1- 141 of SEQ ID NO: 39; or nucleotides 248-377 of SEQ ID NO: 49, or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of nucleotides 248-377 of SEQ ID NO:26; nucleotides 1-141 of SEQ ID NO: 39; or nucleotides 248-377 of SEQ ID NO: 49. In one embodiment, a 3’ ITR includes nucleotides 4571-4201 of SEQ ID NO:26; nucleotides 2301-2441 of SEQ ID NO: 39; or nucleotides 4378-4508 of SEQ ID NO: 49, or a nucleotide sequence having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of nucleotides 4571-4201 of SEQ ID NO:26; nucleotides 2301-2441 of SEQ ID NO: 39; or nucleotides 4378-4508 of SEQ ID NO: 49. In addition, an AAV vector can contain one or more selectable or screenable marker genes for initially isolating, identifying, or tracking host cells that contain DNA encoding the ithe AAV vector (and / or rep, cap and / helper genes), e.g., antibiotic resistance, as described herein. As indicated above, the AAV vectors of the invention may be packaged into AAV viral particles for use in the methods, e.g., gene therapy methods, of the invention (discussed below) to produce AAV vector particles using methods known in the art. Such methods generally include packaging the AAV vectors of the invention into infectious AAV viral particles in a host cell that has been transfected with a vector encoding and expressing rep and cap gene products (i.e. AAV Rep and Cap proteins), and with a vector which encodes and expresses a protein from the adenovirus open reading frame E4orf6. Suitable AAV Caps may be derived from any serotype. In one embodiment, the capsid is derived from the AAV of the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8 and AAV9. In another embodiment, the AAV of the invention comprises a capsid derived from the AAV7m8, AAV5 or AAV8 serotypes. In some embodiments, an AAV Cap for use in the method of the invention can be generated by mutagenesis (i.e. by insertions, deletions, or substitutions) of one of the aforementioned AAV Caps or its encoding nucleic acid. In some embodiments, the AAV Cap is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% or more similar to one or more of the aforementioned AAV Caps. In some embodiments, the AAV Cap is chimeric, comprising domains from two, three, four, or more of the aforementioned AAV Caps. In some embodiments, the AAV Cap is a mosaic of VP1, VP2, and VP3 monomers originating from two or three different AAV or a recombinant AAV. In some embodiments, a rAAV composition comprises more than one of the aforementioned Caps. Suitable rep may be derived from any AAV serotype. In one embodiment, the rep is derived from any of the serotypes selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, or AAV9. In another embodiment, the AAV rep is derived from the serotype AAV2. 26 ME149103561v.1 117823-35920 Suitable helper genes may be derived from any AAV serotype and include adenovirus E4, E2a and VA. The AAV rep, AAV cap and genes providing helper functions can be introduced into the cell by incorporating the genes into a vector such as, for example, a plasmid, and introducing the vector into a cell. The genes can be incorporated into the same plasmid or into different plasmids. In one, the AAV rep and cap genes are incorporated into one plasmid and the genes providing helper functions are incorporated into another plasmid. The AAV vectors of the invention and the polynucleotides comprising AAV rep and cap genes and genes providing helper functions may be introduced into a host cell using any suitable method well known in the art. See Ausubel F, et al, Eds., "Short Protocols in Molecular Biology", 4th Ed. (John Wiley and Sons, Inc., New York, NY, US, 1997), Brown (1995), Watson (1992), Alberts (2008), Innis (1990), Erlich (1989), Sambrook (1989), Bishop (1987), Reznikoff (1987), Davis (1986), and Schleef (2001), supra. Examples of transfection methods include, but are not limited to, co-precipitation with calcium phosphate, DEAE-dextran, polybrene, electroporation, microinjection, liposome-mediated fusion, lipofection, retrovirus infection and biolistic transfection. When the cell lacks the expression of any of the AAV rep and cap genes and genes providing adenoviral helper functions, said genes can be introduced into the cell simultaneously with the AAV vector. Alternatively, the genes can be introduced in the cell before or after the introduction of the AAV vector of the invention. Methods of culturing packaging cells and exemplary conditions which promote the release of AAV vector particles, such as the producing of a cell lysate, are known in the art. Producer cells are grown for a suitable period of time in order to promote release of viral vectors into the media. Generally, cells may be grown for about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, up to about 10 days. After about 10 days (or sooner, depending on the culture conditions and the particular producer cell used), the level of production generally decreases significantly. Generally, time of culture is measured from the point of viral production. For example, in the case of AAV, viral production generally begins upon supplying helper virus function in an appropriate producer cell as described herein. Generally, cells are harvested about 48 to about 100, preferably about 48 to about 96, preferably about 72 to about 96, preferably about 68 to about 72 hours after helper virus infection (or after viral production begins). The AAV vector particles of the invention can be obtained from both: i) the cells transfected with theforegoing and ii) the culture medium of the cells after a period of time post-transfection, preferably 72 hours. Any method for the purification of the AAV vector particles from the cells or the culture medium can be used for obtaining the AAV vector particles of the invention. In a particular embodiment, the AAV vector particles of the invention are purified following an optimized method based on a polyethylene glycol precipitation step and two consecutive cesium chloride (CsCl) or 27 ME149103561v.1 117823-35920 iodixanol density gradient ultracentrifugation. See Ayuso et al., 2014, Zolotukhin S, et al., Gene Ther. 1999; 6; 973-985. Purified AAV vector particles of the invention can be dialyzed against an appropriate formulation buffer such as PBS, filtered and stored at -80°C. Titers of viral genomes can be determined by quantitative PCR following the protocol described for the AAV2 reference standard material using linearized plasmid DNA as standard curve. See Aurnhammer C, et al., Hum Gene Ther Methods, 2012, 23, 18-28, D’Costa S, et al., Mol Ther Methods Clin Dev.2016, 5, 16019. In some embodiments, the methods further comprise purification steps, such as treatment of the cell lysate with benzonase, purification of the cell lysate with the use of affinity chromatography and / or ion-exchange chromotography. See Halbert C, et al, Methods Mol. Biol.2004; 246:201-212, Nass S, et al., Mol Ther Methods Clin Dev. 2018 Jun 15; 9: 33-46. AAV Rep and Cap proteins and their sequences, as well as methods for isolating or generating, propagating, and purifying such AAV, and in particular, their capsids, suitable for use in producing AAV are known in the art. See Gao, 2004, supra, Russell D, et al, US 6,156,303, Hildinger M, et al, US 7,056,502, Gao G, et al, US 7,198,951, Zolotukhin S, US 7,220,577, Gao G, et al, US 7,235,393, Gao G, et al, US 7,282,199, Wilson J, et al, US 7,319,002, Gao G, et al, US 7,790,449, Gao G, et al, US 20030138772, Gao G, et al, US 20080075740, Hildinger M, et al, WO 2001 / 083692, Wilson J, et al, WO 2003 / 014367, Gao G, et al, WO 2003 / 042397, Gao G, et al, WO 2003 / 052052, Wilson J, et al, WO 2005 / 033321, Vandenberghe L, et al, WO 2006 / 110689, Vandenberghe L, et al, WO 2007 / 127264, and Vandenberghe L, et al, WO 2008 / 027084. III. Pharmaceutical Compositions of the Invention In one aspect of the invention, an AAV viral particle of the invention will be in the form of a pharmaceutical composition containing a pharmaceutically acceptable carrier. As used herein "pharmaceutically acceptable carrier" refers to any substantially non-toxic carrier conventionally useable for administration of pharmaceuticals in which the isolated polypeptide of the present invention will remain stable and bioavailable. The pharmaceutically acceptable carrier must be of sufficiently high purity and of sufficiently low toxicity to render it suitable for administration to the mammal being treated. It further should maintain the stability and bioavailability of an active agent. The pharmaceutically acceptable carrier can be liquid or solid and is selected, with the planned manner of administration in mind, to provide for the desired bulk, consistency, etc., when combined with an active agent and other components of a given composition. Suitable pharmaceutically acceptable carriers include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Pharmaceutically acceptable carriers also include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is well known in the art. 28 ME149103561v.1 117823-35920 Except insofar as any conventional media or agent is incompatible with the gene therapy vector, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions. Pharmaceutical compositions of the invention may be formulated for delivery to animals for veterinary purposes (e.g. livestock (cattle, pigs, dogs, mice, rats), and other non-human mammalian subjects, as well as to human subjects. In a particular embodiment, the pharmaceutical compositions of the present invention are in the form of injectable compositions. The compositions can be prepared as an injectable, either as liquid solutions or suspensions. The preparation may also be emulsified. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, phosphate buffered saline or the like and combinations thereof. In addition, if desired, the preparation may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH-buffering agents, adjuvants, surfactant or immunopotentiators. In a particular embodiment, the AAV particles of the invention are incorporated in a composition suitable for intraocular administration. For example, the compositions may be designed for intravitreal, subretinal, subconjuctival, sub-tenon, periocular, retrobulbar, suprachoroidal, and / or intrascleral administration, for example, by injection, to effectively treat the retinal disorder. Additionally, a sutured or refillable dome can be placed over the administration site to prevent or to reduce "wash out", leaching and / or diffusion of the active agent in a non-preferred direction. Relatively high viscosity compositions, as described herein, may be used to provide effective, and preferably substantially long-lasting delivery of the nucleic acid molecules and / or vectors, for example, by injection to the posterior segment of the eye. A viscosity inducing agent can serve to maintain the nucleic acid molecules and / or vectors in a desirable suspension form, thereby preventing deposition of the composition in the bottom surface of the eye. Such compositions can be prepared as described in U.S. Patent No.5,292,724, the entire contents of which are hereby incorporated herein by reference. Sterile injectable solutions can be prepared by incorporating the compositions of the invention in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Toxicity and therapeutic efficacy of nucleic acid molecules described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the ED50 (the dose therapeutically effective in 50% of the population). Data obtained 29 ME149103561v.1 117823-35920 from cell culture assays and / or animal studies can be used in formulating a range of dosage for use in humans. The dosage typically will lie within a range of concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. IV. Methods of the Invention The present invention also provides methods of use of the compositions of the invention, which generally include contacting an ocular cell with an AAV viral particle or pharmaceutical composition comprising an AAV particle of the invention. Accordingly, in one aspect, the present invention provides methods for prolonging the viability of a photoreceptor cell, e.g., a photoreceptor cell, compromised by degenerative ocular disorder, e.g., retinitis pigmentosa, age related macular degeneration, cone rod dystrophy, and rod cone dystrophy. The methods generally include contacting the cell with a composition, an AAV viral particle or pharmaceutical composition comprising a composition or an AAV particle of the invention. The present invention further provides methods for treating a degenerative ocular disorder in a subject having a degenerative ocular disorder, e.g., retinitis pigmentosa, age related macular degeneration, cone rod dystrophy, and rod cone dystrophy. The methods inlcude administering to the subject a therapeutically effective amount of a composition, an AAV viral particle or pharmaceutical composition comprising a composition or an AAV particle of the invention. The present invention also provides methods for preventing a degenerative ocular disorder in a subject having a degenerative ocular disorder, e.g., retinitis pigmentosa, age related macular degeneration, cone rod dystrophy, and rod cone dystrophy. The methods inlcude administering to the subject a prohylatically effective amount of a composition, an AAV viral particle or pharmaceutical composition comprising a composition or an AAV particle of the invention. In another aspect, the present invention provides methods of treating a subject having retinitis pigmentosa. The methods inlcude administering to the subject a therapeutically effective amount of a composition, an AAV viral particle or pharmaceutical composition comprising a composition or an AAV particle of the invention. In one aspect, the present invention provides methods for delaying loss of functional vision in a subject having a degenerative ocular disorder. The methods inlcude administering to the subject a therapeutically effective amount of a composition, an AAV viral particle or pharmaceutical composition comprising a composition or an AAV particle of the invention. In another aspect, the present invention provides methods of treating a subject having age- related macular degeneration. The methods inlcude administering to the subject a therapeutically 30 ME149103561v.1 117823-35920 effective amount of an AAV viral particle or pharmaceutical composition comprising an AAV particle of the invention. In one embodiment, the methods of the invention further comprise administering to the subject a therapeutically effective amount of a composition comprising an adeno-associated virus (AAV) expression cassette, the expression cassette comprising a photoreceptor-specific (PR- specific) promoter and a short hairpin RNA (shRNA) targeting heat shock protein 90 alpha family class B member 1 (HSP90AB1). In such methods, the AAV comprising the TXNIP and the AAV comprsing HSP90AB1 shRNAmay be formulated in the same composition or different compositions and / or may administered to the subject in the same composition or in separate compositions. The AAV comprising the TXNIP and the AAV comprsing HSP90AB12 may be administered to a subject at the same dose or different doses and at the same time or at different times. Generally, methods are known in the art for viral infection of the cells of interest. The virus can be placed in contact with the cell of interest or alternatively, can be injected into a subject suffering from a disorder associated with photoreceptor cell oxidative stress. Guidance in the introduction of the compositions of the invention into subjects for therapeutic purposes are known in the art and may be obtained in the above-referenced publications, as well as in U.S. Patent Nos.5,631,236, 5,688,773, 5,691,177, 5,670,488, 5,529,774, 5,601,818, and PCT Publication No. WO 95 / 06486, the entire contents of which are incorporated herein by reference. The compositions of the invention may be delivered to a subject by, for example, intravenous injection, local administration (see, e.g., U.S. Patent No.5,328,470), stereotactic injection (see, e.g., Chen et al. (1994) Proc. Natl. Acad. Sci. U.S.A.91:3054-3057), or by in vivo electroporation (see, e.g., Matsuda and Cepko (2007) Proc. Natl. Acad. Sci. U.S.A.104:1027-1032). Preferably, the compositions of the invention are administered to the subject locally. Local administration of the compositions described herein can be by any suitable method in the art including, for example, injection (e.g., intravitreal or subretinal, subvitreal, subconjuctival, sub-tenon, periocular, retrobulbar, suprachoroidal, and / or intrascleral injection), gene gun, by topical application of thecomposition in a gel, oil, or cream, by electroporation, using lipid-based transfection reagents, transcleral delivery, by implantation of scleral plugs or a drug delivery device, or by any other suitable transfection method. Application of the methods of the invention for the treatment and / or prevention of a disorder can result in curing the disorder, decreasing at least one symptom associated with the disorder, either in the long term or short term or simply a transient beneficial effect to the subject. Accordingly, as used herein, the terms “treat,” “treatment” and “treating” include the application or administration of compositions, as described herein, to a subject who is suffering from a degenerative ocular disease or disorder, or who is susceptible to such conditions with the purpose of curing, healing, alleviating, relieving, altering, remedying, ameliorating, improving or affecting such 31 ME149103561v.1 117823-35920 conditions or at least one symptom of such conditions. As used herein, the condition is also “treated” if recurrence of the condition is reduced, slowed, delayed or prevented. The term “prophylactic” or “therapeutic” treatment refers to administration to the subject of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate or maintain the existing unwanted condition or side effects therefrom). "Therapeutically effective amount," as used herein, is intended to include the amount of a composition of the invention that, when administered to a patient for treating a degenerative ocular disease, is sufficient to effect treatment of the disease (e.g., by diminishing, ameliorating or maintaining the existing disease or one or more symptoms of disease). The "therapeutically effective amount" may vary depending on the composition, how the composition is administered, the disease and its severity and the history, age, weight, family history, genetic makeup, stage of pathological processes mediated by the disease expression, the types of preceding or concomitant treatments, if any, and other individual characteristics of the patient to be treated. “Prophylactically effective amount,” as used herein, is intended to include the amount of a composition that, when administered to a subject who does not yet experience or display symptoms of e.g., a degenerative ocular disorder, but who may be predisposed to the disease, is sufficient to prevent or ameliorate the disease or one or more symptoms of the disease. Ameliorating the disease includes slowing the course of the disease or reducing the severity of later-developing disease. The "prophylactically effective amount" may vary depending on the composition, how the composition is administered, the degree of risk of disease, and the history, age, weight, family history, genetic makeup, the types of preceding or concomitant treatments, if any, and other individual characteristics of the patient to be treated. A "therapeutically-effective amount" or “prophylacticaly effective amount” also includes an amount of a composition that produces some desired local or systemic effect at a reasonable benefit / risk ratio applicable to any treatment. A composition employed in the methods of the present invention may be administered in a sufficient amount to produce a reasonable benefit / risk ratio applicable to such treatment. Subjects suitable for treatment using the regimens of the present invention should have or are susceptible to developing a degenerative ocular disease or disorder. For example, subjects may be genetically predisposed to development of the disorders. Alternatively, abnormal progression of the following factors including, but not limited to visual acuity, the rate of death of cone and / or rod cells, night vision, peripheral vision, attenuation of the retinal vessels, and other ophthalmoscopic factors 32 ME149103561v.1 117823-35920 associated with degenerative ocular disorders such as retinitis pigmentosa may indicate the existence of or a predisposition to a retinal disorder. In one embodiment, the disorder includes, but not limited to, retinitis pigmentosa, age related macular degeneration, cone rod dystrophy, and rod cone dystrophy. In other embodiments, the disorder is not associated with blood vessel leakage and / or growth. In certain embodiments, the disorder is not associated with diabetes. In another embodiment, the disorder is not diabetic retinopathy. In further embodiments, the disorder is not NARP (neuropathy, ataxia and retinitis pigmentosa). In one embodiment, the disorder is a disorder associated with decreased viability of cone and / or rod cells. In yet another embodiment, the disorder is a genetic disorder. The compositions, as described herein, may be administered as necessary to achieve the desired effect and depend on a variety of factors including, but not limited to, the severity of the condition, age and history of the subject and the nature of the composition, for example, the identity of the genes or the affected biochemical pathway. The pharmaceutical compositions of the invention may be administered in a single dose or, in particular embodiments of the invention, multiples doses (e.g. two, three, four, or more administrations) may be employed to achieve a therapeutic effect. The therapeutic or preventative regimens may cover a period of at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks, or be chronically administered to the subject. In one embodiment, the viability or survival of photoreceptor cells, such as cones cells, is, e.g., about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 3 years, about 4 years, about 5 years, about 10 years, about 15, years, about 20 years, about 25 years, about 30 years, about 40 years, about 50 years, about 60 years, about 70 years, and about 80 years. In general, the nucleic acid molecules and / or the vectors of the invention are provided in a therapeutically effective amount to elicit the desired effect, e.g., increase C247S variant TXNIP expression. The quantity of the viral particle to be administered, both according to number of treatments and amount, will also depend on factors such as the clinical status, age, previous treatments, the general health and / or age of the subject, other diseases present, and the severity of the disorder. Precise amounts of active ingredient required to be administered depend on the judgment of the gene therapist and will be particular to each individual patient. Moreover, treatment of a subject with a therapeutically effective amount of the nucleic acid molecules and / or the vectors of the invention can include a single treatment or, preferably, can include a series of treatments. It will also be appreciated that the effective dosage used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result from the results of diagnostic assays as described herein. The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. 33 ME149103561v.1 117823-35920 In some embodiments, a therapeutically effective amount or a prophylactically effective amount of a viral particle of the invention (or pharmaceutical composition of the invention) is in titers ranging from about 1x105, about 1.5x105, about 2x105, about 2.5x105, about 3x105, about 3.5x105, about 4x105, about 4.5x105, about 5x105, about 5.5x105, about 6x105, about 6.5x105, about 7x105, about 7.5x105, about 8x105, about 8.5x105, about 9x105, about 9.5x105, about 1x106, about 1.5x106, about 2x106, about 2.5x106, about 3x106, about 3.5x106, about 4x106, about 4.5x106, about 5x106, about 5.5x106, about 6x106, about 6.5x106, about 7x106, about 7.5x106, about 8x106, about 8.5x10, about 9x106, about 9.5x106, about 1x107, about 1.5x107, about 2x107, about 2.5x107, about 3x107, about 3.5x107, about 4x107, about 4.5x107, about 5x107, about 5.5x107, about 6x107, about 6.5x107, about 7x107, about 7.5x107, about 8x107, about 8.5x107, about 9x107, about 9.5x107, about 1x108, about 1.5x108, about 2x108, about 2.5x108, about 3x108, about 3.5x108, about 4x108, about 4.5x108, about 5x108, about 5.5x108, about 6x108, about 6.5x108, about 7x108, about 7.5x108, about 8x108, about 8.5x108, about 9x108, about 9.5x108, about 1x109, about 1.5x109, about 2x109, about 2.5x1098, about 3x109, about 3.5x109, about 4x109, about 4.5x109, about 5x109, about 5.5x109, about 6x109, about 6.5x109, about 7x109, about 7.5x109, about 8x109, about 8.5x109, about 9x109, about 9.5x109, about 1x1010, about 1.5x1010, about 2x1010, about 2.5x1010, about 3x1010, about 3.5x1010, about 4x1010, about 4.5x1010, about 5x1010, about 5.5x1010, about 6x1010, about 6.5x1010, about 7x1010, about 7.5x1010, about 8x1010, about 8.5x1010, about 9x1010, about 9.5x1010, about 1x1011, about 1.5x1011, about 2x1011, about 2.5x1011, about 3x1011, about 3.5x1011, about 4x1011, about 4.5x1011, about 5x1011, about 5.5x1011, about 6x1011, about 6.5x1011, about 7x1011, about 7.5x1011, about 8x1011, about 8.5x1011, about 9x1011, about 9.5x1011, about 1x1012viral particles (vp). In some embodiments, a therapeutically effective amount or a prophylactically effective amount of a viral particle of the invention (or pharmaceutical composition of the invention) is in genome copies (“GC”), also referred to as “viral genomes” ("vg") ranging from about 1x105, about 1.5x105, about 2x105, about 2.5x105, about 3x105, about 3.5x105, about 4x105, about 4.5x105, about 5x105, about 5.5x105, about 6x105, about 6.5x105, about 7x105, about 7.5x105, about 8x105, about 8.5x105, about 9x105, about 9.5x105, about 1x106, about 1.5x106, about 2x106, about 2.5x106, about 3x106, about 3.5x106, about 4x106, about 4.5x106, about 5x106, about 5.5x106, about 6x106, about 6.5x106, about 7x106, about 7.5x106, about 8x106, about 8.5x10, about 9x106, about 9.5x106, about 1x107, about 1.5x107, about 2x107, about 2.5x107, about 3x107, about 3.5x107, about 4x107, about 4.5x107, about 5x107, about 5.5x107, about 6x107, about 6.5x107, about 7x107, about 7.5x107, about 8x107, about 8.5x107, about 9x107, about 9.5x107, about 1x108, about 1.5x108, about 2x108, about 2.5x108, about 3x108, about 3.5x108, about 4x108, about 4.5x108, about 5x108, about 5.5x108, about 6x108, about 6.5x108, about 7x108, about 7.5x108, about 8x108, about 8.5x108, about 9x108, about 9.5x108, about 1x109, about 1.5x109, about 2x109, about 2.5x1098, about 3x109, about 3.5x109, about 4x109, about 4.5x109, about 5x109, about 5.5x109, about 6x109, about 6.5x109, about 7x109, about 7.5x109, about 8x109, about 8.5x109, about 9x109, about 9.5x109, about 1x1010, about 1.5x1010, about 34 ME149103561v.1 117823-35920 2x1010, about 2.5x1010, about 3x1010, about 3.5x1010, about 4x1010, about 4.5x1010, about 5x1010, about 5.5x1010, about 6x1010, about 6.5x1010, about 7x1010, about 7.5x1010, about 8x1010, about 8.5x1010, about 9x1010, about 9.5x1010, about 1x1011, about 1.5x1011, about 2x1011, about 2.5x1011, about 3x1011, about 3.5x1011, about 4x1011, about 4.5x1011, about 5x1011, about 5.5x1011, about 6x1011, about 6.5x1011, about 7x1011, about 7.5x1011, about 8x1011, about 8.5x1011, about 9x1011, about 9.5x1011, about 1x1012vg. Any method known in the art can be used to determine the genome copy (GC) number of the viral compositions of the invention. One method for performing AAV GC number titration is as follows: purified AAV viral particle samples are first treated with DNase to eliminate un-encapsidated AAV genome DNA or contaminating plasmid DNA from the production process. The DNase resistant particles are then subjected to heat treatment to release the genome from the capsid. The released genomes are then quantitated by real-time PCR using primer / probe sets targeting specific region of the viral genome. In various embodiments, the methods of the present invention further comprise monitoring the effectiveness of treatment. For example, visual acuity, the rate of death of cone and / or rod cells, night vision, peripheral vision, attenuation of the retinal vessels, and other ophthalmoscopic changes associated with retinal disorders such as retinitis pigmentosa may be monitored to assess the effectiveness of treatment. Additionally, the rate of death of cells associated with the particular disorder that is the subject of treatment and / or prevention, may be monitored. Alternatively, the viability of such cells may be monitored, for example, as measured by phospholipid production. The assays described in the Examples section below may also be used to monitor the effectiveness of treatment (e.g., electroretinography – ERG). In certain embodiments of the invention, a composition of the invention is administered in combination with an additional therapeutic agent or treatment. The compositions and an additional therapeutic agent can be administered in combination in the same composition or the additional therapeutic agent can be administered as part of a separate composition or by another method described herein. Examples of additional therapeutic agents suitable for use in the methods of the invention include those agents known to treat retinal disorders, such as retinitis pigmentosa and age-related macular degeneration and include, for example, fat soluble vitamins (e.g., vitamin A, vitamin E, and ascorbic acid), calcium channel blockers (e.g., diltiazem) carbonic anhydrase inhibitors (e.g., acetazolamide and methazolamide), anti-angiogenics (e.g.,antiVEGF antibodies), growth factors (e.g., rod-derived cone viability factor (RdCVF), BDNF, CNTF, bFGF, and PEDF), antioxidants, other gene therapy agents (e.g., optogenetic gene threrapy, e.g., channelrhodopsin, melanopsin, and halorhodopsin), and compounds that drive photoreceptor regeneration by, e.g., reprogramming Müller cells into photoreceptor progenitors (e.g., alpha-aminoadipate). Exemplary treatments for use in combination with the treatment methods of the present invention include, for example, retinal and / or 35 ME149103561v.1 117823-35920 retinal pigmented epithelium transplantation, stem cell therapies, retinal prostheses, laser photocoagulation, photodynamic therapy, low vision aid implantation, submacular surgery, and retinal translocation. This invention is further illustrated by the following examples which should not be construed as limiting. The contents of all references, patents and published patent applications cited throughout this application, as well as the Figures and Sequence Listing, are hereby incorporated by reference. EXAMPLES The following Materials and Methods were used in the Examples below. 36 ME149103561v.1 117823-35920 The cone number of the central retina is defined as the counts of H2BGFP-positive cells within the central portion of the retina. Txnip deletions were cloned from the Txnip plasmid using Gibson assembly (Figure 4). The following sense strand sequences were used to knock down the Hsp90ab1: siHsp90ab1(#a) 5′- GCATCTACCGCATGATTAAAC-3′; siHsp90ab1(#b) 5′- CCAGAAGTCCATCTACTATAT-3′; siHsp90ab1(#c) 5′- CCTGAGTACCTCAACTTTATC-3′ Animals rd1 mice were the albino FVB strain, which carries the Pde6brd1 allele (MGI: 1856373). BALB / c, CD1, and FVB mice were purchased from Charles River Laboratories and from Taconic. C57BL / 6J, rd10, and parp1- / - mice were purchased from The Jackson Laboratories and bred in house. parp1- / - mice were crossed with FVB mice to generate homozygous parp1- / - rd1 and parp1+ / + rd1 mice. Genotyping of these mice was done by Transnetyx (Cordova, TN). The rho- / - mice were provided from by Lem (Tufts University, MA) (Lem et al., 1999). AAV vector design, authentication, and preparation cDNAs of mouse txnip, hif1a, hk2, ldha, ldhb, slc2a1, bsg1, cpt1a, oxct1, mpc1 and mpc2, and human nrf2, were purchased from GeneCopeia (Rockville, MD). Mouse vegf164 cDNA (Robinson and Stringer, 2001) was synthesized by Integrated DNA Technologies (Coralville, Iowa). The following plasmids were gifts from various depositors through Addgene (Watertown, MA): hk1, pfkm and pkm2 (William Hahn & David Root; #23730, #23728, #23757), pkm1 (Lewis Cantley & Matthew Vander Heiden; #44241), H2B-GFP (Geoff Wahl; #11680), mitoRFP (i.e. DsRed2-mito, Michael Davidson; #55838), GFP-Txnip (Clark Distelhorst; #18758), W3SL (Bong-Kiun Kaang; #61463), 3xFLAG (Thorsten Mascher, #55180), PercevalHR and pHRed (Gary Yellen; #490820, #31473). The cDNA of mouse RdCVF was a gift from Leah Byrne and John Flannery (UC Berkeley, CA). iGlucoSnFR was provided under a Material Transfer Agreement by Jacob Keller and Loren Looger (Janelia Research Campus, VA). RedO promoter was provided as a gift, and SynPVI and SynP136 promoters were provided under a Material Transfer Agreement, from Botond Roska (IOB, Switzerland). The Best1 promoter was synthesized by lab member, Wenjun Xiong, using Integrated 37 ME149103561v.1 117823-35920 DNA Technologies based on literature (Esumi et al., 2009). Mutated Txnip, dominant-negative HIF1α (Jiang et al., 1996) and RO1.7 promoter (Ye et al., 2016) were created from the corresponding wildtype plasmids in house using Gibson assembly. Subretinal injection On the day of birth (P0), ≈1 x 109vg / eye of AAV was injected into the eyes of pups as previously described(Matsuda and Cepko, 2007; Xiong et al., 2015). For all experiments in which cones were quantified, and to provide a means to trace infection (e.g. for immunohistochemistry), 2.5 x 108vg / eye of AAV8-RedO-H2BGFP was co-injected with other AAVs, or alone as a control. For all other experiments, such as FACS sorting and ex vivo live-imaging, 1 x 109vg / eye of AAV8- SynP136-H2BGFP was co-injected. Photopic visual acuity measured for optomotor response The photopic optomotor response of mice were measured using the OptoMotry System (CerebralMechanics) at a background light of ≈70 cd / m2as previously described (Xiong et al., 2019). The contrast of the grates was set to be 100%, and temporal frequency was 1.5 Hz. The threshold of mouse visual acuity (i.e. maximal spatial frequency) was tested by an examiner without knowledge of the injected or the treatment group. During each test, the direction of movement of the grates (i.e. clockwise or counterclockwise) was randomized, and the spatial frequency of each testing episode was determined by the software. Without knowing the spatial frequency of the moving grates, the examiner reported either “yes” or “no” to the system until the threshold of acuity was determined by the software. Histology Mice were euthanized with CO2and cervical dislocation, and the eye was enucleated. For flat- mounts, retinas were separated from the rest of the eye using a dissecting microscope and were fixed in 4% paraformaldehyde solution for 30 minutes. The retinas were then flat mounted on a glass slide and coverslip. For H2BGFP labeled cone imaging, we used a Keyence microscope with a 10x objective (Plan Apo Lamda 10x / 0.45 Air DIC N1) and GFP filter box (OP66836). For cone opsin antibody staining in whole-mount retinas, after fixation, retinas were blocked for 1 hour in PBS with 5% normal donkey serum and 0.3% Triton X-100 at room temperature. After blocking, retinas were incubated with a mixture of 1:200 anti-s-opsin antibody (AB5407, EMD Millipore) and 1:600 anti-m-opsin antibody (AB5405, EMD Millipore) in the same blocking solution overnight at 4oC, followed by secondary donkey-anti-rabbit antibody staining (1:1000, Alexa Fluor 594) at room temperature for 2 hours, then flat-mounted on a glass slide and coverslip. For frozen sections, whole eyes were fixed in 4% paraformaldehyde solution for 2 hours at room temperature, followed by removing the cornea, lens and iris. Then the eye cups went through 38 ME149103561v.1 117823-35920 15% and 30% sucrose gradient to dehydrate at room temperature, followed by overnight incubation in 1:130% sucrose and Tissue-Tek® O.C.T. solution at 4oC. Eye cups were embedded in a plastic mold, frozen in a -80oC freezer, and cut into 20 μm or 12 μm thin radial cross-sections which were placed on glass slides. Antibody staining was done similarly to whole-mounts as described above and previously (Wang et al., 2014). PBS with 0.1% Triton X-100, 5% normal donkey serum and 1% bovine serum albumin (BSA) was used as the blocking solution, except for FLAG detection (10% donkey serum and 3% BSA). Glut1 (encoded by slc2a1 gene) antibody (GT11-A, Alpha Diagnostics) was used at 1:300 dilution, Parp1 antibody (ab227244, Abcam) was used at 1:300 dilution, GFP antibody (ab13970, Abcam) was used at 1:1000 dilution to detect GFP-Txnip, and FLAG antibody (ab1257, Abcam) was used at 1:2000 based on a previous study(Ferrando et al., 2015). If applicable, 1:1000 PNA (CY5 or Rhodamine labeled) for cone extracellular matrix labeling, and 1:1000 DAPI were used to co-stain with secondary antibodies. Stained sections were imaged with a confocal microscope (LSM710, Zeiss) using 20x or 63x objectives (Plan Apo 20x / 0.8 Air DIC II, or Plan Apo 63X / 1.4 Oil DIC III). Automated RP cone counting The cone-H2BGFP images of whole flat-mounted retinas were first analyzed in ImageJ to acquire the diameter and the center parameters of the sample. We used a custom MATLAB script to automatically count the number of H2BGFP-positive cones in the central half of the retina, since RP cones degenerate faster in the central than the peripheral retina. The algorithm was based on a Gaussian model to identify the centers of labeled cells, and published recently (Wu et al., n.d.). The threshold of peak intensity and the variance of distribution were initially determined using visual inspection, and a comparison to the number of manually counted cones from 6 retinas. The threshold of intensity and variance thus determined were then set at fixed values for all the experiments that used cone quantification. The background intensity did not interfere with the accurate counting on the raw images by this MATLAB script, despite the representative images at low-magnification might look differently. Live-imaging of cones on ex vivo retinal explants For JC-1 mitochondrial dye staining, the retina was quickly dissected in a solution of 50% Ham's F-12 Nutrient Mix (11765054, Thermo Fisher Scientific) and 50% Dulbecco's Modified Eagle Medium (DMEM; 11995065, Thermo Fisher Scientific) at room temperature. They were then incubated in a culture solution containing 50% Fluorobrite DMEM (A1896701, Thermo Fisher Scientific), 25% heat inactivated horse serum (26050088, Thermo Fisher Scientific) and 25% Hanks' Balanced Salt Solution (HBSS; 14065056, Thermo Fisher Scientific) with 2 μM JC-1 dye (M34152, 39 ME149103561v.1 117823-35920 Thermo Fisher Scientific) at 37oC in a 5% CO2 incubator for 20 minutes. The retinas were washed in 37oC culture medium without JC-1 for three times, transferred in a glass-bottom culture dish (MatTek P50G-1.5-30-F) with culture medium, and imaged using a confocal microscope (LSM710 Zeiss), which was equipped with a chamber pre-heated to 37oC with pre-filled 5% CO2. Right before imaging, a cover slip (VWR 89015-725) was gently applied to flatten the retina. Regions of interest (with H2BGFP as an indicator of successful AAV infection and to set the correct focal plane on the cone layer) were selected under the eyepiece with a 63x objective (Plan Apo 63X / 1.4 Oil DIC III). Fluorescent images from the same region of interest were obtained with the excitation-wavelength in the order of 561 nm (for J-aggregates), 514 nm (for JC-1 monomer), and 488 nm (for H2BGFP). Four different regions of interest from the central part of the same retina were imaged before moving to the next retina. For RH421 (Na+ / K+ATPase dye) staining, similar steps were taken as for JC-1 staining, with the following modifications: 1) 0.83 μM RH421 dye (61017, Biotium) was added to the glass-bottom culture dishes just before imaging, but not during incubation in the incubator, due to the fast action of RH421.2) 5 regions of interest were imaged per retina from the central area.3) The dissection and culture medium were lactate-only medium (see below).4) Excitation wavelengths: 561 nm (RH421), and 488 nm (H2BGFP). For imaging genetically-encoded metabolic sensors (PercevalHR, iGlucoSnFR and pHRed), retinas were placed in the incubator for 12 minutes and then taken to confocal imaging without any staining. For the high-glucose condition, the culture medium described above contains ≈15 mM glucose without lactate or pyruvate. For the lactate-only condition, the culture and dissection media were both glucose-pyruvate-free DMEM (A144300, Thermo Fisher Scientific) and were supplemented with 20mM sodium L-lactate (71718, Sigma-Aldrich). For the pyruvate-only condition, the culture and dissection media, were both glucose-pyruvate-free DMEM plus 10 or 20 mM sodium pyruvate (P2256, Sigma-Aldrich). No AAV-H2BGFP was co-injected with these sensors, since the sensors themselves could be used to trace the area of infection. The excitation wavelengths for sensors were 488 nm and 405 nm (PercevalHR, ratiometric high and low ATP:ADP), 488 nm and 561 nm (iGlucoSnFR, glucose-sensing GFP and normalization mRuby), and 561 nm and 458 nm (pHRed, ratiometric low and high pH). The fluorescent intensity of all acquired images was measured by ImageJ. The ratio of sensors / dye was normalized to averaged control results taken at the same condition. Flow cytometry and cell sorting All flow cytometry and cell sorting were performed on MoFlo Astrios EQ equipment. Retinas were freshly dissected and dissociated using cysteine-activated papain followed by gentle pipetting (Shekhar et al., 2016). Before sorting, all samples were passed through a 35-μm filter with buffer containing Fluorobrite DMEM (A1896701, Thermo Fisher Scientific) and 0.4% BSA. Cones labeled 40 ME149103561v.1 117823-35920 with AAV8-SynP136-H2BGFP (highly cone-specific) were sorted into the appropriate buffer for either ddPCR or RNA-sequencing. RNA sequencing RNA sequencing was done as previously described (Wang et al., 2019).1,000 H2BGFP- positive cones per retina were sorted into 10 μL of Buffer TCL (Qiagen) containing 1% β- mercaptoethanol and immediately frozen in -80oC. On the day of sample submission, the frozen cone lysates were thawed on ice and loaded into a 96-well plate for cDNA library synthesis and sequencing. A modified Smart-Seq2 protocol was performed on samples by the Broad Institute Genomics Platform with ∼6 million reads per sample (Picelli et al., 2013). The reads were mapped to the GRCm38.p6 reference genome after quality control measures. Reads assigned to each gene were quantified using featureCounts (Liao et al., 2014). Count data were analyzed using DESeq2 to identify differentially expressed genes, with an adjusted p value less than 0.05 considered significant(Anders and Huber, 2010). The raw results have been deposited to Gene Expression Omnibus (accession number GSE161622). Electron microscopy Intracardial perfusion (4% PFA+1% glutaraldehyde) was performed on ketamine / xylazine (100 / 10 mg / kg) anesthetized mice before the removal of eyes. The cornea was sliced open and the eye was fixed with a fixative buffer (1.25% formaldehyde+ 2.5 % glutaraldehyde + 0.03% picric acid in 0.1 M sodium cacodylate buffer, pH 7.4) overnight at 4oC. The cornea, lens and retina were removed before resin embedding, ultrathin sectioning and negative staining at Harvard Medical School Electron Microscopy Core. The detailed methods can be found on the core’s website (https: / / electron- microscopy.hms.harvard.edu / methods). The stained thin sections were imaged on a conventional transmission electron microscope (JEOL 1200EX) with an AMT 2k CCD camera. Statistics For the comparison of two sample groups, two-tailed unpaired Student’s t test was used to test for the significance of difference, except for P140 rho- / -optomotor assay (paired two-tail t-test). For comparison of more than two sample groups, ANOVA and Dunnett's multiple comparison test was performed in Prism 8 software to determine the significance. A p value of less than 0.05 was considered statistically significant. All error bars are presented as mean ± standard deviation, except for the rd10 optomotor assays (mean ± SEM). EXAMPLE1: TXNIP DELETIONS AND MISSENSE ALLELES PROLONG THE SURVIVAL OF CONES IN ARETINITIS PIGMENTOSA MOUSE MODEL Introduction and Summary 41 ME149103561v.1 117823-35920 Retinitis pigmentosa (RP) is an inherited retinal degenerative disease that affects one in ~4,000 people worldwide (Hartong et al.2006). The disease first manifests as poor night vision, likely due to the fact that many RP disease genes are expressed in rod photoreceptors, which initiate night vision. Cone photoreceptors, which are required for daylight, color and high acuity vision, also are affected, so are the retina pigmented epithelial (RPE) cells (Chrenek et al.2012; Wu et al.2021; Napoli et al.2021; Napoli and Strettoi 2022), which support both rod and cone photoreceptors. However, cones and RPE cells typically do not express RP disease genes. Nonetheless, RP cones lose function and die after most of the rods in their immediate neighborhood die. While it is not entirely clear what causes cone death, there are data suggesting problems with metabolism, oxidative stress, lack of trophic factors, oversupply of chromophore, and inflammation (Mohand-Said et al.1998; Komeima et al.2006; Punzo et al.2009; Zhao et al.2015; Xue et al.2023). We have been pursuing gene therapy to address some of these problems. Our hope is to create therapies that are disease-gene agnostic by targeting common problems for cones across disease-gene families. One of our strategies is aimed at cone metabolism. Several lines of evidence suggest that RP cones do not have enough glucose, their main fuel source (Reviewed in Xue and Cepko 2023). We found that overexpression of Txnip, an α-arrestin protein with multiple functions, including glucose metabolism, prolonged the survival of cones and cone-mediated vision in three RP mouse strains (Xue et al.2021). Regarding the mechanism of rescue, we found that it relied upon the use of lactate as a fuel source by cones. In addition, cones treated with Txnip showed improved mitochondrial morphology and function. As Txnip is known to bind directly to thioredoxin, we tested a Txnip allele with a single amino acid (aa) change, C247S, which abolishes the interaction with thioredoxin (Patwari et al.2006). This allele provided better rescue than the wildtype (wt) Txnip allele, ruling out its interaction with thioredoxin as required for cone rescue. These findings inspired us to further modify Txnip in various ways to look for better rescue, as well as to explore potential mechanisms for Txnip's action in cones. To this end, we also tested a related α-arrestin protein, as well as an interacting partner, for rescue effects. As indicated above, it was previously demonstrated that that Txnip can delay the non- autonomous death of RP cones by switching the fuel from glucose to lactate via LDHB. However, the exact molecular mechanism is not well understood. Txnip is a member of alpha-arrestin proteins, and this protein family is best known for inhibiting other protein through direct binding. Based on a previous study (Forred et al., 2016; PMID: 27437069), a list of proteins that interact with Txnip was identified. Forred et al. also identified a subset of proteins that interact with Txnip.C247S, which is a mutant that provides better RP cone rescue than wildtype Txnip allele. It was known that Txnip switches the cells from “glycolytic” to “mitochondrial”, thus it was determined if any of the Txnip.C247S-interative proteins listed by Forred et al. was related to “mitochondria”. Two proteins PARP1 and HSP90AB1 were identified from this literature search. Because it was ruled out that PARP1-inhibition is sufficient to rescue RP cones (Xue et al., 2021, eLife), the effect of HSP90AB1-inhibition was focused on. Hsp90ab1 knockdown was 42 ME149103561v.1 117823-35920 shown to improve skeletal muscle mitochondrial metabolism in a diabetes mouse model (Jing et al., 2018, PMID: 29434648) As described herein, shRNAs inhibiting expression of Hsp90ab1 (siHsp90ab1) targeting at different parts of the mRNA were cloned into a cone-specific promoter (RedO), packaged into AAV8 capsid, and tested with a FLAG-tagged Hsp90ab1 vector (AAV8-RO1.7-Hsp90ab1-FLAG) in wildtype mouse retina. All three shRNAs reduced the Hsp90ab1-FLAG signals compared to the siNC, the non-targeting control shRNA (Figure 4A&B), demonstrating that they are able to inhibit the expression of HSP90AB1 protein in vivo. Then, the efficacy of these shRNAs with rd1 mice, which is a RP strain, were tested. It was found that siHsp90ab1#a and siHsp90ab1#c increased the survival of the rd1 cones at P50 (Figure 4C&D). The data also showed an additive effect of siHsp90ab1 and Txnip.C247S in rescuing RP cones (Figure 4E&F). In addition, no any rescue effect on a PARP1- deficient background with siHSP90ab1 (Figure 4G&H) was observed. The results described herein demonstrate that inhibiting Hsp90ab1 expression by shRNA knockdown is beneficial for RP cone survival. This rescue may also be combined with Txnip.C247S vector to provide additive benefits. Results Arrdc4 reduces rd1 cone survival As Txnip is a member of the α-arrestin protein family, we explored whether another family member might prolong RP cone survival. There are six known α-arrestins in mammals (Puca and Brou 2014). Among them, arrestin domain containing protein 4 (Arrdc4) is the closest to Txnip in amino acid sequence, sharing ~60% similar amino acids with Txnip (Figure 1A). Arrdc4 is thought to have functions that are similar to those of Txnip in regulating glucose metabolism in vitro (Patwari et al.2009; Dagdeviren et al.2020). Like Txnip and other α-arrestins, Arrdc4 is composed of three parts: a N-terminal arrestin (Arrestin N-) domain, a C-terminal arrestin (Arrestin C-) domain, and an intrinsically disordered region (IDR) at the C-terminus. Because an IDR lacks a stable 3D structure under physiological conditions, previous studies using crystallography did not reveal the full structure of the TXNIP protein (Hwang et al.2014). None of the other α-arrestins have been characterized structurally. To begin to examine potential similarities in structure among some of these family members, we utilized an artificial intelligence (AI) algorithm, AlphaFold-2, to visualize the predicted 3D full structure of ARRDC4 (Jumper et al.2021). Similar to TXNIP, ARRDC4 is predicted to have a “W” shaped arrestin structure, which is composed of the Arrestin N- and C-domains, plus a long IDR which looks like a tail (Figure 1B). Arrdc4 was tested for its ability to prolong cone survival in rd1 mice using AAV-mediated gene delivery, as was done for Txnip previously (Xue et al.2021). Expression of Arrdc4 was driven by a cone-specific promoter, RO1.7, derived from human red opsin (Wang et al.1992; Busskamp et al.2010; Ye et al.2016). The vector was packaged into the AAV8 serotype capsid. AAV-Arrdc4 was 43 ME149103561v.1 117823-35920 injected sub-retinally into P0 rd1 mouse eyes along with AAV-H2BGFP, which is used to trace the infection and to label the cone nuclei for counting. At P50, the treated retinas were harvested and flat- mounted for further quantification of cones within the central retina, the area that first degenerates. Unlike Txnip, the cone counts were much lower in Arrdc4 treated retina relative to the AAV- H2BGFP control (Figure 1C&D). Evaluation of cone survival using Txnip deletion alleles expressed in the RPE We previously showed that overexpressing the Txnip wt allele in the RPE using an RPE- specific promoter, derived from the Best1 gene (Esumi et al. 2009), did not improve RP cone survival. The wt allele removes the glucose transporter from the plasma membrane, thus preventing the RPE from taking up glucose for its own metabolism, and preventing it from serving as a conduit for glucose to flow from the blood to the cones. However, a double mutant, Txnip.C247S.LL351 and 352AA, improved cone survival when expressed only in the RPE. The C247S mutation eliminates the interaction with thioredoxin, and enhances the Txnip rescue when expressed in cones (Xue et al. 2021). The LL351 and 352AA mutations eliminate a clathrin-binding site, which reduces the ability of Txnip to remove the glucose transporter member 1 (GLUT1, encoded by Slc2a1 gene) from the cell surface (Wu et al.2013). Accordingly, we proposed a model in which Txnip.C247S.LL351 and 352AA promotes the use of lactate by the RPE, as we found was the case when Txnip was expressed in cones. Although the RPE normally uses lactate in wt animals, in RP, it is hypothesized that it retains the glucose that it normally would deliver to cones (Reviewed in Hurley 2021). The retention of glucose by the RPE is thought to be due to a reduction in lactate supply, as rods normally provide lactate for the RPE, and with rod loss that source would be greatly diminished. If the RPE can utilize lactate in RP, perhaps using lactate supplied by the blood, and the LL351 and 352AA mutation impairs the ability of Txnip to remove the glucose transporter from the plasma membrane, this allele of Txnip may then allow glucose to flow from the blood to the cones via the GLUT1 transporter. The expression of Txnip.C247S.LL351 and 352AA allele thus has the potential to address the proposed glucose shortage of RP cones. However, we noted two caveats. One is that survival of cones was not as robust as when Txnip was expressed directly in cones. In addition, the rd1 retina in the FVB strain used here, even without any treatment, shows holes in the cone layer, which appear as “craters”. When Txnip.C247S.LL351 and 352AA is expressed in the RPE, there are more craters in the photoreceptor layer. We note that these craters are common only in the rd1 allele on the FVB background, i.e. not as common on other inbred mouse strains that also harbor the rd1 allele. Arrestins are well-known for their protein-protein interactions via different domains. Different regions of Txnip are known to physically bind to different protein partners to affect several different functions. For example, the N-terminus is sufficient to interact with KPNA2 for Txnip’s localization to the nucleus (Nishinaka et al.2004), while the C-terminus of Txnip is critical for interactions with COPS5, to inhibit cancer cell proliferation (Jeon et al.2005). The C-terminus of 44 ME149103561v.1 117823-35920 Txnip is also necessary for inhibition of glycolysis, at least in vitro, through an unclear mechanism (Patwari et al.2009). Based on these studies, we made several deletion alleles of Txnip, and expressed them in the RPE. We assayed their ability to clear GLUT1 from the RPE surface (Figure 2A), as well as promote cone survival (Figure 2B-G). The 149-397aa portion of Txnip.C247S (C.Txnip.C247S) had the highest activity for GLUT1 removal from the RPE surface in vivo. As predicted by ColabFold, an AI algorithm based on AlphaFold-2 (Mirdita et al.2022), the Arrestin C-domain of Txnip, which is part of C.Txnip.C247S, interacts with the intracellular C-terminal IDR of GLUT1 (Figure 2-figure supplement 1). These results suggest that the C-terminal portion of Txnip is sufficient to bind and clear GLUT1 from cell surface. Cone survival was assayed in vivo following infection of rd1 with these missense and deletion alleles at P0 and sacrifice at P50 (Figure 2B-G). Best1-Txnip.C247S, Best1-N.Txnip (1- 228aa), and Best1-sC.Txnip (255-397aa, sC: short C-) did not show significant improvement in cone survival. However, Best1-C.Txnip.C247S (149-397aa), Best1-C.Txnip.C247S.LL351 and 352AA (149-397aa), and Best1-nt.Txnp.C247S320 (1-320aa, nt: no-tail) promoted significant cone survival compared to the corresponding control retinas. Best1-N.Txnip and Best1-sC.Txnip treated rd1 retina did not have increased numbers of craters, while all other vectors increased the number of craters. These results suggest that the C-terminal portion of Txnip expressed in the RPE is required for RP cone survival, for a function(s) that is unrelated to the removal of GLUT1 or to the mechanism that leads to an increase in craters. Evaluation of Txnip deletions for autonomous cone survival Our previous study used the human red opsin promoter, "RedO", in AAV to drive the expression of Txnip in rd1 cones, with some low level of expression in some rods. This same strategy was used to evaluate whether the aforementioned deletion alleles of Txnip could prolong cone survival. Neither N.Txnip (1-228aa) nor C.Txnip.C247S (149-397aa) promoted significant improvement in rd1 cone survival. However, nt.Tnxip.C247S301 (1-301aa) and nt.Txnip.C247S320 (1-320aa) promoted survival of rd1 cones: 47% and 63% more cones than the control GFP virus, respectively (Figure 3A&B). In comparison, the full-length Txnip.C247S promoted an increase of 97% in cones in our previous study (Xue et al.2021). These results show that the full-length Txnip provides the most benefit in terms of RP cone survival. To determine if expression of this allele might give increased survival when expressed in both the RPE and in cones, we used a CMV promoter to drive expression, as CMV expresses highly in both cell types (Xiong et al.2015). CMV-Txnip.C247S provided a 38% rescue (Figure 3A&C), which is lower than RedO-Txnip.C247S (97%) alone. These and previous results are summarized in Figure 4. 45 ME149103561v.1 117823-35920 Inhibiting Hsp90ab1 prolongs rd1 cone survival To further investigate the potential mechanism(s) of cone survival induced by Txnip, we considered the list of protein interactors that were identified in HEK293 cells using biotinylated protein interaction pull-down assay plus mass spectrometry (Forred et al.2016). Forred et al. identified a subset of proteins that interact with Txnip.C247S, the mutant that provides better cone rescue than the wt Txnip allele (Xue et al.2021). As we found that Txnip promotes the use of lactate in cones, and improves mitochondrial morphology and function, we looked for Txnip interactors that are relevant to mitochondria. We identified two candidates, PARP1 and HSP90AB1. PARP1 mutants have been shown to protect mitochondria under stress (Szczesny et al.2014; Hocsak et al.2017). Accordingly, in our previous study, we crossed the null PARP1 mice with rd1 mice, to ask if mitochondrial improvements alone were sufficient to induce cone rescue. We found that it was not. In our current study, we thus prioritized HSP90AB1 inhibition, which had been shown to improve skeletal muscle mitochondrial metabolism in a diabetes mouse model (Jing et al.2018). Three shRNAs targeting different regions of the mRNA of Hsp90ab1 (shHsp90ab1) were delivered by AAV into the retinas of wt mice. Knock-down was evaluated using an AAV encoding a FLAG-tagged Hsp90ab1 that was co-injected with the AAV-shRNA. All three shRNAs reduced the HSP90AB1-FLAG signal compared to the shNC, the non-targeting control shRNA (Figure 5A&B), suggesting that they are able to inhibit the expression of HSP90AB1 protein in vivo. The promotion of cone survival was then tested in rd1 mice using these shRNA constructs. The two shRNAs with the most activity in reducing the FLAG-tagged HSP90AB1 signal, shHsp90ab1(#a) and shHsp90ab1(#c), were found to increase the survival of rd1 cones at P50 (Figure 5C&D). To determine if this effect was capable of increasing the Txnip effect, the shRNAs were co-injected with Txnip.C247S. A slight additive effect of shHsp90ab1 and Txnip.C247S was observed (Figure 5E&F). We also asked if there might be an effect of the knock-down of Hsp90ab1 on a Parp1 loss of function background. We did not observe any rescue effect of the shRNAs on this background (Figure 5G&H). Discussion In RP, the RPE cells and cones degenerate due to non-autonomous causes after the death of rods. Although the causes of cone death are not entirely clear, one model proposes that they do not have enough glucose, their main fuel source (Punzo et al.2009; Hurley 2021; Xue and Cepko 2023). In a previous study, we found that Txnip promoted the use of lactate within cones and led to healthier mitochondria. The mechanisms for these effects are unclear, and we sought to determine what domains of Txnip might contribute to these effects, as well as explore alleles of Txnip that might be more potent for cone survival. We further tested the rescue effects of several alleles when expressed in the RPE, a support layer for cones, through which nutrients, such as glucose, flow to the cones from the choriocapillaris. The results suggest that Txnip has different mechanisms for Txnip-mediated cone survival when expressed in the RPE versus in cones. 46 ME149103561v.1 117823-35920 The C-terminal portion of Txnip.C247S (149-397aa) expressed within the RPE, but not within cones, delayed the degeneration of cones (Figure 2). The full length Txnip.C247S expressed within cones, but not within the RPE, was the most effective configuration for cone survival (Figure 3). The expression of full length Txnip.C247S in both the RPE and cones did not provide better rescue than in cones alone. As Txnip has several domains, that presumably interact with different partners, it is possible that these different effects on cone survival are due to the interaction of different Txnip domains with different partners in the RPE versus the cones, or different results from the interactions of the same domains and partners in the two cell types. The N-terminal half of Txnip (1-228aa) might exert harmful effects in the RPE, that negate the beneficial effects from the C-terminal half. This hypothesis is supported by the observation that N.Txnip led to an obvious thinning of the outer nuclear layer of the wt retina, reflecting a loss of photoreceptors (Figure 2A). A negative effect of the N-terminal half of Txnip in the RPE is further supported by the observation that its removal, in the C- terminal 149-397 allele, led to better cone survival when expressed in the RPE. In cones, the C- terminal half, including the C-terminal IDR tail, may cooperate with the N-terminal half, or negate its negative effects, to benefit RP cone survival. However, the C-terminal half is not sufficient for cone rescue when expressed in cones, as the 149-397 allele did not rescue. The C-terminal half of Txnip apparently affects cone survival differently when expressed within the two cell types. This notion is informed by the different rescue effects of expression of the 149-397 allele, which rescues cones when expressed in the RPE, but not when expressed in cones. This domain loses the cone rescue activity if it loses aa 149-254, when expressed in the RPE, as shown by the 255-397 allele. In cones, the rescue activity is present in the 1-301 and the 1-320 allele, but is lost in the 149-397 allele. It is possible that effects on protein structure cause this loss, or that an interaction between N-terminal and C-terminal domains are required for cone rescue within cones. One Txnip function that likely is important to these effects in the two cell types is Txnip’s removal of the glucose transporter from the plasma membrane. The LLAA Txnip mutant is unable to effectively remove the transporter, due to its loss of interaction with clathrin. When this mutant allele is expressed in the RPE, it leads to improved cone survival, in contrast to the wt allele. This might be due to better health in the RPE, when it is able to take up glucose to fuel its own metabolism, and / or to provide glucose to cones. When the LLAA allele is expressed in cones, it also promotes cone survival, though not as well as the wt allele (Xue et al.2021). The wt allele might be more beneficial in cones if it is part of the mechanism that forces cones to rely more heavily on lactate vs. glucose. All of these observations of cone rescue from expression within cones suggest that cone rescue relies on activities that reside in both the N and C-terminal portions, including the ability of Txnip to interact with clathrin. However, it will be important to probe structural alterations and stability of Txnip in cones and RPE when these various alleles are expressed to further support these hypotheses. Regarding potential protein interactions beyond the glucose transporter, the interaction of Txnip with thioredoxin is apparently negative, as we found in our previous study with the C247S 47 ME149103561v.1 117823-35920 allele. This is most easily understood by the release of thioredoxin from Txnip, whereupon it can play its anti-oxidation role, which would be important in the RP retina which exhibits oxidative damage. It also would free Txnip to interact with other partners. Another partner interaction suggested by previous studies and explored here is the interaction with HSP90AB1 (Figure 5). Knocking down Hsp90ab1 improved mitochondrial metabolism of skeletal muscle in a diabetic mouse model (Jing et al.2018). Here we found that it enhanced cone survival in rd1 mice. This rescue seems to be dependent on PARP1, another binding partner of Txnip. As shown by PARP1 knock out mice, PARP1 is deleterious to mitochondrial heath under stressful conditions (Szczesny et al.2014; Hocsak et al.2017; Xue et al.2021). When we examined a possible rescue effect of PARP1 loss on rd1 cone survival, we did not see a benefit, indicating that the Txnip-mediated rescue is not due solely to its beneficial effects on mitochondria, nor does Txnip-mediated rescue rely upon PARP1 (Xue et al. 2021). These results indicate that the Txnip rescue is more complex than inhibition of HSP90AB1, and a PARP1-independent mechanism is involved. 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EMBO Mol Med 7:1179–1197. https: / / doi.org / 10.15252 / emmm.201505298 51 ME149103561v.1 117823-35920 Partial List of Sequences Disclosed in the Application and Informal Sequence Listing SEQ ID NO:1 >NP_006463.3 thioredoxin-interacting protein isoform 1 [Homo sapiens] SEQ ID NO:2 >NP_001300901.1 thioredoxin-interacting protein isoform 2 [Homo sapiens] SEQ ID NO:3 >NP_001009935.1 thioredoxin-interacting protein isoform 1 [Mus musculus] SEQ ID NO:4 >NP_076208.2 thioredoxin-interacting protein isoform 2 [Mus musculus] SEQ ID NO::8 >NG_009105.2 Homo sapiens opsin 1, long wave sensitive (OPN1LW), RefSeqGene on chromosome X SEQ ID NO:9 >NC_000001.11:c109619929-109602906 Homo sapiens chromosome 1, GRCh38.p12 Primary Assembly SEQ ID NO:10 WPRE SEQ ID NO:11 WPRE SEQ ID NO:12 Human beta-globin intron SEQ ID NO:13 SV40 poly-adenylation (polyA) SEQ ID NO:14 5’ ITR SEQ ID NO:15 3’ ITR SEQ ID NO:16 >KT886395.1 Homo sapiens clone PR1.7 red cone opsin gene, promoter region and partial cds SEQ ID NO:17 >hg38_knownGene_ENST00000351050.7 range=chr1:109613058-1096150575'pad=03'pad=0 strand=- repeatMasking=none SEQ ID NO:18 SynPVI: SEQ ID NO:19 SynP136: SEQ ID NO:20 SV40 Intron SEQ ID NO:21 2A SEQ ID NO:22 P2A 52 ME149103561v.1 117823-35920 SEQ ID NO:23 T2a SEQ ID NO:24 E2a SEQ ID NO:25 Bovine Growth Hormone Polyadenylation Signal (BGH pA) SEQ ID NO:101 >NM_006472.6 Homo sapiens thioredoxin interacting protein (TXNIP), transcript variant 1, mRNA SEQ ID NO:102 >NM_001313972.2 Homo sapiens thioredoxin interacting protein (TXNIP), transcript variant 2, mRNA SEQ ID NO:103 >NM_001009935.2 Mus musculus thioredoxin interacting protein (Txnip), transcript variant 1, mRNA SEQ ID NO:104 >NM_023719.2 Mus musculus thioredoxin interacting protein (Txnip), transcript variant 2, mRNA SEQ ID NO:105 >NP_006463.3 thioredoxin-interacting protein isoform 1 [Homo sapiens] SEQ ID NO:106 >NP_001300901.1 thioredoxin-interacting protein isoform 2 [Homo sapiens] SEQ ID NO:107 >NP_001009935.1 thioredoxin-interacting protein isoform 1 [Mus musculus] SEQ ID NO:108 >NP_076208.2 thioredoxin-interacting protein isoform 2 [Mus musculus] SEQ ID NO:115 >TXNIP.C247S.LL351&352AA SEQ ID NO:116 >Mouse HIF1a SEQ ID NO:117 >Dominant-negative HIF1alpha SEQ ID NO:118 Homo sapiens bestrophin 1 (BEST1), RefSeqGene on chromosome 11 NCBI Reference Sequence: NG_009033.1 >NG_009033.1 Homo sapiens bestrophin 1 (BEST1), RefSeqGene on chromosome 11 SEQ ID NO:119 >RO1.7 sequence (modified hRedO promoter) SEQ ID NO:120 >-C.Txnip.C247S sequence SEQ ID NO: 121 >-C.Txnip.C247S.LL351&352AA sequence 53 ME149103561v.1 117823-35920 SEQ ID NO: 122 AAV-Best1-C.Txnip.C247S SEQ ID NO: 123 AAV-Best1-C.Txnip.C247S.LL351&352AA SEQ ID NO: 124 AAV-RedO-C.Txnip.C247S <160> 168 <170> PatentIn version 3.5 <210> 1 <211> 391 <212> PRT <213> Homo sapiens <400> 1 Met Val Met Phe Lys Lys Ile Lys Ser Phe Glu Val Val Phe Asn Asp 1 5 10 15 Pro Glu Lys Val Tyr Gly Ser Gly Glu Lys Val Ala Gly Arg Val Ile 20 25 30 Val Glu Val Cys Glu Val Thr Arg Val Lys Ala Val Arg Ile Leu Ala 35 40 45 Cys Gly Val Ala Lys Val Leu Trp Met Gln Gly Ser Gln Gln Cys Lys 50 55 60 Gln Thr Ser Glu Tyr Leu Arg Tyr Glu Asp Thr Leu Leu Leu Glu Asp 65 70 75 80 Gln Pro Thr Gly Glu Asn Glu Met Val Ile Met Arg Pro Gly Asn Lys 85 90 95 Tyr Glu Tyr Lys Phe Gly Phe Glu Leu Pro Gln Gly Pro Leu Gly Thr 100 105 110 Ser Phe Lys Gly Lys Tyr Gly Cys Val Asp Tyr Trp Val Lys Ala Phe 115 120 125 Leu Asp Arg Pro Ser Gln Pro Thr Gln Glu Thr Lys Lys Asn Phe Glu 130 135 140 Val Val Asp Leu Val Asp Val Asn Thr Pro Asp Leu Met Ala Pro Val 145 150 155 160 Ser Ala Lys Lys Glu Lys Lys Val Ser Cys Met Phe Ile Pro Asp Gly 165 170 175 Arg Val Ser Val Ser Ala Arg Ile Asp Arg Lys Gly Phe Cys Glu Gly 180 185 190 Asp Glu Ile Ser Ile His Ala Asp Phe Glu Asn Thr Cys Ser Arg Ile 195 200 205Val Val Pro Lys Ala Ala Ile Val Ala Arg His Thr Tyr Leu Ala Asn210 215 220 Gly Gln Thr Lys Val Leu Thr Gln Lys Leu Ser Ser Val Arg Gly Asn 225 230 235 240 His Ile Ile Ser Gly Thr Cys Ala Ser Trp Arg Gly Lys Ser Leu Arg 245 250 255 Val Gln Lys Ile Arg Pro Ser Ile Leu Gly Cys Asn Ile Leu Arg Val 260 265 270 Glu Tyr Ser Leu Leu Ile Tyr Val Ser Val Pro Gly Ser Lys Lys Val 275 280 285 Ile Leu Asp Leu Pro Leu Val Ile Gly Ser Arg Ser Gly Leu Ser Ser 290 295 300 Arg Thr Ser Ser Met Ala Ser Arg Thr Ser Ser Glu Met Ser Trp Val 305 310 315 320 Asp Leu Asn Ile Pro Asp Thr Pro Glu Ala Pro Pro Cys Tyr Met Asp 325 330 335Val Ile Pro Glu Asp His Arg Leu Glu Ser Pro Thr Thr Pro Leu Leu 340 345 350 Asp Asp Met Asp Gly Ser Gln Asp Ser Pro Ile Phe Met Tyr Ala Pro 355 360 365 Glu Phe Lys Phe Met Pro Pro Pro Thr Tyr Thr Glu Val Asp Pro Cys 54 ME149103561v.1 117823-35920 370 375 380 Ile Leu Asn Asn Asn Val Gln 385 390 <210> 2 <211> 336 <212> PRT <213> Homo sapiens <400> 2 Met Pro Pro Lys His Ser Leu Ser His Arg Cys Ile Leu Ser Val Thr1 5 10 15Ala Ser Leu Met Ala Thr Arg Phe Ser Phe Pro Ser Gly Glu Asn Glu 20 25 30 Met Val Ile Met Arg Pro Gly Asn Lys Tyr Glu Tyr Lys Phe Gly Phe 35 40 45 Glu Leu Pro Gln Gly Pro Leu Gly Thr Ser Phe Lys Gly Lys Tyr Gly 50 55 60 Cys Val Asp Tyr Trp Val Lys Ala Phe Leu Asp Arg Pro Ser Gln Pro 65 70 75 80 Thr Gln Glu Thr Lys Lys Asn Phe Glu Val Val Asp Leu Val Asp Val 85 90 95 Asn Thr Pro Asp Leu Met Ala Pro Val Ser Ala Lys Lys Glu Lys Lys 100 105 110 Val Ser Cys Met Phe Ile Pro Asp Gly Arg Val Ser Val Ser Ala Arg 115 120 125 Ile Asp Arg Lys Gly Phe Cys Glu Gly Asp Glu Ile Ser Ile His Ala 130 135 140 Asp Phe Glu Asn Thr Cys Ser Arg Ile Val Val Pro Lys Ala Ala Ile 145 150 155 160 Val Ala Arg His Thr Tyr Leu Ala Asn Gly Gln Thr Lys Val Leu Thr 165 170 175 Gln Lys Leu Ser Ser Val Arg Gly Asn His Ile Ile Ser Gly Thr Cys 180 185 190 Ala Ser Trp Arg Gly Lys Ser Leu Arg Val Gln Lys Ile Arg Pro Ser 195 200 205Ile Leu Gly Cys Asn Ile Leu Arg Val Glu Tyr Ser Leu Leu Ile Tyr210 215 220 Val Ser Val Pro Gly Ser Lys Lys Val Ile Leu Asp Leu Pro Leu Val 225 230 235 240 Ile Gly Ser Arg Ser Gly Leu Ser Ser Arg Thr Ser Ser Met Ala Ser 245 250 255 Arg Thr Ser Ser Glu Met Ser Trp Val Asp Leu Asn Ile Pro Asp Thr 260 265 270 Pro Glu Ala Pro Pro Cys Tyr Met Asp Val Ile Pro Glu Asp His Arg 275 280 285 Leu Glu Ser Pro Thr Thr Pro Leu Leu Asp Asp Met Asp Gly Ser Gln 290 295 300 Asp Ser Pro Ile Phe Met Tyr Ala Pro Glu Phe Lys Phe Met Pro Pro 305 310 315 320 Pro Thr Tyr Thr Glu Val Asp Pro Cys Ile Leu Asn Asn Asn Val Gln 325 330 335<210> 3 <211> 397 <212> PRT <213> Mus musculus <400> 3 Met Val Met Phe Lys Lys Ile Lys Ser Phe Glu Val Val Phe Asn Asp 1 5 10 15 Pro Glu Lys Val Tyr Gly Ser Gly Glu Lys Val Ala Gly Arg Val Ile 20 25 30 Val Glu Val Cys Glu Val Thr Arg Val Lys Ala Val Arg Ile Leu Ala 35 40 45 55 ME149103561v.1 117823-35920 Cys Gly Val Ala Lys Val Leu Trp Met Gln Gly Ser Gln Gln Cys Lys 50 55 60 Gln Thr Leu Asp Tyr Leu Arg Tyr Glu Asp Thr Leu Leu Leu Glu Glu 65 70 75 80 Gln Pro Thr Ala Gly Glu Asn Glu Met Val Ile Met Arg Pro Gly Asn 85 90 95 Lys Tyr Glu Tyr Lys Phe Gly Phe Glu Leu Pro Gln Gly Pro Leu Gly 100 105 110 Thr Ser Phe Lys Gly Lys Tyr Gly Cys Val Asp Tyr Trp Val Lys Ala 115 120 125Phe Leu Asp Arg Pro Ser Gln Pro Thr Gln Glu Ala Lys Lys Asn Phe 130 135 140 Glu Val Met Asp Leu Val Asp Val Asn Thr Pro Asp Leu Met Ala Pro 145 150 155 160 Val Ser Ala Lys Lys Glu Lys Lys Val Ser Cys Met Phe Ile Pro Asp 165 170 175 Gly Arg Val Ser Val Ser Ala Arg Ile Asp Arg Lys Gly Phe Cys Glu 180 185 190 Gly Asp Asp Ile Ser Ile His Ala Asp Phe Glu Asn Thr Cys Ser Arg 195 200 205 Ile Val Val Pro Lys Ala Ala Ile Val Ala Arg His Thr Tyr Leu Ala 210 215 220 Asn Gly Gln Thr Lys Val Phe Thr Gln Lys Leu Ser Ser Val Arg Gly 225 230 235 240 Asn His Ile Ile Ser Gly Thr Cys Ala Ser Trp Arg Gly Lys Ser Leu 245 250 255 Arg Val Gln Lys Ile Arg Pro Ser Ile Leu Gly Cys Asn Ile Leu Lys 260 265 270 Val Glu Tyr Ser Leu Leu Ile Tyr Val Ser Val Pro Gly Ser Lys Lys 275 280 285 Val Ile Leu Asp Leu Pro Leu Val Ile Gly Ser Arg Ser Gly Leu Ser 290 295 300 Ser Arg Thr Ser Ser Met Ala Ser Arg Thr Ser Ser Glu Met Ser Trp 305 310 315 320Ile Asp Leu Asn Ile Pro Asp Thr Pro Glu Ala Pro Pro Cys Tyr Met325 330 335 Asp Ile Ile Pro Glu Asp His Arg Leu Glu Ser Pro Thr Thr Pro Leu 340 345 350 Leu Asp Asp Val Asp Asp Ser Gln Asp Ser Pro Ile Phe Met Tyr Ala 355 360 365 Pro Glu Phe Gln Phe Met Pro Pro Pro Thr Tyr Thr Glu Val Asp Pro 370 375 380 Cys Val Leu Asn Asn Asn Asn Asn Asn Asn Asn Val Gln 385 390 395 <210> 4 <211> 396 <212> PRT <213> Mus musculus <400> 4Met Val Met Phe Lys Lys Ile Lys Ser Phe Glu Val Val Phe Asn Asp1 5 10 15 Pro Glu Lys Val Tyr Gly Ser Gly Glu Lys Val Ala Gly Arg Val Ile 20 25 30 Val Glu Val Cys Glu Val Thr Arg Val Lys Ala Val Arg Ile Leu Ala 35 40 45 Cys Gly Val Ala Lys Val Leu Trp Met Gln Gly Ser Gln Gln Cys Lys 50 55 60 Gln Thr Leu Asp Tyr Leu Arg Tyr Glu Asp Thr Leu Leu Leu Glu Glu 65 70 75 80 Gln Pro Thr Gly Glu Asn Glu Met Val Ile Met Arg Pro Gly Asn Lys 85 90 95 56 ME149103561v.1 117823-35920 Tyr Glu Tyr Lys Phe Gly Phe Glu Leu Pro Gln Gly Pro Leu Gly Thr 100 105 110 Ser Phe Lys Gly Lys Tyr Gly Cys Val Asp Tyr Trp Val Lys Ala Phe 115 120 125 Leu Asp Arg Pro Ser Gln Pro Thr Gln Glu Ala Lys Lys Asn Phe Glu 130 135 140 Val Met Asp Leu Val Asp Val Asn Thr Pro Asp Leu Met Ala Pro Val 145 150 155 160 Ser Ala Lys Lys Glu Lys Lys Val Ser Cys Met Phe Ile Pro Asp Gly 165 170 175Arg Val Ser Val Ser Ala Arg Ile Asp Arg Lys Gly Phe Cys Glu Gly 180 185 190 Asp Asp Ile Ser Ile His Ala Asp Phe Glu Asn Thr Cys Ser Arg Ile 195 200 205 Val Val Pro Lys Ala Ala Ile Val Ala Arg His Thr Tyr Leu Ala Asn 210 215 220 Gly Gln Thr Lys Val Phe Thr Gln Lys Leu Ser Ser Val Arg Gly Asn 225 230 235 240 His Ile Ile Ser Gly Thr Cys Ala Ser Trp Arg Gly Lys Ser Leu Arg 245 250 255 Val Gln Lys Ile Arg Pro Ser Ile Leu Gly Cys Asn Ile Leu Lys Val 260 265 270 Glu Tyr Ser Leu Leu Ile Tyr Val Ser Val Pro Gly Ser Lys Lys Val 275 280 285 Ile Leu Asp Leu Pro Leu Val Ile Gly Ser Arg Ser Gly Leu Ser Ser 290 295 300 Arg Thr Ser Ser Met Ala Ser Arg Thr Ser Ser Glu Met Ser Trp Ile 305 310 315 320 Asp Leu Asn Ile Pro Asp Thr Pro Glu Ala Pro Pro Cys Tyr Met Asp 325 330 335 Ile Ile Pro Glu Asp His Arg Leu Glu Ser Pro Thr Thr Pro Leu Leu 340 345 350 Asp Asp Val Asp Asp Ser Gln Asp Ser Pro Ile Phe Met Tyr Ala Pro 355 360 365Glu Phe Gln Phe Met Pro Pro Pro Thr Tyr Thr Glu Val Asp Pro Cys370 375 380 Val Leu Asn Asn Asn Asn Asn Asn Asn Asn Val Gln 385 390 395 <210> 5 <400> 5 000 <210> 6 <400> 6 000 <210> 7 <400> 7 000 <210> 8 <211> 21782<212> DNA<213> Homo sapiens <400> 8 ccctcgagtc tttgctcaca tgtccccttc tcagaggggc tcaccctggt gcccttcgaa 60 agtgggcatc cactcccttc ccaccctggc acccgcaccc tcctgtcttc ctttttctgt 120 tctccatcct actcatctcc cccaactaga aaggcagctg cagctgcgga gcacgggatc 180 tccatctgca gctgcatccc gggacctaga acaggtacaa aagtacctaa taagtaccca 240 ctgaatgaat aattggctga gttttctgta ccaaagactg agctaagact ctttaaaagg 300 atgatcttat ttaagcctta cagcaagtaa atgttatccc catcttcctg atgaggacac 360 agtgaccacc acgctcaagg acacagaggg tggacgtgcc acattcacac tctgtgactt 420 agagcggctg gacgggcagg gacttaggag gcctacagca gccagggtga gattatgagg 480 ctgagctgag aatatcaaga ctgtaccgag tagggggcct tggcaagtgt ggagagcccg 540 57 ME149103561v.1 117823-35920 gcagctgggg cagagggcgg agtacggtgt gcgtttacgg acctcttcaa acgaggtagg 600 aaggtcagaa gtcaaaaagg gaacaaatga tgtttaacca cacaaaaatg aaaatccaat 660 ggttggatat ccattccaaa tacacaaagg caacggataa gtgatccggg ccaggcacag 720 aaggccatgc acccgtagga ttgcactcag agctcccaaa tgcataggaa tagaagggtg 780 ggtgcaggag gctgaggggt ggggaaaggg catgggtgtt tcatgaggac agagcttccg 840 tttcatgcaa tgaaaagagt ttggagacgg atggtggtga ctggactata cacttacaca 900 cggtagcgat ggtacacttt gtattatgta tattttacca cgatcttttt aaagtgtcaa 960 aggcaaatgg ccaaatggtt ccttgtccta tagctgtagc agccatcggc tgttagtgac 1020 aaagcccctg agtcaagatg acagcagccc ccataactcc taatcggctc tcccgcgtgg 1080agtcatttag gagtagtcgc attagagaca agtccaacat ctaatcttcc accctggcca 1140gggccccagc tggcagcgag ggtgggagac tccgggcaga gcagagggcg ctgacattgg 1200 ggcccggcct ggcttgggtc cctctggcct ttccccaggg gccctctttc cttggggctt 1260 tcttgggccg ccactgctcc cgctcctctc cccccatccc accccctcac cccctcgttc 1320 ttcatatcct tctctagtgc tccctccact ttcatccacc cttctgcaag agtgtgggac 1380 cacaaatgag ttttcacctg gcctggggac acacgtgccc ccacaggtgc tgagtgactt 1440 tctaggacag taatctgctt taggctaaaa tgggacttga tcttctgtta gccctaatca 1500 tcaattagca gagccggtga aggtgcagaa cctaccgcct ttccaggcct cctcccacct 1560 ctgccacctc cactctcctt cctgggatgt gggggctggc acacgtgtgg cccagggcat 1620 tggtgggatt gcactgagct gggtcattag cgtaatcctg gacaagggca gacagggcga 1680 gcggagggcc agctccgggg ctcaggcaag gctgggggct tcccccagac accccactcc 1740 tcctctgctg gacccccact tcatagggca cttcgtgttc tcaaagggct tccaaatagc 1800 atggtggcct tggatgccca gggaagcctc agagttgctt atctccctct agacagaagg 1860 ggaatctcgg tcaagaggga gaggtcgccc tgttcaaggc cacccagcca gctcatggcg 1920 gtaatgggac aaggctggcc agccatccca ccctcagaag ggacccggtg gggcaggtga 1980 tctcagagga ggctcacttc tgggtctcac attcttggat cctcggatcc tctgactctg 2040 gtggggacag gcagaccaag ctctcttgga cccgggaaga gggacccttg gaagtcactt 2100 gggattgagt tctagagtct tgacactgtt tcagcagatc tatactttga acccacctca 2160 ggcatctcat ccacagaaca gggacagtga ccattccatc ttgccaagga gtgcggggca 2220 cacaccatgc tgctggcagc cagggtggaa agtcaagggg tcccagctga agcactgcca 2280 cagaggcagg atgcagtccg agaggggact tcagagcagg ggcccaaggc caaggccatc 2340 agggaggtct ttctgcagga gggacctctt taggagttag gccctaaaaa caaataagag 2400 gaagaaaggc acttggtggt ttttagtcta ttcacggtgc tgtgcagcca tcaccaccat 2460 ccagccgcag aacttgttca tcttcccaaa ctgaagctct ggccccgttc aaccccaact 2520 ccccaccccc cagcccctgg cacccaccct tccactgtct gtctctatgg atttgaccac 2580tctaggccct tcatataagt ggaattttac agtatttacc ctcctgtgac tggctcattt 2640cactgagcaa tgtcctcaag ggtcatccat gttggagcat gtgtcaaact tcatttcttt 2700 ttaagggtga atcatattcc atcgtctgta tagaccacaa tttgtgtagc taatcatccg 2760 ttgatgtttg ttgatttgtt tgtttgtttt gagacagtct tgccatcaga gctcactgca 2820 ggctcaacct cccaggctca agaaatcctc ccgcctctct acctcccaag tagctgtgac 2880 tacaggcacc tgcgactgtg ccctgctaat ttttgtattt tttgtagaga cagggtctca 2940 ctatgttgcc caggctagtc tcgaactcct gggctcaagt gatcctctca cctcggcctc 3000 ccaaagaact gggattacag gcatgagcta ccatgtccag cccaattgcc cattgatggg 3060 cacgggttgc ttccatgttt cagctgttgt gaatcacgct gctgtgaaca tgcgtgtgca 3120 aacagccctt ccagaccctg ccttccattc ctctgggcct atacccagca gtgcggttgc 3180 tgggtcctat gggaattcta cgtttaactt ttggaggagc tgccaaactg ttttccacag 3240 tggctgcgcc atcacaatcc aattttagga catttttatc acccataaag cactccctgt 3300 acccattaag aagtcatcct ccatttccct ccctcccctg tcctggcacc cattcctctg 3360 ctttgtgtgt ctctggattg ccctatctaa gcatttcaca gagatggagc catgcgctcc 3420 gtggtctttt gtgtctggct tcgctcactg agcatgctgt tctccaggtc catccacgtt 3480gtagcgtagg tcagcccttc attccctgtt atggccaaat gatactccat tgtacagaca 3540ggccactttt tacccactca tctgcttctg gacttttggg ttgcttctac catgtggcct 3600 gttgggaaca gtgctctgtt tgtattcatg tacgggtttt tgtgtggaca cacattttca 3660 agtctcttgg gtacacaggt gtagaagtgc cagagttggg gaaaaagctc acctttctag 3720 gctgtgaatg ggccctggca agtctgtggc caggactcgt cttctcttcc acatggggcc 3780 cctagcttgg cacctagcac gtggcaggca gcgacagatg ttaaaagcca ttcttgctat 3840 gggtagccag gctggggctc catgcagccc tggccttcag cttggcagcc agggccccct 3900 tgtgcctgca gcagaagcca tgctgccagg agtgtaagtg tgagccagga atgctggaga 3960 atcgtggctc tgagaacagg gacaagaggc cacaagctca cgccttggct ttcctaagct 4020 taaggaataa acccaaaagg aggtacctgg aaggagctgg atttggggac tgaggagctg 4080 ggagctgatg gaagccgtga aaggggatgt gctcctgggg aggcgctggg gcgggtgggc 4140 cgtggagggg acagggcccg ttggttggaa actgaggcga ggctacggag ttgggcacta 4200 58 ME149103561v.1 117823-35920 acaggtcatc cgtgcccctg cgaagcgtgg ggacacaggg acagcagaga tggcctgtct 4260 ggacactctg tcgacggggg gcctgtggtt ggtgaagccc aaggcaaggc tgtgaactca 4320 gggcaaggga gacgtgagca ggcgctgccg tgggctgatg tgggcactgc atgtgcaccc 4380 tggcggccaa aggacctaca gctcatgggg ggcaaggggg aggagggaag ccaacagcag 4440 gatgtgcgca gtcagtctgc cccccctaca ctggaggagg agccccccgg cacaaatctc 4500 gcccgtttgg gcccacggac atggctggcc tcgcaaggag gatccggttc caggcctcgg 4560 ccctaaatag tctccctggg ctttcaagag aaccacatga gaaaggagga ttcgggctct 4620 gagcagtttc accacccacc ccccagtctg caaatcctga cccgtgggtc cacctgcccc 4680 aaaggcggac gcaggacagt agaagggaac agagaacaca taaacacaga gagggccaca 4740gcggctccca cagtcaccgc caccttcctg gcggggatgg gtggggcgtc tgagtttggt 4800tcccagcaaa tccctctgag ccgcccttgc gggctcgcct caggagcagg ggagcaagag 4860 gtgggaggag gaggtctaag tcccaggccc aattaagaga tcaggtagtg tagggtttgg 4920 gagcttttaa ggtgaagagg cccgggctga tcccacaggc cagtataaag cgccgtgacc 4980 ctcaggtgat gcgccagggc cggctgccgt cggggacagg gctttccata gccatggccc 5040 agcagtggag cctccaaagg ctcgcaggcc gccatccgca ggacagctat gaggacagca 5100 cccagtccag catcttcacc tacaccaaca gcaactccac cagaggtgag ccagcaggcc 5160 cgtggaggct gggtggctgc actgggggcc accggccacc cacctgcccc gcccaaggga 5220 atctctcttc tgcacgtccc caccagcaga gaaggctttc tcccatagct tttctgatga 5280 catgaattgg ggggtcctct ccaaatctag aaggacacca taatatcgaa tatgcattct 5340 caagccacac aggcttccca gcccctttga gaatccgagg ccggggaaga gtttatgtgc 5400 tctttctttg tggcccgtag atgagtgtgt tcactgctag cgaatgacct ctcattccac 5460 ggagtccctc agcttcctgg ggaagagctg ggtctgtctt tacatttgaa gccgaaagga 5520 ggcaacatac tgacacaccc aagggaggcg ggagggtggg gaagacagca gcagagggca 5580 agaaacttct agaacttcag ggtcggcaaa gcctgtagca gtcattttgt caaactccat 5640 gatggggcca cttggctttt ggctgcacac ctctggggga agaggctgca ttggcgccca 5700 gggccatctt tccattcgga gccgtcctgg gagagagggc tcaggcccaa cagaaagctg 5760 aaagctctca tcagggcagc ccgagtcctg ccattgggag ttgcccaatc cgaaagtttt 5820 gcacgcaggc cctcaaagaa gctgaggaca ccagtgaccg ccccactcct ggccctctcc 5880 ccaggtccct cctccaaacc aaattccttt ggtgccttca agaacatcgt gcaggccggg 5940 cacagtggct cacgcctgta atcccagcac tttgggaggc agaggcgggc agatgacgag 6000 gtcaacagat agagatcatc ctggccaaca tactgaaacc tcatgtctac taaaaatgca 6060 aaaattagct gggcttggtg gcgcatgcct gtagtcccag ctactcagga ggctgaggca 6120 ggagaatcgc ttgaacccgg gaggtggagg ttgcagtgag ccgagatcac gccactatgc 6180 tccagcctgg ccacagagtg agactcttgt ctcaaaacaa aacaaaacaa aaaacaacaa 6240catcgtgcag gctgtggttt ccagaagcca cgccagctcc ttgattgcca ataaacatcc 6300cgctgtgggg tggccaggac cgagtgccaa ttagtgacag agtgcccaga ccaaaccgga 6360 tgaggatctt gcagttgacc tcaacatgac tgtgcccaga atttccttgg tggcaatgtc 6420 aacagtctct tcctagatgc ccccagactt catcaatgca tgatgcttca gtgcactctt 6480 ttcaaatgtc ggggtgggtt tttttttttt ccacaaaact tcaagcatct actaaagtag 6540 agggaggagt gtaatgaact ccggtaccca tcactcagct tccacggttt catctcattt 6600 catctgtgac ccctccacta ccctttcttc ctgattcttg gaagcaaatc caagacatca 6660 cacccttccc tctgtaaatc tttactatgt tcctctagga gaaaagggct cttctcaata 6720 cataaccaca agtcatcatc acaccgacaa gtgtaacagt atttcctgaa tagcttcaaa 6780 tatcctagta gtgttcaaaa aatgtcatac gtattttcag tctgcttgaa tcagggctca 6840 aataaggtcc acacattcag attgactgat atgccttttg actacctttg aatctagagg 6900 ttccctttct atctccctgc aatttatttg tggaagcaag caagtcgttc atgacgtagc 6960 ctaacaggcc cctctgacgt tgttcattat gatttttctg taaattggta gttgatctga 7020 ggatctggcc agaggtaggt tggatttgtt ggtgtgtttt ggcaaggaga gtgtctcttt 7080 tctggggtgt tggcagctac tgaaactcaa tgcccagacc aattaaacca ctggggatgg 7140aaaatgacgg cattcggaca ccttaccctg ccttcaccta ttggtgacca aaaccttaac 7200atcttcacag gtcttcttac cctgagggta tatgccacta ggttgtgtag taaaccggtg 7260 tgtttccagt cccttagaat agtccctctc taagtgatat gccactcagt ggatatgcat 7320 ttagcttcat ttcttttgtt gctgattttc agagattgct ctgtaaattt aaacttttat 7380 tttactttat tttatttttt cgagacagtc ttactctgtc gcccaggctg gagtgcagtg 7440 gcgcgatctc agctcactgc aacttccgcc tcctcggttc gagcgattct cctgcctcag 7500 cctcccgagg agctgggact acaggtgccc gccaccacgc ccagctaatt ttttttattt 7560 ttagtagaga cagggtttca ccatgttggc caggctggtc tccaactgct gacctcaagt 7620 cgtccgccca cctcggcttc ccaaagtgct gggattacag gtgtgagcca ccgcccccgg 7680 ccacttaaat tttgttttat aattatgtaa taaaacagtt aaaagtctca aattaaaatc 7740 tagaaaagaa ggtgtatttg aagaagtctg gcttctctgc gccaccaccg accgcccctt 7800 ccctacctgc ctgtatttcc tcgaatcact ttgcctggga gttgactttg attctcttgc 7860 59 ME149103561v.1 117823-35920 tcattgcttc atgaaattca gttccagaac tttcaggagg gaggggtagg ccatgacacc 7920 agctctagtt acactggtgg cagctcctgt cccctccccc actgctgctg ggacctgttc 7980 tctcctttgc ccccttgtcc ctgcactgcc caatttggac cgcaagggtt gccagggaag 8040 ggcactggct gccttgtttt cagaggtcgt agcacctaga ttgctccagc cccttgcact 8100 tgcctgcagg ccagagtgtc ccaaaccctc ccagtctcag ctgctcttcc ccagttcacc 8160 caaggtactt cccagggaag agctgccgac agtttggggg ttctctgttc ttaggtccat 8220 cagcaacccc attgctcccc tctgcttcct tctgcacgga gactgacgcc atgcaggtct 8280 tcaattgtca atggtctgtc cctgctgctc atactggggg ttcctgggga gccagtgcca 8340 ggtatcggga ttgcagacat tgtctgtggg tttccagaag ctccttgtgt taggaacata 8400tggggcccgt gcacagaggg cagcagaggc cttgtgggat ccagctgtgc taggggtgag 8460atttatctgt ctctcctggc catagccagg aaatccccat ttttcttaag ctagcttgag 8520 ttgggctttt ctaacacaca gctaaagaat ctcttgataa accttgggac tctccatgag 8580 gccttatatg gcagcaggtc tgtggcttgc aatcccttca agtaatctgc caaaaacaat 8640 gttatgacga aggtccttcc aacacaaaag gtgtagagcc ctagcaaact cctacagaag 8700 aaaaaggaga aataattcgt ttgtagtccc agctacttgg gaggccaagg tgggaggatc 8760 acttgaagtc aggagttcga gaccagccta ggcaacatag ccagacccca tctctacaga 8820 aataaaaaaa attgccattg tggtaatgca cggcttgtag tcccagatac tcgagaggct 8880 gaggcaggag gatcgcttga gcccaggagg atcgcttgag cccaggagtt ccacgttgca 8940 gtgagctatg attgtgccac tgtactccag cctgggtgcc agagccaggc tctatctcta 9000 tttggtgttg ttgttgttgc tgttgttgtt tttgagacgg agtcttgttc tgtcaccccg 9060 gctggagtgc agtggcgtga tctcagctca ccgcaacctc tgcctcctgg gttcaagtga 9120 ttctcccgcc tcagcctcct gagtagctgg gactacaggc gcccaccacc atacctagct 9180 aatttttttt tcttttgtat ttttagtaga gacggggttt caccatggcc aggctggttt 9240 tgaactcctg acctcaagtg atccaccccc tcggcctccc aaagtgctgg gattacaggc 9300 gtgagccacc gctcccagcc gactgtatct ctaaatatat aataatcata atcataatca 9360 ggacagccgt catattggat tagggcccac cctaatgacc tcatttaaac ttggtcattt 9420 ctgtaaagac cctatctccg aaaacggtca cattctgagg tattggggtt aggactccaa 9480 catatgaatt tgggtgggga cacaattcaa ctcataacac attcattgat taatttcctc 9540 attcatttat tttctgagca tctattgtgt gctggacact ctgtgaggat gaatgagtca 9600 aagtctctgg tgagaaagac aagacttgta cttgtgtctc agtactggct gctataagaa 9660 attaccaggc tgtggccggg cgcagtggct cacgcctgta atcccagcac tttgggaggc 9720 cgaggcaggc ggatcacgag gtcaggagat tgagatcatc ctagctaaca tggtgaagcc 9780 ccgtctctac taaaaataga aaaaattagc caggcgtggt ggcgggcgcc tgtagtccca 9840 gctactcagg aggctgaagc gggagaatgg cgtgaacctg ggaggcggag cttgcagtga 9900gccgagatcg tgccactgca ctccagcctg ggtgacagag caagactccg tctcaaaaaa 9960aaagaaaaaa aaaagaaaag aaaaataaat taccaggctg tgcatggtgg ctcatgcctg 10020 caatcccagt actttgggag gacaaggcag gaggatctct tgaggtcagg agtttgagac 10080 cagcctggtc aacatggtga aaccccatgt ctactaaaag cacaaaaatt agctgggtgt 10140 ggtggtgggt gcctgtaaat cccagctact actccggagg ctgaggcagg agaattgctt 10200 gaacccagga ggcggaggtt gcagtgaccc gagatcacat cactgcactc cagcctgggt 10260 gacagagcaa gactttgtcc caaaaaaaaa aaaaagaaaa gaaagaaagg aaaagaataa 10320 aagagaaatt accatagatt gggtggcttt taaatgataa atttatttct cacagctctg 10380 gaggctggaa gtcagggtgc tagcgtggtg ggctctggcg aggaccctct tcctgactgc 10440 agattgccaa caactcattg tatcctcaca tggaagaaag agagctagag agcactctag 10500 ggactctttt tcttgtttgt tttaattaaa aaaaaatttt ttttacatgg gcatgccatg 10560 ttgcccaggt tggatttgaa ctcctgggct caagcaaccc tccagcctca gcctcccaaa 10620 gtgctgggat tacaggcatg agccaccatt cccagctaat ttgggctgtt cccaaaggct 10680 caagtgatcc tcccacgttg gcctcctgag tagctggggc tacaggcgtg agccaccatg 10740 cccagcttct aggacctctt ttataagggc actaatccca ttcatgaggg ccccactcac 10800tctgcacaca tgacctaaat gacctgccaa aggccccacc tcctaatacc atcaccttgg 10860gggttgggat ttcaacacag aaatttatgg ggggcacgta cattcagatc atcatgaaca 10920 gtaactccta tgtgtgacag aaggtgacag aggtgggtag tggtcttccc ctcaaggggg 10980 tgagttgcca ctagctgggg aatcttctgg aaggcaaatg catatgagct gggctttaca 11040 ggaggcaagc gtttctctat ggaagggcag aggactgtgg gaggtaggag gtggggctgg 11100 ggcaaaggga agaggggagc agggaagtgg ggtgactgca cactgggagt ggggaatcag 11160 atggaggaga cgatgaggag ttctgttaag ttcaagatgc cagtgccagt gaccagcggg 11220 cgatggtctc tggcttgagg gacaggatgg aggggagact gtctgaggat ggacaaagct 11280 ggagggaaac agccaattgc aaaggcagga gggcggaagg gggaggggag aggtgggatc 11340 agcactggta tagacaggcg gtgctgcagc ccagctcctc tctctcctct gcctcctgcc 11400 ctcaggcccc ttcgaaggcc cgaattacca catcgctccc agatgggtgt accacctcac 11460 cagtgtctgg atgatctttg tggtcactgc atccgtcttc acaaatgggc ttgtgctggc 11520 60 ME149103561v.1 117823-35920 ggccaccatg aagttcaaga agctgcgcca cccgctgaac tggatcctgg tgaacctggc 11580 ggtcgctgac ctagcagaga ccgtcatcgc cagcactatc agcattgtga accaggtctc 11640 tggctacttc gtgctgggcc accctatgtg tgtcctggag ggctacaccg tctccctgtg 11700 tggtaagcca gtcggggccc aggctcggcg gaaaccactc attcaccctg caagctcctc 11760 cagccacctc atgatgatcg gggcccagct gctcctgtag gcctgtctcc ctccccatct 11820 gcgcctcaca tccatatact gaagggttct ggaggcttcc atctgaacac tcacattaaa 11880 ttcagctccc ttgagtcaaa cataccctga gttcctactc ttgagtcagg ctctgcccgg 11940 ggacagccag tttggagctg tggggctggt gtgggaggag acagatacag agctagacaa 12000 ccccagaaca gtaggggggc ggggactctg ggcaccctgg acagaactcc cctgcaatta 12060gggatgcctg ctctttcagc tcgccagcat ctgcttttcc cggaggagac acaattccca 12120gatcctctcc ccatccccat cactaatatc tctgtgggcc actattccgc tcaggtcagg 12180 agacagtggc cgagaggtac tagcgtgcca ggctctgtgc taaggagggg gccctatagc 12240 cagacggcaa ccacacagta ccatcatcag tcctctcaga caagaagggg cctggggcag 12300 gtggtggagg agcggctggg agcagtttgt ggttcgagtg gatagagtac caccaagcag 12360 ccgtggctgc tggacacgag gtgggcaggc ccaggtctca gaggcctcag acgtcatgcc 12420 caggagctgg gactttcttt caggaggagg agaccccaca tccagcagca gcagctcctg 12480 ctcttgcctc cccaccactc ttagcagcct ccccaacccc accccgttaa ctgcctcaaa 12540 ttgtacccac gatggcccag accagagagg gtgcttgtcc aagtcccggc actaccccga 12600 tagtgtagaa ggggagccaa gggaaggtca ggcagagaag gtccatcccc aggtccgagt 12660 gctctctgca gcaggcatgg cctcggtggt cacacgaccc ttcccgagtg cccccctgca 12720 tctccgccca cgtctgtctc cgtttctgcc atggtctccc gctcaccctt gcctctgctc 12780 atggtctgtt cttgggtcag tcaggtgcca agcagccagc acttccccac cacttttggt 12840 ccacggatgc ccttggccat ctgggaagcc tgtggacccc atctcaggag aatttttgca 12900 aacgcataaa atgagaccca taggattaca aaggcagcaa attatactga aatacagtta 12960 tcaaagtatt aaacattcat cagtaacata gtctttagtt aaaagcattt actggccagg 13020 ctcatacctg taatcccagc actttgggag gctgaggtgg gaggactgct tgcctccaag 13080 agtttgagac cagcctgggc aacatagtga gacctcttct ctacaacaaa taaaaacagc 13140 tgggcgtggt ggcacaccag tagtcccagc tactcaggag gctcaggcgg gaggatcgct 13200 tgagctctgg aggtcaaggc tgcagtgagc tatgatggca ccactgcact cagcctgggc 13260 aacagagtga gattctgtct caaaaagtaa ataaaaataa aagcatgtgt taaacgtatt 13320 agtgacacca ctcagtatta aggtattaaa taacaggatc ccgcctgaca accactgtta 13380 tttcagagta gtgatgaaca taagtggtat tcgaactctc tgccacctct atgaattgac 13440 aggaaaacat ctgtgacctc tcttgctgac cgagtcacgg gtactgctaa tactgccacg 13500 ttcataatgg aaggaaatgc ccagtgtctg ttcgaggttg gtggaaagaa agatgtcgtt 13560ttttccacct cagtccgtgg agccctgaat tctgtgtgca gacgtttggg gtctaagcag 13620gacagtggga agctttgctt cccacctttg ctttggctca aagccctcat ctgtctgctc 13680 tccccatagg gatcacaggt ctctggtctc tggccatcat ttcctgggag agatggatgg 13740 tggtctgcaa gccctttggc aatgtgagat ttgatgccaa gctggccatc gtgggcattg 13800 ccttctcctg gatctgggct gctgtgtgga cagccccgcc catctttggt tggagcaggt 13860 aagggtgcga ggacgcaaga tggagtgggc agggtcagac tctgtgacct taaggcaaat 13920 cacttccttt ctctgggccc ctctgagcgt gcaatgtcta tcaatgtatg aatgtggctg 13980 caacatagga aaggctctgt ggtccccgaa cctctggaaa catatttatc ccaagcacga 14040 tcaggtcaca ggcgcacacg gagctcaggc catcagcaca gctgtcagtg aacgcatagc 14100 gtgtttgcat tccaggtctc tttcttgcac acgctgccgc accacgcccc ccacctttca 14160 gaggctgctt gggtcataga tccacctggg cctacagagc acatgtcctg gccaggccaa 14220 gcaagtggct caaatgtttg attggagtgg actgggtggg acagcatttc actgttttat 14280 cgacaagctc gtgaataagt tctcgtggtg tttggagagg gaatgttctt tcctcgagaa 14340 cgttccacaa ttctaggaaa caaaccttgt ggaagcctgt ctctgtctcc cgccctcctc 14400 atgccgccat gccccacaca gctgcccgtt atcaaacatg tgtggtgagc tgaccctggt 14460ggaggctctc ccgcgggtta tctcatttaa tcctccaggc cactaagtga gcagggccct 14520ttatttcagt catggcctag ctgacctcag ataaaagact cagctcttca tgggtgttct 14580 cagaaggtca gggcaagaag gaacctcaca atccctttgt aaagaagggg agtgattggg 14640 aagatgaaaa tgtcctggaa gcagatagtg gagatggttg cacagcattg tgaatgtacc 14700 aaaggtcaca atggtacttt tttctttttt tgagacaggg tctcactctg tcactcaggc 14760 tggcacagtg cagtggtgta attatggctc actgcagcct ccacctcctg ggctcaagtg 14820 atcctcctac ctcagcctcc tgaggagctg ggcctacaga tgcaccactt cacctagcta 14880 atttttttta ttttttgtag agacaagatc tcactgtgtt ccaggctagt cttgaactcc 14940 tgggctcgag caatcctcct acctctgcct ccaaatgtgc tgggactata ggcgtgagcc 15000 attgtgcctg gcctataatg gtacatttta tgttatgtgt attttaccac aattcaaaaa 15060 gaagaaaggc atgacatcta aaaatggaca aggattaacc aaaatcctac ccaacggttt 15120 tgttttgggt tgatgaaaat gttctggaag cagaggtggt gactgccaca gaattgatca 15180 61 ME149103561v.1 117823-35920 cttcaaattg ggtaatctca tgcaacatga atttcacctc aatttaaaaa aacaaacccc 15240 acccgagtta gcaccgtgcc tgggccgggg gtcctgggtc accccaccct gcatcaggac 15300 tggctgccgg cccttctctc caggtactgg ccccacggcc tgaagacttc atgcggccca 15360 gacgtgttca gcggcagctc gtaccccggg gtgcagtctt acatgattgt cctcatggtc 15420 acctgctgca tcatcccact cgctatcatc atgctctgct acctccaagt gtggctggcc 15480 atccgagcgg taagcccccc gattcctcct ggcctcaccc gcctcctgcc cctaagctgc 15540 tctgccctca aatgagtcca ctgagactcc taaactattt ttccaaaaat ccttagagaa 15600 gaggatttta cccctataag aaaatattaa gatccagcga tgagaatcag gtgattcctt 15660 tgggactgta ccagtggctg caggttcagc cccagccccg ttgtcctcag ctctgtgaga 15720cgggaaagca ctgccactcc ctccctggag gagtccacta agggaacaga ggtgtgcctt 15780gccccgaccc tggacagttc tccccggggt ggaaaggctg cctttcccac agagtagagt 15840 ggagcagcca catcagcaaa tgacacctgc aaatcaaggc gtgtttttat gaggctgcca 15900 ccggagtacc cttgtccttt tcataggctg tggggccgac caaggagtgg acccgagagt 15960 gccatttgcc cccctgaccc actctccacc tccatgtctg gccctctgcc ctgggaagct 16020 gatcctgtcc acagccgtca ccccccaccc ctagactagg ctaccactgg gagcccttca 16080 ggaagtcaga gcaagggagg agagccaggc tggttctttt ctgttagcag tgggagccct 16140 ttcagggtgc tggctttcct atatgaagct gcctgtgccc acaattggat gggcatgcct 16200 gccaagctct ctctagagga gtctgtgagc ctgtgaaagg ccccctcacc ccgtcacctt 16260 ggggtgaagg ctcccacagg tacccaacca tggcttcggc tgtattagtc tgggatggta 16320 gagccccagc tccacaatgt ggccccagct ctgctgtctc agccatccct gcattccagc 16380 cctcacactc cctctctcat ccccactcat ctgcctgccg ccagtccctc atccctggca 16440 ggtggtggct ggcctctggc ctcccccaca gtgcctctgc ctggaggcca ttcgtctcct 16500 tcctcccagc aggcatgaag gagccacccc accaaagctg ccctcagctg cctcaccgtg 16560 agtccagggc aggatttagt ccacagagtg gccaacctgg cctaggaagc ctgagggaag 16620 tgtatgcatt gctctgacac tcccatcgcg caccccgcca gccactgctt ttgcctcccc 16680 cgccatctcc accttgttaa ctccttcatt ctccacgccc agtcatcaat caaatcaggc 16740 ctccatgctc aggcctgagc gcaggacagg acagtctgtt aagggatcag gtgaagcaaa 16800 ggagcttgtt agatccagct ctggggtcat cttaggccac acctagctgc atgccacctc 16860 caattctaga actcccccag ggccagcctg aggcagccat gtctgcctgg ggccggctgt 16920 gctccactca gggctggaag atggctgctg ggctcctctc ctcctcccca caactcccta 16980 tgcctgggtc acctgcctct tgctgccctc caacccccga ctcactatcc ctgtctccct 17040 taggtggcaa agcagcagaa agagtctgaa tccacccaga aggcagagaa ggaagtgacg 17100 cgcatggtgg tggtgatgat ctttgcgtac tgcgtctgct ggggacccta caccttcttc 17160 gcatgctttg ctgctgccaa ccctggttac gccttccacc ctttgatggc tgccctgccg 17220gcctactttg ccaaaagtgc cactatctac aaccccgtta tctatgtctt tatgaaccgg 17280caggtaagca acaccatcag cagatcccac tcaaaatacc gtgtgcccta gaagggtgca 17340 gtgatggccc cacctggaat catgtctctg ataagaagcc cgcggagcat ctgggggacc 17400 ctccagggaa atgaccggga aaggctcagc gtgtgaccca gccccagcca gagctccagc 17460 tggcccttag cagaaggctt aggtgtgccc tctggaatcc tttatagtct cggcctgagg 17520 gtggcatttc ccaaagcgtc tgtgtgccgt gcgctcttcc cttccggtgg ccctagaact 17580 atggctgccg agcttcaggg gctctcctgg cgttcagacg ctctaggagt tggtgagccc 17640 taggtacatc caccctaggt gtgcccctct tctgttcaga ctcgaccctt ctcaaccttc 17700 atctctccat tttcaaaccg taacctctgg aatttgtctt cctataagaa caaaagccgg 17760 ccctccttgg ctacactgac caagagttca agagctttca cgagttcgtg ggttagttca 17820 ggggggacgt gctgtggtcc tgcccagagg cagcctcctt agctggcata ttgggcctca 17880 gcagcaagct gctcacacac ctaaatcccc ccacctcctg caggttacag gcttcattaa 17940 agcgcagctg tgatgtgact tgatggtggc cagaaaggtg tgcagaggcc tcccatttca 18000 ccaggcccag tccatccctt ccactgggct cttccttgct tctccatctt agagccactc 18060 aatggctcca gcccctttgg ctcagctttg actcacacaa gccaagtctg cagagttcat 18120taagggttca ttctctctgg taacttttaa acagtaagta ggaccaggcc tgcagtggat 18180ttccgggaac tcgctgtagc acactgatgc ccagagtgta gttctatccc tgacccctgt 18240 ttcctgactt tcatgaggat cttttttagg tttctggaat cctaaactat cttgccaagt 18300 actgtcttta ctggattatt tccattctcc tttccagaac tccccctgga cagggggaga 18360 cagatgtctg cacttctgga cctcaccagg cctcgaactt tgcttttacc ctttccacat 18420 aattatcctg tcctgccaca ttctgagaga attttctgga acgcagttcc atgaagacag 18480 caaattttgc tcaggacaga gtctggcaca cagtgggtgc tcaagcagca gctgctgaat 18540 ggattcctca gccctatctc ccagctcttc agccgagctg attctgctgt ttgtcccgtt 18600 tcttatgtta ttaatttcaa ccattatatt ttttattttt gagagttttg atgatagagg 18660 gagttagagc tagtcaagag taggcctgaa atatttagaa aatgcctttg gtctgggtcc 18720 tcaaagcatt gtggttactt cagggatgac acaggacatg atttgagaca ttcatatggc 18780 ccagatctct ttggggtgaa gcagcaaaga cagacccctc ctggtaccgg aagacgcttg 18840 62 ME149103561v.1 117823-35920 gctggagaga tgaggtaggg gctagattgt cattacctag gcctcacctt gccccagatc 18900 catggactgg aaaaaacatg acaaccacat gccttttcat taatattcct ccgagccgct 18960 caccagacag tctggggaca ggtcaccact gccccttagc tgtcactgtg gatgagtgtc 19020 atggggctgc cgtcacaaac taccacaaac tcagtggctt caaaccacag aaatggattc 19080 tctcagggtt ctggaaatct tgagtctgaa atcagggtgt tggcaaatgg aaaggttccc 19140 tatggaggcc gggagggaga agcagctgca gggctgccgg cagtctttgg cgttccttga 19200 ctccaaggtg tgtcacccca gtctctgcct tcatcttcac gtggccttct tccctctgtc 19260 tgcgtgtccg tgtccaagcg ttccttttct tatcaggaca ccagtcattc gattagggcc 19320 caccctgctc cagtgtgacc tcatcttaac ctgaacacat cttttggggg acccacttca 19380acccagtgta gtcaccatca actgctaagt cagatgacat ccccgcgtgt gagggagaaa 19440taatccaagc cttcctccat cccccatggg attcggaatg ggtgaaggga aggctcgggc 19500 acgtacattc agcacagtgc tccacccttc cctgctctgc tcaataacgc tttctgtcct 19560 tccagtttcg aaactgcatc ttgcagcttt tcgggaagaa ggttgacgat ggctctgaac 19620 tctccagcgc ctccaaaacg gaggtctcat ctgtgtcctc ggtatcgcct gcatgaggtc 19680 tgcctcctac ccatcccgcc caccggggct ttggccacct ctcctttccc cctccttctc 19740 catccctgta aaataaatgt aatttatctt tgccaaaacc aacaaagtca cagaggcttt 19800 cactgcagtg tgggaccacc tgagcctctg cgtgtgcagg cactgggtct cgagagggtg 19860 caagggggat aaagaggaga gagcgcttca tagactttaa gttttcccga gcctcatgtc 19920 taccgatggc gtgaaaggat cctggcaaaa cagaagtgtg aggcaggtgg gcgtctatat 19980 ccatttcacc aggctggtgg ttacataatc ggcaagcaag agctgtggag gggcttgctg 20040 gatgccctca gcacccagga ggagggaggg agctagcaag ctaaggcagg tggccctcct 20100 ggccccttaa ggtccatctg ctggaggccc agagtccttg gagtacagtc tacacctgga 20160 ggggacccat tcctgccagt ctgtggcagg gatggcgcgc cacctctgcc aggccaggac 20220 cccaagcccg atcagcatca gcatggtgca ggtgcacagg cgtgagctga tcagtgacga 20280 ggggcaggca cacaaggtgg agacaaagac caagaggacg gttgccagtg agaggcgcgg 20340 actcaggaac ttgaacaaca tctgcggggg acggctttgg aggtgctccg ctgcctccag 20400 ttgggtgact tgctgtagca tctccagctt ggatattcgg ctcttgaagg tctccgtgat 20460 ctcctgcagg agacgaaaat gcacgcacca gaagtcagca cagagttgtg gtcgtttatt 20520 gagttcttag gggtgagcag aaagcactgt ggagtgggta ttcgaggagg gaagcagaga 20580 gcctagagca cattcagggc agaggggagg gcgcaggctc tccagcaaca gggaaagctt 20640 catctgaccc ggctgcactc ccccatccac tgtctcccga agctgaggac ctggtcaaga 20700 cacagctacc cagggacggg ggtgggcgct atgggaatgg aaaagtgagg agagggaagc 20760 caggtctaag gaggggttct gagagggcgc tccctacacc tgcagccgca gcagaagcag 20820 ctccacccca gatctcccga gtcagaggct cacgggtgag cactgcagca ccagagtggc 20880aaaagcagct aagccagatg gtgggaagcg gagcgtgagt gtaaagatca gatgctgcta 20940gctctgaaac aaatgtgtgt ggccatcgaa ccctcaggag ggggcagctc gaggacccgt 21000 gtcttgcttt ggtttggggg tatcagaata gattcgctca tccctccagt cttcttgcaa 21060 ggctccccca ggaggttctc acccatattt ccttggctct ctcataggat agataggcca 21120 ttctctcttc gctgcaggcc agattgtgtt tgaggttgta aatctcattc agctgtccct 21180 gcaggcgacc attcacctgt tcttccatca atgcttgcct tgggagcaaa agagaaagtg 21240 agattccttc agtacctcat ccagagctca tgccaacagc gagcggtcct gacctagact 21300 agattcgggt tcagcttctg ccttcctccc cgctccccag gctctaggga aagcctgcct 21360 cccactccag gtctgcctgg gaacacccca aacacacacc agccacacgc acaccaatat 21420 tcatatatat tttatatgta gttactcttt tgtaacagct ttacaaaaat agccacagac 21480 tagaagttgt agaaatgaca gtgtgaacta tctgtgtgtg ctcttcagtt ccgcaaatcc 21540 cccaggacca gtgttgagca cgaagtctag cctgcagttt agcctgcagt tactctatag 21600 aaacatggtg actataagga ttgaaaagcc acaaaagacc acagattcca gtacaattcc 21660 attagttacg aaatgtccag aataggcaaa tccatagaga cagaaagcag attagtgggt 21720 gccaggggct gggggtgggg gatgggcagt ggctgctaat gagtacaggg ttgctttggg 21780gc 21782<210> 9 <211> 17024 <212> DNA <213> Homo sapiens <400> 9 gtcggactcc cgcggccgga ctgtggggga gtcacgcaac aggtgagacc ccaccaaaat 60 ctcgccggct ccgcgccagg ctctgcggcc cttggccccg cccccgcctg gccccgcctc 120 cgcctgccga ccccgcctcg ccattttttt ctcttcctgg gcgccacgtg ggcagccacc 180 acaccgcggt agggctggcc tgagccgacc ctgggtcttg ggccagttcc gtgcgtcagc 240 ttcctcatca gtaagatggg gtaatgacag tacctcactc aaaggggtta ctgtgaagat 300 taaacgtaaa gtccctttac acagtgcctg gcacgaagtg agggcccagt gaaaggtagc 360 63 ME149103561v.1 117823-35920 tgttatcatt gtcccaggat tcattttaag cagaagtcct gcccctgcaa tctcacttgg 420 tcgtctgttt tcttccggcc ggcgtaggta ggaggctgtg ccctgcaatt ctggctcccc 480 ttcccacatt tctgtatttg gtggttaaga gctttaactc tagccagaat gtctgggttc 540 aaatccagat ttcacctact tcctgactga tactgggcaa gttacctaac ttctctgtgc 600 ttctatttcg tctgtaaaat gagtgtaaga gtacctgctt tatatggtgg ttaagataaa 660 tgagttaata taagttaact gcttagaact gtgcctggcc tgtagttagt actcagtatt 720 catgtattac cattgcttta gccttggcct tggttctcta ttgacactca caggttgatt 780 cacttgcagc cgttctgggg tctatccaac aagcatcccc actgccaagg ggtagataat 840 ccgacctaaa gggaacttgt ggagggaagt ccctaagact tcactgaata taattaaatg 900cattagcagg aattaatctc ttccctattt tccctcttgt gggaggcctt tgccccccac 960acccagttgt tctaatgctg tttgtctggc tcctcccagt tcttaccact cccacagcag 1020 agatccttcc caaactctgc ctccctcttc tctccccacg ctggattctg gaccctgaac 1080 ccttttctcc acctgcatct ggtgccactt ccattgatcc ctggctactg ttccctgaac 1140 aaacttaaaa aaaacttggc ctcttcacct cacacagaat ccataaaact aaaaagagaa 1200 cagagataac caggtttacc taatcaaaat agcaaagact aaaaaacaaa aaaccaaaaa 1260 ataaacgcta atgcaggttg gcaagggtat agttagtgag atgggagaca cacacacacg 1320 tacatgtgca caaacacatt actggtggcc ttgaacactg atataatctt tctgaaagcc 1380 atctggtaat atagaatcaa aattttcaaa aaggttctta ttatttgacc cagtaatcaa 1440 ctttctggaa gttgtttttc taaaaagagc tgccagaaaa atatgtatgc aaaaagttgt 1500 tcagcaccac aatgtgtatt gcatagaaaa gttagatact ttaaaggtcg aacaataggg 1560 gaatgtttat gtaatattca taccatgaaa tacagccatt aaaaattgtt cttggagaaa 1620 tgtttaatga tgtggaaatg tttacaatat aaagttaggt aaaagaatgg atgcaaaaca 1680 ctatacacag tatggtccta cttatgtgat atacatgggt agaaaagaaa cacaccaaca 1740 agtttaccaa tgattatctg tagtgatgga attatgggtt atatttattt tctttatatt 1800 tatttgcatt ttagaaatta taatacatac ccataacttt tataatcaag gggatagaaa 1860 tcaacaaaaa tctgtaaaaa tctgtaattg cctccacagt ccccccaacc cagccttccc 1920 ggggtcttaa ccccagactt aaactattct gtttacattt atggcccact gaattggtct 1980 tggggcgctt agggattttg aggctgatgg actctcaaga atgaataaaa tgaatctcaa 2040 aaatcaagca ccatgtaact acataaatgt catgtatctt ctgataagat gcaaatgttg 2100 acatagtttt aaagatagta tcttgcattg ggccaggtct cttgagcatc ctgcttaatg 2160 cagacctacc tacctcagca gccaataggt ggcaatcctt gccctccacc cagcccaggc 2220 aaaccagttc attagtccct ttatgctagt cccctagtcc catctgcaac acacccttca 2280 ctctacaacc ctcccctatt tccaggtcat ctggtgtatt gttgctgcta ggaagtcggc 2340 cctgattata gttaggcatc aatccctcca cccactccat accagcaaga atctcagtga 2400ggtttcattg tctacgcaga acagagcttg ggaaataaag gagtgagtca tcctatggcc 2460tgggcttttt tcacactgag gccttaacat tcattgcctt tgagcctctg agatattccc 2520 tagctccaaa cacagcttcc tcccctccta gcctgttccc cacatggctc cttaactggc 2580 cctcccggaa tcccagctcc ctaaagatgg tgcactcctg tttctctgaa gaagtgcttt 2640 tctttgcttc tggacttcag ctcacttgtg atgtccgcct ccctagctag gccagaacaa 2700 tcttcacaga tactaaactt gggagagaat atctgcagct ccaaaaaggt ccttggccaa 2760 ggcaatttcc caaaccatac cttatgccta ggcccttcta gaaacaagct gttcagctct 2820 ggtttctcag cttctcccag cagccagctc cctctccccc tcacctcagt cacccagcat 2880 tgtgtttata gcaccataca gctgtttcca tctatacttg tttataagac cccagtggat 2940 tttagtcaaa ccccttgcca ttgaaggcgc ttcactggct ggctccaatt tccctttctt 3000 gtcttcatct tcacctccca accctccact ccatgcacct ttcactccag tccagtcaca 3060 tcaaagtccc agtcttctct gagcacacct tgtactttgt gcctctacct cttttttcat 3120 gctctttcct ttccccaaaa tgcgtatctc ccacttccac tgttattctg cttctctgtg 3180 gaaagtctat tcatttcaca atcacccttt tctttcttcc gctgtagaac tttgtcagtc 3240 tgacagtcag atgtgtgttt gattgccttt cctaccaggg gtgaatgcta ggtcttaaac 3300agctctgaat ttcccagcac tactgcagta tccctttaac tcatttgttt ttctgtgaat 3360ttcccccacc tctgcctatg gactggaagg tcctgaaggt agttcctcat ccttcatgtc 3420 ctcccactcc atctgggaca agtctttacc cacaattcac ttaagacaag gcttaccacg 3480 gatgtcagac agatccctta actcaggaaa catgcccaaa tcactaagaa acagtgattt 3540 acttttcatt caaaatgata atggttataa agggctgtga atcaaaacac ctgagctctg 3600 gcttggcttc tgataccaac ttgcttatta atgtgaggat cacttttctg tacttcagtt 3660 cactcacctc caaaatggaa ctagcactac ataccttatt tacttcatca ggaaactgtt 3720 cgtaaatgtg atcataaagt gggacagcca caggaaaggc acaggaactg acgatagagg 3780 cagaggcagg aggtcacaga catcaggatg atgtatgcac agtaatggat ctgtactctc 3840 aggccaggcg agggctagca gttccctctc tcagcttagc agtgagaaag gggaacttcc 3900 atccagtaag ttagggaaca aagcagaagc agcacagaag tttgcagagg tagtagcaga 3960 aaaaggaaca agcccacttt ccctgtgtgt gaaacaactt agtggttcct ttaacaaggg 4020 64 ME149103561v.1 117823-35920 ctgctgttat agagttcatg catttgtcca tgctttctct ctctggctac ttatgtggaa 4080 gtaatagaaa gaaggatcac cggtttgtct gtttactagg ccatataact ttgttttttt 4140 gtttttgaaa cagagtctca ctctgtcacc caggttggag tgcagtggcg caatctcggc 4200 tcactgcaac ctccacctcc cgggttcaag cgattctcat gcctctatct cccaagtagc 4260 tgggtgcatg ccaccatgct gggctttttc ttttcttttc ttttcttttt tttttttttt 4320 tctgagacgg aatcttgctc tgttgcccag gctggagtgc agtgcctccc gggttcaagt 4380 gattctcctg cctcagcctc ccaagtagct gggattacag gtgcctgcca ccatgcctgg 4440 ctaatttttg tatttttttt aagtagagac agggtttcac catgttgacc aggctgtctc 4500 gaactcctga cctcagatga tctgcccatt ttggcctccc aaagtgttgg aattacaggc 4560gtgagccacc atgcccggcc taatttttgt atttttagtg gatacgggat ttcaccatgt 4620tggccaggaa ctcctgacct caggtcatcc acccacctca gcctcccaaa gtgctgggat 4680 tacaggcatg cgccactatg cccagctgac tttaaatgag ttacttaact ctcaagtctc 4740 agttaatcta gtctgtaaat tggggacaat agcagttatt gtgataatta actggtatga 4800 gccacttaca ttgttcagca gttattaatt ataataacta taacataata attattaata 4860 gttccaggca gccccttgaa cagtgtagcc ttcagcatgg ctctggcctc agtgtgagtt 4920 accagtattg tgagtacgct ggagcagggc tagcagtggg gtataattac tgaaacctta 4980 taaccaagat tccaagatag tcacaatttc aaagagactc tcctgttttt ccttaagtca 5040 ataaggactt gccaatttga ttgggaaaac atggctacca tggaaagcac ctcagcagct 5100 gcatatttct ccatcagccc ctacagtcac tgaaaggtgg tgcgaaggag gaagataatt 5160 agctatggct cagggtacct gataggcggg gagacctaga ttctactcct gaccttccca 5220 gtcccaactg gccactgctg cacaagtcca gctctaaaat gaaagagcaa attacatcct 5280 tcgacctcag tagttctcca ccttggctgt acactagaat cagctgggga cgtttttaaa 5340 tccttgtgcc tggactgcac tccagaccaa ttaaatcagt attttttaaa aagctctcca 5400 ggtaaatgcc actgtacact aaaagttgag aactgtttca ggccagggtt tttcaaactt 5460 cacagatgtg ataactacct gtattagctt aaaatatttt ctctggctct ggagtttgat 5520 gctaacatac catttaaaaa catacactat tttaacatct cggaaagcag ggtaatcttc 5580 tagtcagtgg cacctaagac ttgaggaaac acagacacca gcaacccagg tgattcttag 5640 gattaggtaa gtttagcgga aaacaggtcc ctagggcagt acttcccaat ctttaatgtc 5700 tttagagtca cctgagatct tgttaaactg cggattctga atcagaagtt ctggattaaa 5760 gcctgagatt ctgcatgtct aatgagcttc cgggtgatct gatgttgctg gctcttgatc 5820 cacattttgg gcaacaaaat tctaaaacat ctccacctga ggaggctccg ccagcaacac 5880 tcatttaagt aaactgaaat aattggcata gaggagtaca acctgtggag tcctaaatgt 5940 ctgtgaggca gttgctagac tgcaccctca tttttccccc aggaaagggc agctgggatg 6000 agagccagaa ggagagagag ctgccccaac ctttgagaag ccagagtctg gagtccaatt 6060tcccaaagaa gcagagtttt ttgtgtgagg cagcacaaac cccacactga ataccagcaa 6120agttcattta tgaagtgaag ttgggactca gctggcttta gtgggccaaa gggaagcaac 6180 cccattctct tcaccataca cccttttcct gcatttattc attcaccaaa ccttttgatc 6240 cacaaataaa ctacaagttc tgagaggttc aaagatgagt cagatttggt ccgttgagct 6300 ccagggggag aaatgcagtg agggaaaaga tttgtaaaac gacgtacaat atgaagtgat 6360 aagtgctaat aacagaagta caaagagagg ggccaatgca aaggaacaat gctagtagct 6420 tcctggagca gcagccactg cgggagctga aacattccta atcttcccaa ggaagggcac 6480 cacccaaaac aaatttcctg gccaggacca gcctatggta aacgagtatg ctttgatacc 6540 ctgaagccct tgagatcaag accttataat ctggaggctc aacataagga atgctttcta 6600 catatgtgcc agtaatctct agctctatga tgcaaataaa tctaaggaag caagagactt 6660 tcaggggatg aaccccttaa aggatggaag tagtcgtgca tcctatcctt ccgtcagaac 6720 ccagcagatc atttccctag ttatagaaac atttgagtct ttaccccttg ccatattgac 6780 aaagctctta attggcttga cctatcacat tgctagatat aaaggctaca atccctagac 6840 taagaagtag gtctccagtt gaagtaggga gtctcagtca atgtaggcag agtacaagac 6900 cctacagcct gctctctcac ctgccatcgt acagaccagc ttttagggga gccaagttgg 6960gatactcaat cccaactttt ttccttctct tccatctcac atacaggaaa ccttacgaga 7020gaggattagg ggcctgaaaa agctgacaag acggcaaata tgggaagtgg agccagtgct 7080 gaggacaaag aactggccaa gaggtccaag gagctagaaa agaagctgca ggaggatgct 7140 gataaggaag ccaagactgt caagctgcta ctgctgggtg agtgagatgg gaagatgagc 7200 cagagaaggc aggggtcctt cctactttcc tgaagggttg gtgggttcta cctcacccca 7260 tgggaaggaa gggtggcagg tcatttttcc tctcctctac acagtctggc taggggatca 7320 ggagatctag agctgagtta atatggggcc taaacagcca ccccaagggg atccagaatg 7380 ccaaggctat tccagagttt ttctactctt gagcgaggaa tagtgcaagg gccaccatga 7440 acccacccat ttccaaatct aaccaaacct aacacatcct tttggcttca aggaccctgg 7500 acttgcagac tgtacccaat ctgcagagaa ctctaagcca agaaatcaga agagaacagg 7560 accttccctc accaacaggc tcacaagtcc caccatacag tcagtgccaa cagtaccaga 7620 gatagtccca ctggtttttg ccaagtatag tggttccttc ttgctttcag taaaaacttt 7680 65 ME149103561v.1 117823-35920 ggaagtaggg ggctctgagg aaggaggaat ggtgtcttta tgtacagcag tcccttcctg 7740 gctctctatt caatagctgc ctgcaaagct cctgccagat ggaaggttca tcaacttgat 7800 gagctcctaa gcagatcact ggtctgtgct gagaaaataa aagcacctca atttgtcagg 7860 gaaattgatc acagctgtaa ataaaaccaa gacaagaaca tttgagacac gtggcttagg 7920 aaaacaaacc actggtacca cagaagtagg gtagctggag caggtagggt ctacgtagca 7980 gaagattaga tgcctgagct gggtttccaa gcccccataa gggatctggg agctgacgca 8040 ctaggctaag gcaccttctt ttcccccagc tgatctgtgg cacagtcgta aggacacact 8100 aaaggagcat atctttgtaa gctggaccag actctaagga gcccaggagg ttacgcaggg 8160 ggaaacagag atggtggggc cactgagaga tcttttaagc ctaagcagat ttcttctaca 8220ttcaggataa gctgcttaga gggaacaagc acaagcgaaa taggaggagt tcgaggcatt 8280agggtagtat aaactcagta ctagaaggta tgagtttttg atggagagag cagagtgtga 8340 atgaggacat taggacacat tagtcaataa agggaaccca cttagcccca tccaagacca 8400 ggttgagcaa catggtgaaa acctgcctct acggaggggc ggggggaaat ggccggatgc 8460 agtggcgcac gcctgtaatc ccagcgcttt gggaggccaa gatgggtgga tctacctgag 8520 gtcaggagtt tgagaccagc ctggccaaca tagtgaaacc ccatttctac taaaaataca 8580 aaaattagtc aggcatggtg gcatgcgcct gtagagtccc agctactcag gaggctgagg 8640 cagaagaatt gcttaaaacc caggaggcag aggttgcagt gagccaagat agcaccactg 8700 cactccagcc tgggagacag agcaagactg tctcaaaaaa aaaaaaaaaa atgtagtcgg 8760 gcatgatgtc gcacacctgg aatcccaact actcaggaga ctgaggtggg aggatcactt 8820 gagcctggga agtcaaggct gcagtaagcc gagattgtgc cattacactc cagcctgggc 8880 tacaaacctg agaccctgtc tcaaaaaaaa aaaagggaac cagcaaggtg atgaaaatat 8940 agttattttg gtgaaatgat ccagctctct ccaatcctac cccaagatca ctctcctgag 9000 tcaaaaatag gcagagagga gaaatgttaa aggactcccc ctgaatctgt tagtggtttt 9060 caacaggaag attttgactg ccagtggtca tttggaaatg tctggagaca cttttggttg 9120 tcataactag ggaagtggga tgctattggc ctctagtggg tagaggccag gaatgctgct 9180 gaacatccta ccatgcatga gacagcccaa actaaatagt actgaagtta agaaactgct 9240 ctaaatccag gttgaatggc ctgagctcaa gcctgccaga aattgagggc agcagtcatc 9300 cctatgtatt ctcccctaac aagaccccca agcaagcagt ggctctgact tctcccaggc 9360 catctcctgg aaggctgagg agaactggtg gaaatcgaaa gcataagcat ttttccttcc 9420 aggtgctggg gagtcaggaa agagcaccat cgtcaaacag atgaagtgag tagaaacaaa 9480 gccccaaaag acaagatagg gtgaagaagt cagtacagcc agtggaggta ttcaaagtga 9540 aaggctcttt agcctcaagg agcccaggta taaaggatct gattccaatg cccctcatct 9600 gtaccccttg tccctcaccc tccactttga gaaagcagta gcaacagaga gataggattc 9660 ttatgatcct ttaaataccc ccaaattcct aatcccttag gtctggttac tcaggtccag 9720ctaaagacag agtgtctgcc ccttgcagga tcattcacca ggatggctat tcaccagaag 9780aatgcctgga gttcaaggct atcatctatg gaaatgtgct gcagtccatc ctggctatca 9840 tccgggccat gaccacactg ggcatcgatt atgctgaacc aagctgtgcg gtatgtgatt 9900 actattatgt ggttaagggt ggaagcagaa aggctagcaa gaagaaacat accagaggcc 9960 aacaaactat atggaaagat gggtaagaaa aatagtaact aaaatcccac ctgctgggtg 10020 ggatctcact gctaggtgta ctgtgtatac catctcaagg ccctttaccc atctacgcag 10080 taagacctta aggtagacgg tacctttcta attagcctca ttttacacat ggaaaaactg 10140 aagttcagag aagttaatta actgcccaag gtcatgtaga taaatagcag agactgcatt 10200 tgcattgggc tgcttgacta caaagctgaa tatttttcat aatacaccac aattatgcag 10260 tcctggagaa gtaagcaaca tccaccctta tttttactgg gacagggtct tcctctctta 10320 cccaggctgg aatgcagtgg tgtgatcatg gctcactgca atctcaccct cccaggctta 10380 agtgattctc ccacctcagc cccagtaggt gggaccacag gtgtgcacca ccacacccag 10440 ctatttttta aaattttttt gtagagaagg ggtcttgcca tcttgtctag gctggtgtca 10500 aactcctggc cttaagcaat cctcctgcct cagactccga aagtgttgag attacaggtg 10560 tgagccaccg tgcctgtcct caagccctac tttataacac atatttacaa aataaagctg 10620ctcacagctt cctctgcttt tttactttac catttaaatt gctacccttg ggttcctggc 10680catggaactt ttgtaagtga aatccctact tctagtactg gactttttct agctttcaat 10740 cgctgaagaa caaaggtgat gggtccctgt cttctatctt gtctatttca tggtcaatct 10800 ggcctttaca ttttcagtct ctctgcagca gaggacccac gttttgtggc ggtaaacttt 10860 cagactaagg atggaagcca gaaactccag agaggaaata cctgggaccc ctgccccgct 10920 ttagacacac cccagggctg ggtatagtgc caccctctgc atctggggag catactcaaa 10980 aattcaacag tatgttttct tacatagaat cttcactgga tactgcttcc atcttaggtc 11040 ttcgtagtaa tgtaaaatga tttccattca gcagtattcc cagaagcctc ctggaaagct 11100 attactcctg tgaagttctt aaccaggttt ctgcattaca ggatgacggg cgacagctca 11160 acaacctggc tgactccatt gaggagggaa ccatgcctcc tgagctcgtg gaggtcatta 11220 ggaggttgtg gaaggatggt ggggtgcaag cctgcttcga gagagctgca gaataccagc 11280 ttaatgactc cgcatcttag taagactgac tggtgagagg gtgggttgat gcttaagcaa 11340 66 ME149103561v.1 117823-35920 tcttctagcc agtcttctct ctggttggga gaaacctcac ccaacccaaa atttcaggca 11400 ttgaaagctg gagacccaga ctgaattcag cctgtggatc tgttttgtta ggcttcagca 11460 atgttttgaa tttaatgcta tggggagatc tgccacagtt gtcatgactt tctattgctt 11520 tacactggct cactacagcc tacaaggctg aagatgcaaa attcaaaaga cgtgttctgc 11580 ctagtagccc tcagccctgt tctcttaatt gaggtgtaca ctaagcctct ccttccagaa 11640 ccctaagata gccctgcagt tctgtcatac actctcgcag gagtaatgtg attcatgatg 11700 gctctttcag ggcagaattt tctatctggt aatctaggat ctacttaggc cactaagcag 11760 aaatgagtct cctacaccta gagcatctta tgtcacgatg ccaaggcagg ggacacaaac 11820 tacaagggca aaccaaggga aggtggtcag gaattagtac catcattgca aagctgcttc 11880caaaaagcta agggacataa tttatcaatc ctacctcaga cagtatggga tcatagacaa 11940gtatgggctt caaagtcaaa cctgagttta tttaacctaa ccatctgtct cctaatcttg 12000 taataatgct atcacttact gttcccggag cactcaaagc ccagtcactg ctaggtgtac 12060 tgtgtatacc atctcaacgc cctttaccca tctacgcagt aagaccttaa ggtagatggt 12120 acctttctaa ttagcctcat tttacacatg gaaaaactga agttcagaga agttaattaa 12180 ctgcccaagg tcatgtagat aaatagcaga gactgcattt gcattgggct gcttgactac 12240 aaagctgaat atttttcata atacaccaca atttctcttg accctagcca agtatttaac 12300 tcttctgaat ttctccatct gtaaaatggg gatatgaaac ttgatggctt aggagtttaa 12360 acgagaatct gaacattaaa atgcctggca tacaataggc acttgtgtta cttgtacttc 12420 cctcctcctc tcagtcatct cagttcacat ctgccttcct cttgcctttt ttttttttgg 12480 agacggagtc tcgctttgtc acccaggctg gagtgcagtg gcgcaatctc ggctcactgc 12540 cagctttgcc tcccgggttc acgccattct cctgcctcag cctcccaagt agctggggat 12600 actggcgccc gccaccatgc ccagctaatt ttttgtattt ttagtagaga tggggtttca 12660 ccgtgttagc caggatggtt tcgatctcct gaccttgtga tccgcccgcc tcggcctccc 12720 aaagtactgg gattataggc gcgagccacc gtgcctggcc accttttttt tttttaaaaa 12780 aaataacttt ttctttttta aggtaacttt caaacataca aaagtagaaa taacataatg 12840 aattaccttc aacagttatc aactcatggc caatcttatt tctttttacc tccattccct 12900 actggattat tttgaagcaa attccaggta tcatttcatc ctaaaaatgt cattatggat 12960 ctctaaaata ttgacccttt ttataaaaag aatataatca cacccaaata gttaacaatt 13020 ccttaatagc atcaaatatc accaagtcgg tgttcaaatt tccccagtta tctcaaatgt 13080 ttcctcccca gtttgattca ggatataaac aaagtccatg tgttgcattg gttcatgtct 13140 ttaaagtctc tttcaattta ctgcctcttg atggaacttt tagcacccac taaatctcat 13200 tcaaaaatct acaaaagctt gcagtcaggg caaacccaag gaaaacttat ctaacttgat 13260 ttaaatgcgc tggaactcca gcctcaaatg ggcttgtccc tcagtccatc ccccatttcc 13320 tctagttaat gacatatgaa ggtttgaagg aaagaatcct aaatttaaca atatggcttc 13380tagtcctgat ttctatcacc aaattagctg tgtgactttg ggtaagatac cttttacgtc 13440tcttagcctc gtctgtggaa aatttgtcat tgatgctaat cacttttctc tagctacctg 13500 aaccaattag aacgaattac agaccctgag tacctcccta gtgagcaaga tgtgctccga 13560 tccagagtca aaaccacggg catcattgaa accaagtttt ccgtcaaaga cttgaatttc 13620 aggtaagtgc atggttccct agggcatctc ggatacacgt gtggaatcct gaaaaggggc 13680 acaggcaggc ttcttggcct ttggtgaagc ctaatctaaa ttactgttct gcttctcccc 13740 cttttcctct cccacttcac ggggtgacca tcaaaggcat ataggtcgta tgttgggcat 13800 acctatgaaa atagctgctt cttccctcag gatgtttgat gtgggagggc agagatccga 13860 gagaaagaag tggatccact gcttcgaggg agtcacctgc atcattttct gtgcagccct 13920 cagtgcctat gatatggtgc tggtggaaga tgacgaagtg gtgagtggcc tttgcatcaa 13980 gcagctttgg tagaacaagt tctccccatg accctttctc taagccttgt gtcactctac 14040 tgccccaact taggtaattt cagtctagca gccctccagc agaccaatca atgtctcatg 14100 caaataattc taaaaaacaa cttcttctgc aggttctaga ttagcatttt agagctccaa 14160 atttactgac agtgagcttg gtctcaaatt agacatctaa gtatcacttg gacatcacaa 14220 agctcataag aggaattgag tgcaaagaga taagggacca tcaactaggc aaagcaaagg 14280agttacactt agtactctcc caaattgcct aaggaaggag atgaaaatga cagaacagag 14340aaaataacat atgatatgaa tcttcattgc aacataatag aagggttgag ctagtaaccc 14400 cacttaggag gctaaaaatg tactgtccgt aggagtttaa ggagagactg gcagaccagc 14460 tttctctcat gccaattaaa ttggcagctg gaagactacc caagagtggt tctctttagc 14520 ctgtagaatt ctgtaggaca ggagttctat aggacaagtg ttagagccca gccagtttct 14580 gaatttggga aaggttagag gtgagaaaaa cgttaatttc acccaagcat ctgctttctg 14640 aatttgggaa aagttagagg cgtgaaaaac gttaatttca cccaagcatc tgctcacaaa 14700 tggaggtcca caccttgctg atgacctctg aatttgggaa aggttagagg cgtgaaaaat 14760 gttaatttca cccaagcatc tgcttacaaa tggaggtcca cagcttgctg atgaaaggga 14820 tactcctatc ccttgccaca gcttgttctc ttcccttccc tttggtagtt ttaacttcac 14880 attagagcac tctgaatatc gtctaatcaa aatgtcttac agagctattc acttcccatc 14940 tttaagccta aagattacag tctatgagac tttccatctt taaccctaaa gtctatgagt 15000 67 ME149103561v.1 117823-35920 ctatgaggtt tattaaagtc tatgagacat taataaaaca agtctatgag accttaaagg 15060 gttgtacagg agtattatgg ggaaaaagcc acaaatggga ttgttcttgc tttattagat 15120 aagtagactg aacgcaagtc agctgatagt atacttcaaa accctaaaga cctgctccct 15180 aaaagcaagc tgggctgggg caatgggcag cctctgcaga tatgcagccc gacttctcgc 15240 taagtagcaa tcagagaagg aaatgagaga gcagaaatgc ttgtggtatg gcactgggaa 15300 attctctaac tctcaccatg tggcagcagg accaaagtag cccaaactga gatctgggac 15360 cccatgaaag aagcctatca aaatcatcct ggagatgcat atgggcacat gctaacttgg 15420 gcctgtttca acccattatc agcactactt ataaaatgtc aagttctcag ttgcatcctg 15480 gctgctaaag atctgcataa cacattatag acctatatgc cagccactat catggacaat 15540atacatacac aatctcattt agctttcatt gtaaccctat aagataggaa aacagactca 15600gaaaaagctc aataattttc cacaagtcac acagctatta gaaagatagg gaactagaat 15660 gatcccacat ctctctggct ttactctggt acattgagat aagctgttct ctgtcttgct 15720 ttttacattt ggagcactgg tctctccaag gggaacaaga gcaggaagta ggtagatatt 15780 ctataagcca aatctgatat ttccaatggt gtttcctctt actagaatcg tatgcatgag 15840 tctttgcatc tgttcaacag catatgtaac cacaaattct ttgcggctac ttccattgtc 15900 ctctttctca acaagaagga cctctttgag gaaaaaatca agaaagtcca tctcagcatt 15960 tgttttccag agtatgatgg taagtgtcag gggctggaaa taataataat gccttttagt 16020 agagactggc aattgtctca ttttttaggc caagatgaca caaaggaact taagggagaa 16080 ccttgggcac agttacaggg tttaaattca gatactctgg aatacagcag gcattagatg 16140 caggagagcc actgacttca tatgatacct actgaaaacc aaaggtggaa agacacctct 16200 cctcaatttc ttttcaacta aagtgagaaa cactggagtg caatagagaa tcttccctcc 16260 aaaaataggc ccccaactgc tgttgtctaa taacatttca aggatcaagt caatcaccta 16320 aagtgagtca gcaactaaca agggttcatt tattctactt tttcactatt tttctggaaa 16380 accaggtaac aactcctatg atgatgcggg gaattacata aagagccagt tccttgacct 16440 caatatgcga aaagatgtca aagaaatcta cagtcacatg acctgtgcta cagatacaca 16500 gaatgtcaaa tttgtgtttg atgcagttac agatattatc atcaaagaaa acctcaagga 16560 ctgcggcctc ttctaatcct caccattcct caggtataag ttctataaac aggcttggaa 16620 tctgggtaat taaaaacaga aaattatagt caatatacca tgacatgaag aatgaatcca 16680 ttctttggag atggagtata catgactgca actgtatttc atacgttctt ttcaaagtgg 16740 gatagctatt gcagcttaaa gagcacaggc cagtagttag aagacccccc aggttccagt 16800 actggttttc caacttaata caaaactgtg aatactttat ttctgagtct tgagtctttc 16860 aactataaaa tgaagatgac ttccctacct actttacagg gttattctga ggagcacgaa 16920 cataactgaa gggaaggcac ataaaaactg cttgtgcagg ccaggcacag tggctcacgc 16980 ttgtaatccc agcactttgg gaggccaagg tgggcagatc acga 17024<210> 10<211> 592 <212> DNA <213> Woodchuck hepatitis virus <400> 10 aatcaacctc tggattacaa aatttgtgaa agattgactg gtattcttaa ctatgttgct 60 ccttttacgc tatgtggata cgctgcttta atgcctttgt atcatgctat tgcttcccgt 120 atggctttca ttttctcctc cttgtataaa tcctggttgc tgtctcttta tgaggagttg 180 tggcccgttg tcaggcaacg tggcgtggtg tgcactgtgt ttgctgacgc aacccccact 240 ggttggggca ttgccaccac ctgtcagctc ctttccggga ctttcgcttt ccccctccct 300 attgccacgg cggaactcat cgccgcctgc cttgcccgct gctggacagg ggctcggctg 360 ttgggcactg acaattccgt ggtgttgtcg gggaagctga cgtcctttcc atggctgctc 420 gcctgtgttg ccacctggat tctgcgcggg acgtccttct gctacgtccc ttcggccctc 480 aatccagcgg accttccttc ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt 540 cgccttcgcc ctcagacgag tcggatctcc ctttgggccg cctccccgcc tg 592<210> 11<211> 542 <212> DNA <213> Woodchuck hepatitis virus <400> 11 aatcaacctc tggattacaa aatttgtgaa agattgactg gtattcttaa ctatgttgct 60 ccttttacgc tatgtggata cgctgcttta atgcctttgt atcatgctat tgcttcccgt 120 atggctttca ttttctcctc cttgtataaa tcctggttgc tgtctcttta tgaggagttg 180 tggcccgttg tcaggcaacg tggcgtggtg tgcactgtgt ttgctgacgc aacccccact 240 ggttggggca ttgccaccac ctgtcagctc ctttccggga ctttcgcttt ccccctccct 300 attgccacgg cggaactcat cgccgcctgc cttgcccgct gctggacagg ggctcggctg 360 ttgggcactg acaattccgt ggtgttgtcg gggaagctga cgtcctttcc atggctgctc 420 68 ME149103561v.1 117823-35920 gcctgtgttg ccacctggat tctgcgcggg acgtccttct gctacgtccc ttcggccctc 480 aatccagcgg accttccttc ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt 540 cg 542 <210> 12 <211> 384 <212> DNA <213> Homo sapiens <400> 12 ctttcttctt ttaatatact tttttgttta tcttatttct aatactttcc ctaatctctt 60tctttcaggg caataatgat acaatgtatc atgcctcttt gcaccattct aaagaataac 120agtgataatt tctgggttaa ggcaatagca atatttctgc atataaatat ttctgcatat 180 aaattgtaac tgatgtaaga ggtttcatat tgctaatagc agctacaatc cagctaccat 240 tctgctttta ttttatggtt gggataaggc tggattattc tgagtccaag ctaggccctt 300 ttgctaatca tgttcatacc tcttatcttc ctcccacagc tcctgggcaa cgtgctggtc 360 tgtgtgctgg cccatcactt tggc 384 <210> 13 <211> 122 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 13 aacttgttta ttgcagctta taatggttac aaataaagca atagcatcac aaatttcaca 60 aataaagcat ttttttcact gcattctagt tgtggtttgt ccaaactcat caatgtatct 120 ta 122 <210> 14 <211> 141 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 14cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcaaag cccgggcgtc 60gggcgacctt tggtcgcccg gcctcagtga gcgagcgagc gcgcagagag ggagtggcca 120 actccatcac taggggttcc t 141 <210> 15 <211> 141 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 15 aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg 60 ccgggcgacc aaaggtcgcc cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc 120 gagcgcgcag ctgcctgcag g 141 <210> 16<211> 1727<212> DNA <213> Homo sapiens <400> 16 ggaggctgag gggtggggaa agggcatggg tgtttcatga ggacagagct tccgtttcat 60 gcaatgaaaa gagtttggag acggatggtg gtgactggac tatacactta cacacggtag 120 cgatggtaca ctttgtatta tgtatatttt accacgatct ttttaaagtg tcaaaggcaa 180 atggccaaat ggttccttgt cctatagctg tagcagccat cggctgttag tgacaaagcc 240 cctgagtcaa gatgacagca gcccccataa ctcctaatcg gctctcccgc gtggagtcat 300 ttaggagtag tcgcattaga gacaagtcca acatctaatc ttccaccctg gccagggccc 360 cagctggcag cgagggtggg agactccggg cagagcagag ggcgctgaca ttggggcccg 420 gcctggcttg ggtccctctg gcctttcccc aggggccctc tttccttggg gctttcttgg 480 69 ME149103561v.1 117823-35920 gccgccactg ctcccgctcc tctcccccca tcccaccccc tcaccccctc gttcttcata 540 tccttctcta gtgctccctc cactttcatc cacccttctg caagagtgtg ggaccacaaa 600 tgagttttca cctggcctgg ggacacacgt gcccccacag gtgctgagtg actttctagg 660 acagtaatct gctttaggct aaaatgggac ttgatcttct gttagcccta atcatcaatt 720 agcagagccg gtgaaggtgc agaacctacc gcctttccag gcctcctccc acctctgcca 780 cctccactct ccttcctggg atgtgggggc tggcacacgt gtggcccagg gcattggtgg 840 gattgcactg agctgggtca ttagcgtaat cctggacaag ggcagacagg gcgagcggag 900 ggccagctcc ggggctcagg caaggctggg ggcttccccc agacacccca ctcctcctct 960 gctggacccc cacttcatag ggcacttcgt gttctcaaag ggcttccaaa tagcatggtg 1020gccttggatg cccagggaag cctcagagtt gcttatctcc ctctagacag aaggggaatc 1080tcggtcaaga gggagaggtc gccctgttca aggccaccca gccagctcat ggcggtaatg 1140 ggacaaggct ggccagccat cccaccctca gaagggaccc ggtggggcag gtgatctcag 1200 aggaggctca cttctgggtc tcacattctt ggatccggtt ccaggcctcg gccctaaata 1260 gtctccctgg gctttcaaga gaaccacatg agaaaggagg attcgggctc tgagcagttt 1320 caccacccac cccccagtct gcaaatcctg acccgtgggt ccacctgccc caaaggcgga 1380 cgcaggacag tagaagggaa cagagaacac ataaacacag agagggccac agcggctccc 1440 acagtcaccg ccaccttcct ggcggggatg ggtggggcgt ctgagtttgg ttcccagcaa 1500 atccctctga gccgcccttg cgggctcgcc tcaggagcag gggagcaaga ggtgggagga 1560 ggaggtctaa gtcccaggcc caattaagag atcaggtagt gtagggtttg ggagctttta 1620 aggtgaagag gcccgggctg atcccacagg ccagtataaa gcgccgtgac cctcaggtga 1680 tgcgccaggg ccggctgccg tcggggacag ggctttccat agccatg 1727 <210> 17 <211> 2000 <212> DNA <213> Homo sapiens <400> 17 cccttgaaca gtgtagcctt cagcatggct ctggcctcag tgtgagttac cagtattgtg 60 agtacgctgg agcagggcta gcagtggggt ataattactg aaaccttata accaagattc 120 caagatagtc acaatttcaa agagactctc ctgtttttcc ttaagtcaat aaggacttgc 180 caatttgatt gggaaaacat ggctaccatg gaaagcacct cagcagctgc atatttctcc 240 atcagcccct acagtcactg aaaggtggtg cgaaggagga agataattag ctatggctca 300 gggtacctga taggcgggga gacctagatt ctactcctga ccttcccagt cccaactggc 360 cactgctgca caagtccagc tctaaaatga aagagcaaat tacatccttc gacctcagta 420 gttctccacc ttggctgtac actagaatca gctggggacg tttttaaatc cttgtgcctg 480gactgcactc cagaccaatt aaatcagtat tttttaaaaa gctctccagg taaatgccac 540tgtacactaa aagttgagaa ctgtttcagg ccagggtttt tcaaacttca cagatgtgat 600 aactacctgt attagcttaa aatattttct ctggctctgg agtttgatgc taacatacca 660 tttaaaaaca tacactattt taacatctcg gaaagcaggg taatcttcta gtcagtggca 720 cctaagactt gaggaaacac agacaccagc aacccaggtg attcttagga ttaggtaagt 780 ttagcggaaa acaggtccct agggcagtac ttcccaatct ttaatgtctt tagagtcacc 840 tgagatcttg ttaaactgcg gattctgaat cagaagttct ggattaaagc ctgagattct 900 gcatgtctaa tgagcttccg ggtgatctga tgttgctggc tcttgatcca cattttgggc 960 aacaaaattc taaaacatct ccacctgagg aggctccgcc agcaacactc atttaagtaa 1020 actgaaataa ttggcataga ggagtacaac ctgtggagtc ctaaatgtct gtgaggcagt 1080 tgctagactg caccctcatt tttcccccag gaaagggcag ctgggatgag agccagaagg 1140 agagagagct gccccaacct ttgagaagcc agagtctgga gtccaatttc ccaaagaagc 1200 agagtttttt gtgtgaggca gcacaaaccc cacactgaat accagcaaag ttcatttatg 1260 aagtgaagtt gggactcagc tggctttagt gggccaaagg gaagcaaccc cattctcttc 1320 accatacacc cttttcctgc atttattcat tcaccaaacc ttttgatcca caaataaact 1380acaagttctg agaggttcaa agatgagtca gatttggtcc gttgagctcc agggggagaa 1440atgcagtgag ggaaaagatt tgtaaaacga cgtacaatat gaagtgataa gtgctaataa 1500 cagaagtaca aagagagggg ccaatgcaaa ggaacaatgc tagtagcttc ctggagcagc 1560 agccactgcg ggagctgaaa cattcctaat cttcccaagg aagggcacca cccaaaacaa 1620 atttcctggc caggaccagc ctatggtaaa cgagtatgct ttgataccct gaagcccttg 1680 agatcaagac cttataatct ggaggctcaa cataaggaat gctttctaca tatgtgccag 1740 taatctctag ctctatgatg caaataaatc taaggaagca agagactttc aggggatgaa 1800 ccccttaaag gatggaagta gtcgtgcatc ctatccttcc gtcagaaccc agcagatcat 1860 ttccctagtt atagaaacat ttgagtcttt accccttgcc atattgacaa agctcttaat 1920 tggcttgacc tatcacattg ctagatataa aggctacaat ccctagacta agaagtaggt 1980 ctccagttga agtagggagt 2000 <210> 18 70 ME149103561v.1 117823-35920 <211> 500 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 18 catcctgaga gatgagccag gacaaagaac cagtaatagc tcctggagca gcacatctgt 60 tttgccagga ttatcccttg gatctcttaa aaccgagacc ttgtaatctg aagactcaac 120ttgggctgta cccttaacct tcagctctat gatgcaagtg agtccacagg accggaggct 180ttgagatgag cttttcagaa gggaggagtt ggccgcttgc tcccagagct ccagcacctg 240 cattcttctg gctatgtcag aagccagatc atttccctcg ttaaaaacaa aaacaaaaaa 300 acaaacaaac aaaatgttag tctttgccct ttatctgcct ggcaaagctt ttaattggct 360 tgatctgtca ttccgctaga cataaagggg acaatccccg gattaggaag gagctctcca 420 gctcgggtaa ggagtctcaa ggcaaggtag gcaagcacca ccggtccgca ctctcgccca 480 gcttttacgg gaagaagaga 500 <210> 19 <211> 2012 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 19 acgcgtagag gcaggccgag tttgaggcca gcctggtcta cacaggcgtt ctaggagaac 60 ctgtctcata tgcacatggg cctgggatta cacatacaac tgcaatggca gcacttggaa 120 agcggaagca ggagaatcgg aatttcacac tcatccttca ttatagaagt ccaaacctgt 180 gctaagctac ttggacatcg ctaaaaaaca gcaaaaatct ttctaggaat tgccaatgta 240 tacacaccaa gttgtatttt tgtagggcag acttttccaa cttgccagat gataataatc 300 atttatatta gctacatttc aggctccaga attaacactg ttactgaaat gtataggttc 360 taaaacatac catttccaaa tattttaaag gattaacatt tttgaaaagc atgtgatctt 420 ccaaccatat tttagggaac agacataaga agtaggcaag tttgggaaga aacagttcct 480 gagggcattt cttcccaacc ttgaatgccc tgtgggttaa ctgaggtctt ggtaaaatgt 540 agattattta ctggactttt tgaactgaga gtgcatttct aacaaaactc cagggtatgt 600ggtccttgca ttacatatgg ggtagcaaca ttctaaagca gtgtttttca acctgtggat 660caagacccac agaagtcaca tagcagatat cctgcctatt agatatttac attaagattc 720 agagcagtag cagaatagga gtcatcccaa cctgaggaac tgcatcagag tcccagcatc 780 aggaagggtg agagccactg agctaaagtc ctctaggtga gggggctgcc ccggaaagac 840 tcatttaaat gaaaccactg acacagagag ctgacagatg aggtgggttc cgtgtctgtg 900 aggctctgct ggtcgtctcc tcactcccat ggaagaacca ccgagatgag ggcgaggggc 960 agagctaacc cagcctctaa gtaggcagag tctagtgtcc agctgcccaa ggaagaagtt 1020 tgctgtgtga ggtggccctg atgtccgcac acacaaaatg ccagtgaagt ctacttgacc 1080 aagtgaagct ggtgtggaat gggaagaagc acacacagtc agtctctctg cacacactct 1140 gtccttcact tcttcactta ccagagattt gatgagaacc tactagcaga tcagatttga 1200 tccctgagtg gaaaaaacgt acagtgggag ataaaagagg aaaacaacgg atctgagttt 1260 gaggttagcc tagtctgagc aagccggata cacagtaaga ccctgtctca catacatcca 1320 ctcgcacgcg cgcgcacaca aacacacaca cacacacaca cacacacaca cacacacaca 1380 cacatcgtgc taaggacaag ataggcatcc tgagagatga gccaggacaa agaaccagta 1440 atagctcctg gagcagcaca tctgttttgc caggattatc ccttggatct cttaaaaccg 1500agaccttgta atctgaagac tcaacttggg ctgtaccctt aaccttcagc tctatgatgc 1560aagtgagtcc acaggaccgg aggctttgag atgagctttt cagaagggag gagttggccg 1620 cttgctccca gagctccagc acctgcattc ttctggctat gtcagaagcc agatcatttc 1680 cctcgttaaa aacaaaaaca aaaaaacaaa caaacaaaat gttagtcttt gccctttatc 1740 tgcctggcaa agcttttaat tggcttgatc tgtcattccg ctagacataa aggggacaat 1800 ccccggatta ggaaggagct ctccagctcg ggtaaggagt ctcaaggcaa ggtaggcaag 1860 caccaccggt ccgcactctc gcccagcttt tacgggaaga agagaatgtt actctatcct 1920 aacatatttt tccttttcct ctatctcaca gataggaaaa atttaagagc cagagggaac 1980 gtcccttctc agaggagaca gcagaaggat cc 2012 <210> 20 <211> 133 <212> DNA 71 ME149103561v.1 117823-35920 <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 20 gtaagtatca aggttacaag acaggtttaa ggagaccaat agaaactggg cttgtcgaga 60 cagagaagac tcttgcgttt ctgataggca cctattggtc ttactgacat ccactttgcc 120 tttctctcca cag 133 <210> 21<211> 66<212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 21 ggaagcggag ctactaactt cagcctgctg aagcaggctg gagacgtgga ggagaaccct 60 ggacct 66 <210> 22 <211> 66 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 22 ggcagcggcg ccacaaactt ctctctgcta aagcaagcag gtgatgttga agaaaacccc 60 gggcct 66 <210> 23 <211> 63 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide<400> 23 ggctccggcg agggcagggg aagtcttcta acatgcgggg acgtggagga aaatcccggc 60 cca 63 <210> 24 <211> 69 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 24 ggctcgggcc agtgtactaa ttatgctctc ttgaaattgg ctggagatgt tgagagcaac 60 ccaggtccc 69 <210> 25<211> 479<212> DNA <213> Bos taurus <400> 25 acgggtggca tccctgtgac ccctccccag tgcctctcct ggccctggaa gttgccactc 60 cagtgcccac cagccttgtc ctaataaaat taagttgcat cattttgtct gactaggtgt 120 ccttctataa tattatgggg tggagggggg tggtatggag caaggggcaa gttgggaaga 180 caacctgtag ggcctgcggg gtctattggg aaccaagctg gagtgcagtg gcacaatctt 240 ggctcactgc aatctccgcc tcctgggttc aagcgattct cctgcctcag cctcccgagt 300 tgttgggatt ccaggcatgc atgaccaggc tcagctaatt tttgtttttt tggtagagac 360 ggggtttcac catattggcc aggctggtct ccaactccta atctcaggtg atctacccac 420 cttggcctcc caaattgctg ggattacagg cgtgaaccac tgctcccttc cctgtcctt 479 72 ME149103561v.1 117823-35920 <210> 26 <211> 7265 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 26 agcgcccaat acgcaaaccg cctctccccg cgcgttggcc gattcattaa tgcagctggc 60acgacaggtt tcccgactgg aaagcgggca gtgagcgcaa cgcaattaat gtgagttagc 120tcactcatta ggcaccccag gctttacagt ttatgcttcc ggctcgtatg ttgtgtggaa 180 ttgtgagcgg ataacaattt cacacaggaa acagctatga ccatgattac gccagattta 240 attaaggctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg ggcgtcgggc 300 gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagagggag tggccaactc 360 catcactagg ggttccttgt agttaatgat taacccgcca tgctacttat ctacgtagcc 420 atgctctagg aagatcggaa ttcgccctta agctagccta cagcagccag ggtgagatta 480 tgaggctgag ctgagaatat caagactgta ccgagtaggg ggccttggca agtgtggaga 540 gcccggcagc tggggcagag ggcggagtac ggtgtgcgtt tacggacctc ttcaaacgag 600 gtaggaaggt cagaagtcaa aaagggaaca aatgatgttt aaccacacaa aaatgaaaat 660 ccaatggttg gatatccatt ccaaatacac aaaggcaacg gataagtgat ccgggccagg 720 cacagaaggc catgcacccg taggattgca ctcagagctc ccaaatgcat aggaatagaa 780 gggtgggtgc aggaggctga ggggtgggga aagggcatgg gtgtttcatg aggacagagc 840 ttccgtttca tgcaatgaaa agagtttgga gacggatggt ggtgactgga ctatacactt 900 acacacggta gcgatggtac actttgtatt atgtatattt taccacgatc tttttaaagt 960 gtcaaaggca aatggccaaa tggttccttg tcctatagct gtagcagcca tcggctgtta 1020 gtgacaaagc ccctgagtca agatgacagc agcccccata actcctaatc ggctctcccg 1080 cgtggagtca tttaggagta gtcgcattag agacaagtcc aacatctaat cttccaccct 1140 ggccagggcc ccagctggca gcgagggtgg gagactccgg gcagagcaga gggcgctgac 1200 attggggccc ggcctggctt gggtccctct ggcctttccc caggggccct ctttccttgg 1260 ggctttcttg ggccgccact gctcccgctc ctctcccccc atcccacccc ctcaccccct 1320 cgttcttcat atccttctct agtgctccct ccactttcat ccacccttct gcaagagtgt 1380 gggaccacaa atgagttttc acctggcctg gggacacacg tgcccccaca ggtgctgagt 1440 gactttctag gacagtaatc tgctttaggc taaaatggga cttgatcttc tgttagccct 1500 aatcatcaat tagcagagcc ggtgaaggtg cagaacctac cgcctttcca ggcctcctcc 1560cacctctgcc acctccactc tccttcctgg gatgtggggg ctggcacacg tgtggcccag 1620ggcattggtg ggattgcact gagctgggtc attagcgtaa tcctggacaa gggcagacag 1680 ggcgagcgga gggccagctc cggggctcag gcaaggctgg gggcttcccc cagacacccc 1740 actcctcctc tgctggaccc ccacttcata gggcacttcg tgttctcaaa gggcttccaa 1800 atagcatggt ggccttggat gcccagggaa gcctcagagt tgcttatctc cctctagaca 1860 gaaggggaat ctcggtcaag agggagaggt cgccctgttc aaggccaccc agccagctca 1920 tggcggtaat gggacaaggc tggccagcca tcccaccctc agaagggacc cggtggggca 1980 ggtgatctca gaggaggctc acttctgggt ctcacattct tggatccggt tccaggcctc 2040 ggccctaaat agtctccctg ggctttcaag agaaccacat gagaaaggag gattcgggct 2100 ctgagcagtt tcaccaccca ccccccagtc tgcaaatcct gacccgtggg tccacctgcc 2160 ccaaaggcgg acgcaggaca gtagaaggga acagagaaca cataaacaca gagagggcca 2220 cagcggctcc cacagtcacc gccaccttcc tggcggggat gggtggggcg tctgagtttg 2280 gttcccagca aatccctctg agccgccctt gcgggctcgc ctcaggagca ggggagcaag 2340 aggtgggagg aggaggtcta agtcccaggc ccaattaaga gatcaggtag tgtagggttt 2400 gggagctttt aaggtgaaga ggcccgggct gatcccacag gccagtataa agcgccgtga 2460ccctcaggtg atgcgccagg gccggctgcc gtcggggaca gggctttcca tagcggtacc 2520atggtgatgt tcaagaagat caagtctttt gaggtggtct tcaacgaccc cgagaaagtg 2580 tacggcagcg gggagaaggt ggccggacgg gtaattgtgg aagtgtgtga agttacccga 2640 gtcaaagctg tcaggatcct ggcttgcggc gtggccaagg tcctgtggat gcaagggtct 2700 cagcagtgca aacagacttt ggactacttg cgctatgaag acacacttct cctagaagag 2760 cagcctacag caggtgagaa cgagatggtg atcatgaggc ctggaaacaa atatgagtac 2820 aagttcggct tcgagcttcc tcaagggccc ctgggaacat cctttaaagg aaaatatggt 2880 tgcgtagact actgggtgaa ggcttttctc gatcgcccca gccagccaac tcaagaggca 2940 aagaaaaact tcgaagtgat ggatctagtg gatgtcaata cccctgactt aatggcacca 3000 gtgtctgcca aaaaggagaa gaaagtttcc tgcatgttca ttcctgatgg acgtgtgtca 3060 gtctctgctc gaattgaccg aaaaggattc tgtgaaggtg atgacatctc catccatgct 3120 gactttgaga acacgtgttc ccgaatcgtg gtccccaaag cggctattgt ggcccgacac 3180 73 ME149103561v.1 117823-35920 acttaccttg ccaatggcca gaccaaagtg ttcactcaga agctgtcctc ggtcagaggc 3240 aatcacatta tctcagggac ttgcgcatcg tggcgtggca agagcctcag agtgcagaag 3300 atcagaccat ccatcctggg ctgcaacatc ctcaaagtcg aatactcctt gctgatctac 3360 gtcagtgtcc ctggctccaa gaaagtcatc cttgatctgc ccctagtgat tggcagcagg 3420 tctggtctga gcagccggac atccagcatg gccagccgga cgagctctga gatgagctgg 3480 atagacctaa acatcccaga taccccagaa gctcctcctt gctatatgga catcattcct 3540 gaagatcaca gactagagag ccccaccacc cctctgctgg acgatgtgga cgactctcaa 3600 gacagcccta tctttatgta cgcccctgag ttccagttca tgcccccacc cacttacact 3660 gaggtggatc cgtgcgtcct taacaacaac aacaacaaca acaacgtgca gtagtggatc 3720caatcaacct ctggattaca aaatttgtga aagattgact ggtattctta actatgttgc 3780tccttttacg ctatgtggat acgctgcttt aatgcctttg tatcatgcta ttgcttcccg 3840 tatggctttc attttctcct ccttgtataa atcctggttg ctgtctcttt atgaggagtt 3900 gtggcccgtt gtcaggcaac gtggcgtggt gtgcactgtg tttgctgacg caacccccac 3960 tggttggggc attgccacca cctgtcagct cctttccggg actttcgctt tccccctccc 4020 tattgccacg gcggaactca tcgccgcctg ccttgcccgc tgctggacag gggctcggct 4080 gttgggcact gacaattccg tggtgttgtc ggggaagctg acgtcctttc catggctgct 4140 cgcctgtgtt gccacctgga ttctgcgcgg gacgtccttc tgctacgtcc cttcggccct 4200 caatccagcg gaccttcctt cccgcggcct gctgccggct ctgcggcctc ttccgcgtct 4260 tcgagatctg cctcgactgt gccttctagt tgccagccat ctgttgtttg cccctccccc 4320 gtgccttcct tgaccctgga aggtgccact cccactgtcc tttcctaata aaatgaggaa 4380 attgcatcgc attgtctgag taggtgtcat tctattctgg ggggtggggt ggggcaggac 4440 agcaaggggg aggattggga agacaatagc aggcatgctg gggactcgag ttaagggcga 4500 attcccgatt aggatcttcc tagagcatgg ctacgtagat aagtagcatg gcgggttaat 4560 cattaactac aaggaacccc tagtgatgga gttggccact ccctctctgc gcgctcgctc 4620 gctcactgag gccgggcgac caaaggtcgc ccgacgcccg ggctttgccc gggcggcctc 4680 agtgagcgag cgagcgcgca gccttaatta acctaattca ctggccgtcg ttttacaacg 4740 tcgtgactgg gaaaaccctg gcgttaccca acttaatcgc cttgcagcac atcccccttt 4800 cgccagctgg cgtaatagcg aagaggcccg caccgatcgc ccttcccaac agttgcgcag 4860 cctgaatggc gaatgggacg cgccctgtag cggcgcatta agcgcggcgg gtgtggtggt 4920 tacgcgcagc gtgaccgcta cacttgccag cgccctagcg cccgctcctt tcgctttctt 4980 cccttccttt ctcgccacgt tcgccggctt tccccgtcaa gctctaaatc gggggctccc 5040 tttagggttc cgatttagtg ctttacggca cctcgacccc aaaaaacttg attagggtga 5100 tggttcacgt agtgggccat cgccccgata gacggttttt cgccctttga cgctggagtt 5160 cacgttcctc aatagtggac tcttgttcca aactggaaca acactcaacc ctatctcggt 5220ctattctttt gatttataag ggatttttcc gatttcggcc tattggttaa aaaatgagct 5280gatttaacaa aaatttaacg cgaattttaa caaaatatta acgtttataa tttcaggtgg 5340 catctttcgg ggaaatgtgc gcggaacccc tatttgttta tttttctaaa tacattcaaa 5400 tatgtatccg ctcatgagac aataaccctg ataaatgctt caataatatt gaaaaaggaa 5460 gagtatgagt attcaacatt tccgtgtcgc ccttattccc ttttttgcgg cattttgcct 5520 tcctgttttt gctcacccag aaacgctggt gaaagtaaaa gatgctgaag atcagttggg 5580 tgcacgagtg ggttacatcg aactggatct caatagtggt aagatccttg agagttttcg 5640 ccccgaagaa cgttttccaa tgatgagcac ttttaaagtt ctgctatgtg gcgcggtatt 5700 atcccgtatt gacgccgggc aagagcaact cggtcgccgc atacactatt ctcagaatga 5760 cttggttgag tactcaccag tcacagaaaa gcatcttacg gatggcatga cagtaagaga 5820 attatgcagt gctgccataa ccatgagtga taacactgcg gccaacttac ttctgacaac 5880 gatcggagga ccgaaggagc taaccgcttt tttgcacaac atgggggatc atgtaactcg 5940 ccttgatcgt tgggaaccgg agctgaatga agccatacca aacgacgagc gtgacaccac 6000 gatgcctgta gtaatggtaa caacgttgcg caaactatta actggcgaac tacttactct 6060 agcttcccgg caacaattaa tagactggat ggaggcggat aaagttgcag gaccacttct 6120gcgctcggcc cttccggctg gctggtttat tgctgataaa tctggagccg gtgagcgtgg 6180gtctcgcggt atcattgcag cactggggcc agatggtaag ccctcccgta tcgtagttat 6240 ctacacgacg gggagtcagg caactatgga tgaacgaaat agacagatcg ctgagatagg 6300 tgcctcactg attaagcatt ggtaactgtc agaccaagtt tactcatata tactttagat 6360 tgatttaaaa cttcattttt aatttaaaag gatctaggtg aagatccttt ttgataatct 6420 catgaccaaa atcccttaac gtgagttttc gttccactga gcgtcagacc ccgtagaaaa 6480 gatcaaagga tcttcttgag atcctttttt tctgcgcgta atctgctgct tgcaaacaaa 6540 aaaaccaccg ctaccagcgg tggtttgttt gccggatcaa gagctaccaa ctctttttcc 6600 gaaggtaact ggcttcagca gagcgcagat accaaatact gtccttctag tgtagccgta 6660 gttaggccac cacttcaaga actctgtagc accgcctaca tacctcgctc tgctaatcct 6720 gttaccagtg gctgctgcca gtggcgataa gtcgtgtctt accgggttgg actcaagacg 6780 atagttaccg gataaggcgc agcggtcggg ctgaacgggg ggttcgtgca cacagcccag 6840 74 ME149103561v.1 117823-35920 cttggagcga acgacctaca ccgaactgag atacctacag cgtgagctat gagaaagcgc 6900 cacgcttccc gaagggagaa aggcggacag gtatccggta agcggcaggg tcggaacagg 6960 agagcgcacg agggagcttc cagggggaaa cgcctggtat ctttatagtc ctgtcgggtt 7020 tcgccacctc tgacttgagc gtcgattttt gtgatgctcg tcaggggggc ggagcctatg 7080 gaaaaacgcc agcaacgcgg cctttttacg gttcctggcc ttttgctgcg gttttgctca 7140 catgttcttt cctgcgttat cccctgattc tgtggataac cgtattaccg cctttgagtg 7200 agctgatacc gctcgccgca gccgaacgac cgagcgcagc gagtcagtga gcgaggaagc 7260 ggaag 7265 <210> 27<211> 90<212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 27 Met Lys Val Glu Gly Ala Leu Glu Lys Asp Met Lys Asn Glu Gly Val 1 5 10 15 Arg Gly Trp Asp Gly Gly Arg Gly Ala Gly Ala Val Ala Ala Gln Glu 20 25 30 Ser Pro Lys Glu Arg Gly Pro Leu Gly Lys Gly Gln Arg Asp Pro Ser 35 40 45 Gln Ala Gly Pro Gln Cys Gln Arg Pro Leu Leu Cys Pro Glu Ser Pro 50 55 60 Thr Leu Ala Ala Ser Trp Gly Pro Gly Gln Gly Gly Arg Leu Asp Val 65 70 75 80 Gly Leu Val Ser Asn Ala Thr Thr Pro Lys 85 90 <210> 28 <211> 99 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide<400> 28 Met Arg Lys Glu Asp Ser Gly Ser Glu Gln Phe His His Pro Pro Pro 1 5 10 15 Ser Leu Gln Ile Leu Thr Arg Gly Ser Thr Cys Pro Lys Gly Gly Arg 20 25 30 Arg Thr Val Glu Gly Asn Arg Glu His Ile Asn Thr Glu Arg Ala Thr 35 40 45 Ala Ala Pro Thr Val Thr Ala Thr Phe Leu Ala Gly Met Gly Gly Ala 50 55 60 Ser Glu Phe Gly Ser Gln Gln Ile Pro Leu Ser Arg Pro Cys Gly Leu 65 70 75 80 Ala Ser Gly Ala Gly Glu Gln Glu Val Gly Gly Gly Gly Leu Ser Pro 85 90 95 Arg Pro Asn <210> 29 <211> 397 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 29 Met Val Met Phe Lys Lys Ile Lys Ser Phe Glu Val Val Phe Asn Asp 1 5 10 15 Pro Glu Lys Val Tyr Gly Ser Gly Glu Lys Val Ala Gly Arg Val Ile 75 ME149103561v.1 117823-35920 20 25 30 Val Glu Val Cys Glu Val Thr Arg Val Lys Ala Val Arg Ile Leu Ala 35 40 45 Cys Gly Val Ala Lys Val Leu Trp Met Gln Gly Ser Gln Gln Cys Lys 50 55 60 Gln Thr Leu Asp Tyr Leu Arg Tyr Glu Asp Thr Leu Leu Leu Glu Glu 65 70 75 80 Gln Pro Thr Ala Gly Glu Asn Glu Met Val Ile Met Arg Pro Gly Asn 85 90 95Lys Tyr Glu Tyr Lys Phe Gly Phe Glu Leu Pro Gln Gly Pro Leu Gly100 105 110 Thr Ser Phe Lys Gly Lys Tyr Gly Cys Val Asp Tyr Trp Val Lys Ala 115 120 125 Phe Leu Asp Arg Pro Ser Gln Pro Thr Gln Glu Ala Lys Lys Asn Phe 130 135 140 Glu Val Met Asp Leu Val Asp Val Asn Thr Pro Asp Leu Met Ala Pro 145 150 155 160 Val Ser Ala Lys Lys Glu Lys Lys Val Ser Cys Met Phe Ile Pro Asp 165 170 175 Gly Arg Val Ser Val Ser Ala Arg Ile Asp Arg Lys Gly Phe Cys Glu 180 185 190 Gly Asp Asp Ile Ser Ile His Ala Asp Phe Glu Asn Thr Cys Ser Arg 195 200 205 Ile Val Val Pro Lys Ala Ala Ile Val Ala Arg His Thr Tyr Leu Ala 210 215 220 Asn Gly Gln Thr Lys Val Phe Thr Gln Lys Leu Ser Ser Val Arg Gly 225 230 235 240 Asn His Ile Ile Ser Gly Thr Cys Ala Ser Trp Arg Gly Lys Ser Leu 245 250 255 Arg Val Gln Lys Ile Arg Pro Ser Ile Leu Gly Cys Asn Ile Leu Lys 260 265 270 Val Glu Tyr Ser Leu Leu Ile Tyr Val Ser Val Pro Gly Ser Lys Lys 275 280 285 Val Ile Leu Asp Leu Pro Leu Val Ile Gly Ser Arg Ser Gly Leu Ser 290 295 300Ser Arg Thr Ser Ser Met Ala Ser Arg Thr Ser Ser Glu Met Ser Trp 305 310 315 320 Ile Asp Leu Asn Ile Pro Asp Thr Pro Glu Ala Pro Pro Cys Tyr Met 325 330 335 Asp Ile Ile Pro Glu Asp His Arg Leu Glu Ser Pro Thr Thr Pro Leu 340 345 350 Leu Asp Asp Val Asp Asp Ser Gln Asp Ser Pro Ile Phe Met Tyr Ala 355 360 365 Pro Glu Phe Gln Phe Met Pro Pro Pro Thr Tyr Thr Glu Val Asp Pro 370 375 380 Cys Val Leu Asn Asn Asn Asn Asn Asn Asn Asn Val Gln 385 390 395 <210> 30 <211> 102<212> PRT<213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 30 Met Asp Val Cys Gln Ser Leu Leu Glu Leu Thr Glu Lys Asp Ser Val 1 5 10 15 Lys Val Met Thr Ser Pro Ser Met Leu Thr Leu Arg Thr Arg Val Pro 20 25 30 Glu Ser Trp Ser Pro Lys Arg Leu Leu Trp Pro Asp Thr Leu Thr Leu 35 40 45 76 ME149103561v.1 117823-35920 Pro Met Ala Arg Pro Lys Cys Ser Leu Arg Ser Cys Pro Arg Ser Glu 50 55 60 Ala Ile Thr Leu Ser Gln Gly Leu Ala His Arg Gly Val Ala Arg Ala 65 70 75 80 Ser Glu Cys Arg Arg Ser Asp His Pro Ser Trp Ala Ala Thr Ser Ser 85 90 95 Lys Ser Asn Thr Pro Cys 100 <210> 31<211> 249<212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 31 Met Trp Thr Thr Leu Lys Thr Ala Leu Ser Leu Cys Thr Pro Leu Ser 1 5 10 15 Ser Ser Ser Cys Pro His Pro Leu Thr Leu Arg Trp Ile Arg Ala Ser 20 25 30 Leu Thr Thr Thr Thr Thr Thr Thr Thr Cys Ser Ser Gly Ser Asn Gln 35 40 45 Pro Leu Asp Tyr Lys Ile Cys Glu Arg Leu Thr Gly Ile Leu Asn Tyr 50 55 60 Val Ala Pro Phe Thr Leu Cys Gly Tyr Ala Ala Leu Met Pro Leu Tyr 65 70 75 80 His Ala Ile Ala Ser Arg Met Ala Phe Ile Phe Ser Ser Leu Tyr Lys 85 90 95 Ser Trp Leu Leu Ser Leu Tyr Glu Glu Leu Trp Pro Val Val Arg Gln 100 105 110 Arg Gly Val Val Cys Thr Val Phe Ala Asp Ala Thr Pro Thr Gly Trp 115 120 125 Gly Ile Ala Thr Thr Cys Gln Leu Leu Ser Gly Thr Phe Ala Phe Pro 130 135 140Leu Pro Ile Ala Thr Ala Glu Leu Ile Ala Ala Cys Leu Ala Arg Cys145 150 155 160 Trp Thr Gly Ala Arg Leu Leu Gly Thr Asp Asn Ser Val Val Leu Ser 165 170 175 Gly Lys Leu Thr Ser Phe Pro Trp Leu Leu Ala Cys Val Ala Thr Trp 180 185 190 Ile Leu Arg Gly Thr Ser Phe Cys Tyr Val Pro Ser Ala Leu Asn Pro 195 200 205 Ala Asp Leu Pro Ser Arg Gly Leu Leu Pro Ala Leu Arg Pro Leu Pro 210 215 220 Arg Leu Arg Asp Leu Pro Arg Leu Cys Leu Leu Val Ala Ser His Leu 225 230 235 240 Leu Phe Ala Pro Pro Pro Cys Leu Pro 245 <210> 32<211> 98<212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 32 Met Leu Leu Leu Pro Val Trp Leu Ser Phe Ser Pro Pro Cys Ile Asn 1 5 10 15 Pro Gly Cys Cys Leu Phe Met Arg Ser Cys Gly Pro Leu Ser Gly Asn 20 25 30 Val Ala Trp Cys Ala Leu Cys Leu Leu Thr Gln Pro Pro Leu Val Gly 77 ME149103561v.1 117823-35920 35 40 45 Ala Leu Pro Pro Pro Val Ser Ser Phe Pro Gly Leu Ser Leu Ser Pro 50 55 60 Ser Leu Leu Pro Arg Arg Asn Ser Ser Pro Pro Ala Leu Pro Ala Ala 65 70 75 80 Gly Gln Gly Leu Gly Cys Trp Ala Leu Thr Ile Pro Trp Cys Cys Arg 85 90 95 Gly Ser<210> 33<211> 78 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 33 Met Ala Ala Arg Leu Cys Cys His Leu Asp Ser Ala Arg Asp Val Leu 1 5 10 15 Leu Leu Arg Pro Phe Gly Pro Gln Ser Ser Gly Pro Ser Phe Pro Arg 20 25 30 Pro Ala Ala Gly Ser Ala Ala Ser Ser Ala Ser Ser Arg Ser Ala Ser 35 40 45 Thr Val Pro Ser Ser Cys Gln Pro Ser Val Val Cys Pro Ser Pro Val 50 55 60 Pro Ser Leu Thr Leu Glu Gly Ala Thr Pro Thr Val Leu Ser 65 70 75 <210> 34 <211> 97 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide<400> 34Met Pro Ala Ile Val Phe Pro Ile Leu Pro Leu Ala Val Leu Pro His 1 5 10 15 Pro Thr Pro Gln Asn Arg Met Thr Pro Thr Gln Thr Met Arg Cys Asn 20 25 30 Phe Leu Ile Leu Leu Gly Lys Asp Ser Gly Ser Gly Thr Phe Gln Gly 35 40 45 Gln Gly Arg His Gly Gly Gly Ala Asn Asn Arg Trp Leu Ala Thr Arg 50 55 60 Arg His Ser Arg Gly Arg Ser Arg Arg Arg Gly Arg Gly Arg Arg Ala 65 70 75 80 Gly Ser Arg Pro Arg Glu Gly Arg Ser Ala Gly Leu Arg Ala Glu Gly 85 90 95 Thr<210> 35<211> 286 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 35 Met Ser Ile Gln His Phe Arg Val Ala Leu Ile Pro Phe Phe Ala Ala 1 5 10 15 Phe Cys Leu Pro Val Phe Ala His Pro Glu Thr Leu Val Lys Val Lys 20 25 30 78 ME149103561v.1 117823-35920 Asp Ala Glu Asp Gln Leu Gly Ala Arg Val Gly Tyr Ile Glu Leu Asp 35 40 45 Leu Asn Ser Gly Lys Ile Leu Glu Ser Phe Arg Pro Glu Glu Arg Phe 50 55 60 Pro Met Met Ser Thr Phe Lys Val Leu Leu Cys Gly Ala Val Leu Ser 65 70 75 80 Arg Ile Asp Ala Gly Gln Glu Gln Leu Gly Arg Arg Ile His Tyr Ser 85 90 95 Gln Asn Asp Leu Val Glu Tyr Ser Pro Val Thr Glu Lys His Leu Thr 100 105 110Asp Gly Met Thr Val Arg Glu Leu Cys Ser Ala Ala Ile Thr Met Ser 115 120 125 Asp Asn Thr Ala Ala Asn Leu Leu Leu Thr Thr Ile Gly Gly Pro Lys 130 135 140 Glu Leu Thr Ala Phe Leu His Asn Met Gly Asp His Val Thr Arg Leu 145 150 155 160 Asp Arg Trp Glu Pro Glu Leu Asn Glu Ala Ile Pro Asn Asp Glu Arg 165 170 175 Asp Thr Thr Met Pro Val Val Met Val Thr Thr Leu Arg Lys Leu Leu 180 185 190 Thr Gly Glu Leu Leu Thr Leu Ala Ser Arg Gln Gln Leu Ile Asp Trp 195 200 205 Met Glu Ala Asp Lys Val Ala Gly Pro Leu Leu Arg Ser Ala Leu Pro 210 215 220 Ala Gly Trp Phe Ile Ala Asp Lys Ser Gly Ala Gly Glu Arg Gly Ser 225 230 235 240 Arg Gly Ile Ile Ala Ala Leu Gly Pro Asp Gly Lys Pro Ser Arg Ile 245 250 255 Val Val Ile Tyr Thr Thr Gly Ser Gln Ala Thr Met Asp Glu Arg Asn 260 265 270 Arg Gln Ile Ala Glu Ile Gly Ala Ser Leu Ile Lys His Trp 275 280 285 <210> 36 <211> 88<212> PRT<213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 36 Met Ile Pro Arg Asp Pro Arg Ser Pro Ala Pro Asp Leu Ser Ala Ile 1 5 10 15 Asn Gln Pro Ala Gly Arg Ala Glu Arg Arg Ser Gly Pro Ala Thr Leu 20 25 30 Ser Ala Ser Ile Gln Ser Ile Asn Cys Cys Arg Glu Ala Arg Val Ser 35 40 45 Ser Ser Pro Val Asn Ser Leu Arg Asn Val Val Thr Ile Thr Thr Gly 50 55 60 Ile Val Val Ser Arg Ser Ser Phe Gly Met Ala Ser Phe Ser Ser Gly65 70 75 80Ser Gln Arg Ser Arg Arg Val Thr 85 <210> 37 <211> 43 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic primer <400> 37 acagggcttt ccatagcggt accatggtga tgttcaagaa gat 43 79 ME149103561v.1 117823-35920 <210> 38 <211> 40 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic primer <400> 38 ccagaggttg attggatcca ctactgcacg ttgttgttgt 40<210> 39<211> 5038 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 39 cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcaaag cccgggcgtc 60 gggcgacctt tggtcgcccg gcctcagtga gcgagcgagc gcgcagagag ggagtggcca 120 actccatcac taggggttcc tgcggccgca cgcgtcatcc tgagagatga gccaggacaa 180 agaaccagta atagctcctg gagcagcaca tctgttttgc caggattatc ccttggatct 240 cttaaaaccg agaccttgta atctgaagac tcaacttggg ctgtaccctt aaccttcagc 300 tctatgatgc aagtgagtcc acaggaccgg aggctttgag atgagctttt cagaagggag 360 gagttggccg cttgctccca gagctccagc acctgcattc ttctggctat gtcagaagcc 420 agatcatttc cctcgttaaa aacaaaaaca aaaaaacaaa caaacaaaat gttagtcttt 480 gccctttatc tgcctggcaa agcttttaat tggcttgatc tgtcattccg ctagacataa 540 aggggacaat ccccggatta ggaaggagct ctccagctcg ggtaaggagt ctcaaggcaa 600 ggtaggcaag caccaccggt ccgcactctc gcccagcttt tacgggaaga agagagggta 660 ccatggtgat gttcaagaag atcaagtctt ttgaggtggt cttcaacgac cccgagaaag 720 tgtacggcag cggggagaag gtggccggac gggtaattgt ggaagtgtgt gaagttaccc 780 gagtcaaagc tgtcaggatc ctggcttgcg gcgtggccaa ggtcctgtgg atgcaagggt 840 ctcagcagtg caaacagact ttggactact tgcgctatga agacacactt ctcctagaag 900 agcagcctac agcaggtgag aacgagatgg tgatcatgag gcctggaaac aaatatgagt 960 acaagttcgg cttcgagctt cctcaagggc ccctgggaac atcctttaaa ggaaaatatg 1020gttgcgtaga ctactgggtg aaggcttttc tcgatcgccc cagccagcca actcaagagg 1080caaagaaaaa cttcgaagtg atggatctag tggatgtcaa tacccctgac ttaatggcac 1140 cagtgtctgc caaaaaggag aagaaagttt cctgcatgtt cattcctgat ggacgtgtgt 1200 cagtctctgc tcgaattgac cgaaaaggat tctgtgaagg tgatgacatc tccatccatg 1260 ctgactttga gaacacgtgt tcccgaatcg tggtccccaa agcggctatt gtggcccgac 1320 acacttacct tgccaatggc cagaccaaag tgttcactca gaagctgtcc tcggtcagag 1380 gcaatcacat tatctcaggg acttgcgcat cgtggcgtgg caagagcctc agagtgcaga 1440 agatcagacc atccatcctg ggctgcaaca tcctcaaagt cgaatactcc ttgctgatct 1500 acgtcagtgt ccctggctcc aagaaagtca tccttgatct gcccctagtg attggcagca 1560 ggtctggtct gagcagccgg acatccagca tggccagccg gacgagctct gagatgagct 1620 ggatagacct aaacatccca gataccccag aagctcctcc ttgctatatg gacatcattc 1680 ctgaagatca cagactagag agccccacca cccctctgct ggacgatgtg gacgactctc 1740 aagacagccc tatctttatg tacgcccctg agttccagtt catgccccca cccacttaca 1800 ctgaggtgga tccgtgcgtc cttaacaaca acaacaacaa caacaacgtg cagtagccgc 1860 tcgagataat caacctctgg attacaaaat ttgtgaaaga ttgactggta ttcttaacta 1920tgttgctcct tttacgctat gtggatacgc tgctttaatg cctttgtatc atgctattgc 1980ttcccgtatg gctttcattt tctcctcctt gtataaatcc tggttagttc ttgccacggc 2040 ggaactcatc gccgcctgcc ttgcccgctg ctggacaggg gctcggctgt tgggcactga 2100 caattccgtg gtgtttattt gtgaaatttg tgatgctatt gctttatttg taaccatcta 2160 gctttatttg tgaaatttgt gatgctattg ctttatttgt aaccattata agctgcaata 2220 aacaagttaa caacaacaat tgcattcatt ttatgtttca ggttcagggg gagatgtggg 2280 aggtttttta aagcggccgc aggaacccct agtgatggag ttggccactc cctctctgcg 2340 cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc cgacgcccgg gctttgcccg 2400 ggcggcctca gtgagcgagc gagcgcgcag ctgcctgcag gggcgcctga tgcggtattt 2460 tctccttacg catctgtgcg gtatttcaca ccgcatacgt caaagcaacc atagtacgcg 2520 ccctgtagcg gcgcattaag cgcggcgggt gtggtggtta cgcgcagcgt gaccgctaca 2580 cttgccagcg ccctagcgcc cgctcctttc gctttcttcc cttcctttct cgccacgttc 2640 80 ME149103561v.1 117823-35920 gccggctttc cccgtcaagc tctaaatcgg gggctccctt tagggttccg atttagtgct 2700 ttacggcacc tcgaccccaa aaaacttgat ttgggtgatg gttcacgtag tgggccatcg 2760 ccctgataga cggtttttcg ccctttgacg ttggagtcca cgttctttaa tagtggactc 2820 ttgttccaaa ctggaacaac actcaaccct atctcgggct attcttttga tttataaggg 2880 attttgccga tttcggccta ttggttaaaa aatgagctga tttaacaaaa atttaacgcg 2940 aattttaaca aaatattaac gtttacaatt ttatggtgca ctctcagtac aatctgctct 3000 gatgccgcat agttaagcca gccccgacac ccgccaacac ccgctgacgc gccctgacgg 3060 gcttgtctgc tcccggcatc cgcttacaga caagctgtga ccgtctccgg gagctgcatg 3120 tgtcagaggt tttcaccgtc atcaccgaaa cgcgcgagac gaaagggcct cgtgatacgc 3180ctatttttat aggttaatgt catgataata atggtttctt agacgtcagg tggcactttt 3240cggggaaatg tgcgcggaac ccctatttgt ttatttttct aaatacattc aaatatgtat 3300 ccgctcatga gacaataacc ctgataaatg cttcaataat attgaaaaag gaagagtatg 3360 agtattcaac atttccgtgt cgcccttatt cccttttttg cggcattttg ccttcctgtt 3420 tttgctcacc cagaaacgct ggtgaaagta aaagatgctg aagatcagtt gggtgcacga 3480 gtgggttaca tcgaactgga tctcaacagc ggtaagatcc ttgagagttt tcgccccgaa 3540 gaacgttttc caatgatgag cacttttaaa gttctgctat gtggcgcggt attatcccgt 3600 attgacgccg ggcaagagca actcggtcgc cgcatacact attctcagaa tgacttggtt 3660 gagtactcac cagtcacaga aaagcatctt acggatggca tgacagtaag agaattatgc 3720 agtgctgcca taaccatgag tgataacact gcggccaact tacttctgac aacgatcgga 3780 ggaccgaagg agctaaccgc ttttttgcac aacatggggg atcatgtaac tcgccttgat 3840 cgttgggaac cggagctgaa tgaagccata ccaaacgacg agcgtgacac cacgatgcct 3900 gtagcaatgg caacaacgtt gcgcaaacta ttaactggcg aactacttac tctagcttcc 3960 cggcaacaat taatagactg gatggaggcg gataaagttg caggaccact tctgcgctcg 4020 gcccttccgg ctggctggtt tattgctgat aaatctggag ccggtgagcg tgggtctcgc 4080 ggtatcattg cagcactggg gccagatggt aagccctccc gtatcgtagt tatctacacg 4140 acggggagtc aggcaactat ggatgaacga aatagacaga tcgctgagat aggtgcctca 4200 ctgattaagc attggtaact gtcagaccaa gtttactcat atatacttta gattgattta 4260 aaacttcatt tttaatttaa aaggatctag gtgaagatcc tttttgataa tctcatgacc 4320 aaaatccctt aacgtgagtt ttcgttccac tgagcgtcag accccgtaga aaagatcaaa 4380 ggatcttctt gagatccttt ttttctgcgc gtaatctgct gcttgcaaac aaaaaaacca 4440 ccgctaccag cggtggtttg tttgccggat caagagctac caactctttt tccgaaggta 4500 actggcttca gcagagcgca gataccaaat actgtccttc tagtgtagcc gtagttaggc 4560 caccacttca agaactctgt agcaccgcct acatacctcg ctctgctaat cctgttacca 4620 gtggctgctg ccagtggcga taagtcgtgt cttaccgggt tggactcaag acgatagtta 4680ccggataagg cgcagcggtc gggctgaacg gggggttcgt gcacacagcc cagcttggag 4740cgaacgacct acaccgaact gagataccta cagcgtgagc tatgagaaag cgccacgctt 4800 cccgaaggga gaaaggcgga caggtatccg gtaagcggca gggtcggaac aggagagcgc 4860 acgagggagc ttccaggggg aaacgcctgg tatctttata gtcctgtcgg gtttcgccac 4920 ctctgacttg agcgtcgatt tttgtgatgc tcgtcagggg ggcggagcct atggaaaaac 4980 gccagcaacg cggccttttt acggttcctg gccttttgct ggccttttgc tcacatgt 5038 <210> 40 <211> 104 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 40 Met Gln Val Leu Glu Leu Trp Glu Gln Ala Ala Asn Ser Ser Leu Leu1 5 10 15Lys Ser Ser Ser Gln Ser Leu Arg Ser Cys Gly Leu Thr Cys Ile Ile 20 25 30 Glu Leu Lys Val Lys Gly Thr Ala Gln Val Glu Ser Ser Asp Tyr Lys 35 40 45 Val Ser Val Leu Arg Asp Pro Arg Asp Asn Pro Gly Lys Thr Asp Val 50 55 60 Leu Leu Gln Glu Leu Leu Leu Val Leu Cys Pro Gly Ser Ser Leu Arg 65 70 75 80 Met Thr Arg Ala Ala Ala Gly Thr Pro Ser Asp Gly Val Gly His Ser 85 90 95 Leu Ser Ala Arg Ser Leu Ala His 81 ME149103561v.1 117823-35920 100 <210> 41 <211> 81 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 41Met Arg Cys Glu Ile Pro His Arg Cys Val Arg Arg Lys Tyr Arg Ile1 5 10 15 Arg Arg Pro Cys Arg Gln Leu Arg Ala Arg Ser Leu Thr Glu Ala Ala 20 25 30 Arg Ala Lys Pro Gly Arg Arg Ala Thr Phe Gly Arg Pro Ala Ser Val 35 40 45 Ser Glu Arg Ala Arg Arg Glu Gly Val Ala Asn Ser Ile Thr Arg Gly 50 55 60 Ser Cys Gly Arg Phe Lys Lys Pro Pro Thr Ser Pro Pro Glu Pro Glu 65 70 75 80 Thr <210> 42 <211> 74 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 42 Met Glu Leu Ala Thr Pro Ser Leu Arg Ala Arg Ser Leu Thr Glu Ala 1 5 10 15 Gly Arg Pro Lys Val Ala Arg Arg Pro Gly Phe Ala Arg Ala Ala Ser 20 25 30 Val Ser Glu Arg Ala Arg Ser Cys Leu Gln Gly Arg Leu Met Arg Tyr 35 40 45Phe Leu Leu Thr His Leu Cys Gly Ile Ser His Arg Ile Arg Gln Ser 50 55 60 Asn His Ser Thr Arg Pro Val Ala Ala His 65 70 <210> 43 <211> 286 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 43 Met Ser Ile Gln His Phe Arg Val Ala Leu Ile Pro Phe Phe Ala Ala 1 5 10 15Phe Cys Leu Pro Val Phe Ala His Pro Glu Thr Leu Val Lys Val Lys20 25 30 Asp Ala Glu Asp Gln Leu Gly Ala Arg Val Gly Tyr Ile Glu Leu Asp 35 40 45 Leu Asn Ser Gly Lys Ile Leu Glu Ser Phe Arg Pro Glu Glu Arg Phe 50 55 60 Pro Met Met Ser Thr Phe Lys Val Leu Leu Cys Gly Ala Val Leu Ser 65 70 75 80 Arg Ile Asp Ala Gly Gln Glu Gln Leu Gly Arg Arg Ile His Tyr Ser 85 90 95 Gln Asn Asp Leu Val Glu Tyr Ser Pro Val Thr Glu Lys His Leu Thr 100 105 110 82 ME149103561v.1 117823-35920 Asp Gly Met Thr Val Arg Glu Leu Cys Ser Ala Ala Ile Thr Met Ser 115 120 125 Asp Asn Thr Ala Ala Asn Leu Leu Leu Thr Thr Ile Gly Gly Pro Lys 130 135 140 Glu Leu Thr Ala Phe Leu His Asn Met Gly Asp His Val Thr Arg Leu 145 150 155 160 Asp Arg Trp Glu Pro Glu Leu Asn Glu Ala Ile Pro Asn Asp Glu Arg 165 170 175 Asp Thr Thr Met Pro Val Ala Met Ala Thr Thr Leu Arg Lys Leu Leu 180 185 190Thr Gly Glu Leu Leu Thr Leu Ala Ser Arg Gln Gln Leu Ile Asp Trp 195 200 205 Met Glu Ala Asp Lys Val Ala Gly Pro Leu Leu Arg Ser Ala Leu Pro 210 215 220 Ala Gly Trp Phe Ile Ala Asp Lys Ser Gly Ala Gly Glu Arg Gly Ser 225 230 235 240 Arg Gly Ile Ile Ala Ala Leu Gly Pro Asp Gly Lys Pro Ser Arg Ile 245 250 255 Val Val Ile Tyr Thr Thr Gly Ser Gln Ala Thr Met Asp Glu Arg Asn 260 265 270 Arg Gln Ile Ala Glu Ile Gly Ala Ser Leu Ile Lys His Trp 275 280 285 <210> 44 <211> 88 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 44 Met Ile Pro Arg Asp Pro Arg Ser Pro Ala Pro Asp Leu Ser Ala Ile 1 5 10 15 Asn Gln Pro Ala Gly Arg Ala Glu Arg Arg Ser Gly Pro Ala Thr Leu 20 25 30Ser Ala Ser Ile Gln Ser Ile Asn Cys Cys Arg Glu Ala Arg Val Ser35 40 45 Ser Ser Pro Val Asn Ser Leu Arg Asn Val Val Ala Ile Ala Thr Gly 50 55 60 Ile Val Val Ser Arg Ser Ser Phe Gly Met Ala Ser Phe Ser Ser Gly 65 70 75 80 Ser Gln Arg Ser Arg Arg Val Thr 85 <210> 45 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic primer<400> 45ctcgggtaag gagtctcaag 20 <210> 46 <211> 40 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic primer <400> 46 cttttacggg aagaagagag ggtaccatgg tgatgttcaa 40 <210> 47 83 ME149103561v.1 117823-35920 <211> 40 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic primer <400> 47 aggttgatta tctcgagcgg ctactgcacg ttgttgttgt 40 <210> 48<211> 20<212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic primer <400> 48 aagcagcgta tccacatagc 20 <210> 49 <211> 7072 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 49 agcgcccaat acgcaaaccg cctctccccg cgcgttggcc gattcattaa tgcagctggc 60 acgacaggtt tcccgactgg aaagcgggca gtgagcgcaa cgcaattaat gtgagttagc 120 tcactcatta ggcaccccag gctttacact ttatgcttcc ggctcgtatg ttgtgtggaa 180 ttgtgagcgg ataacaattt cacacaggaa acagctatga ccatgattac gccagattta 240 attaaggctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg ggcgtcgggc 300 gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagagggag tggccaactc 360 catcactagg ggttccttgt agttaatgat taacccgcca tgctacttat ctacgtagcc 420 atgctctagg aagatcggaa ttcgccctta agctagccta cagcagccag ggtgagatta 480 tgaggctgag ctgagaatat caagactgta ccgagtaggg ggccttggca agtgtggaga 540gcccggcagc tggggcagag ggcggagtac ggtgtgcgtt tacggacctc ttcaaacgag 600gtaggaaggt cagaagtcaa aaagggaaca aatgatgttt aaccacacaa aaatgaaaat 660 ccaatggttg gatatccatt ccaaatacac aaaggcaacg gataagtgat ccgggccagg 720 cacagaaggc catgcacccg taggattgca ctcagagctc ccaaatgcat aggaatagaa 780 gggtgggtgc aggaggctga ggggtgggga aagggcatgg gtgtttcatg aggacagagc 840 ttccgtttca tgcaatgaaa agagtttgga gacggatggt ggtgactgga ctatacactt 900 acacacggta gcgatggtac actttgtatt atgtatattt taccacgatc tttttaaagt 960 gtcaaaggca aatggccaaa tggttccttg tcctatagct gtagcagcca tcggctgtta 1020 gtgacaaagc ccctgagtca agatgacagc agcccccata actcctaatc ggctctcccg 1080 cgtggagtca tttaggagta gtcgcattag agacaagtcc aacatctaat cttccaccct 1140 ggccagggcc ccagctggca gcgagggtgg gagactccgg gcagagcaga gggcgctgac 1200 attggggccc ggcctggctt gggtccctct ggcctttccc caggggccct ctttccttgg 1260 ggctttcttg ggccgccact gctcccgctc ctctcccccc atcccacccc ctcaccccct 1320 cgttcttcat atccttctct agtgctccct ccactttcat ccacccttct gcaagagtgt 1380 gggaccacaa atgagttttc acctggcctg gggacacacg tgcccccaca ggtgctgagt 1440gactttctag gacagtaatc tgctttaggc taaaatggga cttgatcttc tgttagccct 1500aatcatcaat tagcagagcc ggtgaaggtg cagaacctac cgcctttcca ggcctcctcc 1560 cacctctgcc acctccactc tccttcctgg gatgtggggg ctggcacacg tgtggcccag 1620 ggcattggtg ggattgcact gagctgggtc attagcgtaa tcctggacaa gggcagacag 1680 ggcgagcgga gggccagctc cggggctcag gcaaggctgg gggcttcccc cagacacccc 1740 actcctcctc tgctggaccc ccacttcata gggcacttcg tgttctcaaa gggcttccaa 1800 atagcatggt ggccttggat gcccagggaa gcctcagagt tgcttatctc cctctagaca 1860 gaaggggaat ctcggtcaag agggagaggt cgccctgttc aaggccaccc agccagctca 1920 tggcggtaat gggacaaggc tggccagcca tcccaccctc agaagggacc cggtggggca 1980 ggtgatctca gaggaggctc acttctgggt ctcacattct tggatccggt tccaggcctc 2040 ggccctaaat agtctccctg ggctttcaag agaaccacat gagaaaggag gattcgggct 2100 ctgagcagtt tcaccaccca ccccccagtc tgcaaatcct gacccgtggg tccacctgcc 2160 84 ME149103561v.1 117823-35920 ccaaaggcgg acgcaggaca gtagaaggga acagagaaca cataaacaca gagagggcca 2220 cagcggctcc cacagtcacc gccaccttcc tggcggggat gggtggggcg tctgagtttg 2280 gttcccagca aatccctctg agccgccctt gcgggctcgc ctcaggagca ggggagcaag 2340 aggtgggagg aggaggtcta agtcccaggc ccaattaaga gatcaggtag tgtagggttt 2400 gggagctttt aaggtgaaga ggcccgggct gatcccacag gccagtataa agcgccgtga 2460 ccctcaggtg atgcgccagg gccggctgcc gtcggggaca gggctttcca tagcatatgg 2520 caacccttaa ggagaagctc attgcgtccg ttgcagatga tgaggctgcc gtcccgaaca 2580 acaagatcac tgtagtgggc gttggacaag tgggtatggc atgtgccatc agcattctgg 2640 gaaagtctct ggctgatgaa cttgccctgg tggatgtgtt ggaagacaag ctcaaaggag 2700agatgatgga cctgcagcac gggagcttgt tcctccagac tccgaaaatt gtggccgata 2760aagattactc tgtgacagcc aactctaaga ttgtggtggt gacggcagga gtccgccagc 2820 aggaggggga gagtcggctc aacctggtgc agagaaatgt caacgtgttc aagttcatca 2880 ttcctcagat cgtcaagtac agccctgact gcaccatcat cgtggtttcc aacccagtgg 2940 atattctgac ttacgtcacc tggaaactga gcgggctacc taagcaccgt gtgattggaa 3000 gcggatgcaa tctggattct gctcgattcc gctacctcat ggcagagaag cttggcattc 3060 atcccagcag ctgccacgga tggatcctgg gcgagcatgg agactccagt gtggctgtgt 3120 ggagcggggt gaatgtggca ggagtctccc tccaggaact gaatccagaa atggggacag 3180 acaatgacag tgagaactgg aaggaggtgc ataagatggt ggtggacagt gcctatgaag 3240 tcatcaagct caaaggctac accaactggg ccatcggcct gagcgtggct gacctcatcg 3300 agtccatgct gaaaaacctc tcccggattc accccgtgtc taccatggtg aagggaatgt 3360 acggcattga gaatgaagtc ttcctcagtc tcccgtgcat cctcaatgct cgggggctga 3420 ccagcgtcat caatcagaag ctgaaggacg atgaggtcgc tcagctcagg aagagtgcgg 3480 acaccctgtg ggacatccag aaagacctca aagacctgtg atggatccaa tcaacctctg 3540 gattacaaaa tttgtgaaag attgactggt attcttaact atgttgctcc ttttacgcta 3600 tgtggatacg ctgctttaat gcctttgtat catgctattg cttcccgtat ggctttcatt 3660 ttctcctcct tgtataaatc ctggttgctg tctctttatg aggagttgtg gcccgttgtc 3720 aggcaacgtg gcgtggtgtg cactgtgttt gctgacgcaa cccccactgg ttggggcatt 3780 gccaccacct gtcagctcct ttccgggact ttcgctttcc ccctccctat tgccacggcg 3840 gaactcatcg ccgcctgcct tgcccgctgc tggacagggg ctcggctgtt gggcactgac 3900 aattccgtgg tgttgtcggg gaagctgacg tcctttccat ggctgctcgc ctgtgttgcc 3960 acctggattc tgcgcgggac gtccttctgc tacgtccctt cggccctcaa tccagcggac 4020 cttccttccc gcggcctgct gccggctctg cggcctcttc cgcgtcttcg agatctgcct 4080 cgactgtgcc ttctagttgc cagccatctg ttgtttgccc ctcccccgtg ccttccttga 4140 ccctggaagg tgccactccc actgtccttt cctaataaaa tgaggaaatt gcatcgcatt 4200gtctgagtag gtgtcattct attctggggg gtggggtggg gcaggacagc aagggggagg 4260attgggaaga caatagcagg catgctgggg actcgagtta agggcgaatt cccgattagg 4320 atcttcctag agcatggcta cgtagataag tagcatggcg ggttaatcat taactacaag 4380 gaacccctag tgatggagtt ggccactccc tctctgcgcg ctcgctcgct cactgaggcc 4440 gggcgaccaa aggtcgcccg acgcccgggc tttgcccggg cggcctcagt gagcgagcga 4500 gcgcgcagcc ttaattaacc taattcactg gccgtcgttt tacaacgtcg tgactgggaa 4560 aaccctggcg ttacccaact taatcgcctt gcagcacatc cccctttcgc cagctggcgt 4620 aatagcgaag aggcccgcac cgatcgccct tcccaacagt tgcgcagcct gaatggcgaa 4680 tgggacgcgc cctgtagcgg cgcattaagc gcggcgggtg tggtggttac gcgcagcgtg 4740 accgctacac ttgccagcgc cctagcgccc gctcctttcg ctttcttccc ttcctttctc 4800 gccacgttcg ccggctttcc ccgtcaagct ctaaatcggg ggctcccttt agggttccga 4860 tttagtgctt tacggcacct cgaccccaaa aaacttgatt agggtgatgg ttcacgtagt 4920 gggccatcgc cccgatagac ggtttttcgc cctttgacgc tggagttcac gttcctcaat 4980 agtggactct tgttccaaac tggaacaaca ctcaacccta tctcggtcta ttcttttgat 5040 ttataaggga tttttccgat ttcggcctat tggttaaaaa atgagctgat ttaacaaaaa 5100tttaacgcga attttaacaa aatattaacg tttataattt caggtggcat ctttcgggga 5160aatgtgcgcg gaacccctat ttgtttattt ttctaaatac attcaaatat gtatccgctc 5220 atgagacaat aaccctgata aatgcttcaa taatattgaa aaaggaagag tatgagtatt 5280 caacatttcc gtgtcgccct tattcccttt tttgcggcat tttgccttcc tgtttttgct 5340 cacccagaaa cgctggtgaa agtaaaagat gctgaagatc agttgggtgc acgagtgggt 5400 tacatcgaac tggatctcaa tagtggtaag atccttgaga gttttcgccc cgaagaacgt 5460 tttccaatga tgagcacttt taaagttctg ctatgtggcg cggtattatc ccgtattgac 5520 gccgggcaag agcaactcgg tcgccgcata cactattctc agaatgactt ggttgagtac 5580 tcaccagtca cagaaaagca tcttacggat ggcatgacag taagagaatt atgcagtgct 5640 gccataacca tgagtgataa cactgcggcc aacttacttc tgacaacgat cggaggaccg 5700 aaggagctaa ccgctttttt gcacaacatg ggggatcatg taactcgcct tgatcgttgg 5760 gaaccggagc tgaatgaagc cataccaaac gacgagcgtg acaccacgat gcctgtagta 5820 85 ME149103561v.1 117823-35920 atggtaacaa cgttgcgcaa actattaact ggcgaactac ttactctagc ttcccggcaa 5880 caattaatag actggatgga ggcggataaa gttgcaggac cacttctgcg ctcggccctt 5940 ccggctggct ggtttattgc tgataaatct ggagccggtg agcgtgggtc tcgcggtatc 6000 attgcagcac tggggccaga tggtaagccc tcccgtatcg tagttatcta cacgacgggg 6060 agtcaggcaa ctatggatga acgaaataga cagatcgctg agataggtgc ctcactgatt 6120 aagcattggt aactgtcaga ccaagtttac tcatatatac tttagattga tttaaaactt 6180 catttttaat ttaaaaggat ctaggtgaag atcctttttg ataatctcat gaccaaaatc 6240 ccttaacgtg agttttcgtt ccactgagcg tcagaccccg tagaaaagat caaaggatct 6300 tcttgagatc ctttttttct gcgcgtaatc tgctgcttgc aaacaaaaaa accaccgcta 6360ccagcggtgg tttgtttgcc ggatcaagag ctaccaactc tttttccgaa ggtaactggc 6420ttcagcagag cgcagatacc aaatactgtc cttctagtgt agccgtagtt aggccaccac 6480 ttcaagaact ctgtagcacc gcctacatac ctcgctctgc taatcctgtt accagtggct 6540 gctgccagtg gcgataagtc gtgtcttacc gggttggact caagacgata gttaccggat 6600 aaggcgcagc ggtcgggctg aacggggggt tcgtgcacac agcccagctt ggagcgaacg 6660 acctacaccg aactgagata cctacagcgt gagctatgag aaagcgccac gcttcccgaa 6720 gggagaaagg cggacaggta tccggtaagc ggcagggtcg gaacaggaga gcgcacgagg 6780 gagcttccag ggggaaacgc ctggtatctt tatagtcctg tcgggtttcg ccacctctga 6840 cttgagcgtc gatttttgtg atgctcgtca ggggggcgga gcctatggaa aaacgccagc 6900 aacgcggcct ttttacggtt cctggccttt tgctgcggtt ttgctcacat gttctttcct 6960 gcgttatccc ctgattctgt ggataaccgt attaccgcct ttgagtgagc tgataccgct 7020 cgccgcagcc gaacgaccga gcgcagcgag tcagtgagcg aggaagcgga ag 7072 <210> 50 <211> 86 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 50 Met Leu Met Ala His Ala Ile Pro Thr Cys Pro Thr Pro Thr Thr Val 1 5 10 15 Ile Leu Leu Phe Gly Thr Ala Ala Ser Ser Ser Ala Thr Asp Ala Met 20 25 30 Ser Phe Ser Leu Arg Val Ala Ile Cys Tyr Gly Lys Pro Cys Pro Arg 35 40 45Arg Gln Pro Ala Leu Ala His His Leu Arg Val Thr Ala Leu Tyr Thr 50 55 60 Gly Leu Trp Asp Gln Pro Gly Pro Leu His Leu Lys Ser Ser Gln Thr 65 70 75 80 Leu His Tyr Leu Ile Ser 85 <210> 51 <211> 334 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 51Met Ala Thr Leu Lys Glu Lys Leu Ile Ala Ser Val Ala Asp Asp Glu1 5 10 15 Ala Ala Val Pro Asn Asn Lys Ile Thr Val Val Gly Val Gly Gln Val 20 25 30 Gly Met Ala Cys Ala Ile Ser Ile Leu Gly Lys Ser Leu Ala Asp Glu 35 40 45 Leu Ala Leu Val Asp Val Leu Glu Asp Lys Leu Lys Gly Glu Met Met 50 55 60 Asp Leu Gln His Gly Ser Leu Phe Leu Gln Thr Pro Lys Ile Val Ala 65 70 75 80 Asp Lys Asp Tyr Ser Val Thr Ala Asn Ser Lys Ile Val Val Val Thr 85 90 95 86 ME149103561v.1 117823-35920 Ala Gly Val Arg Gln Gln Glu Gly Glu Ser Arg Leu Asn Leu Val Gln 100 105 110 Arg Asn Val Asn Val Phe Lys Phe Ile Ile Pro Gln Ile Val Lys Tyr 115 120 125 Ser Pro Asp Cys Thr Ile Ile Val Val Ser Asn Pro Val Asp Ile Leu 130 135 140 Thr Tyr Val Thr Trp Lys Leu Ser Gly Leu Pro Lys His Arg Val Ile 145 150 155 160 Gly Ser Gly Cys Asn Leu Asp Ser Ala Arg Phe Arg Tyr Leu Met Ala 165 170 175Glu Lys Leu Gly Ile His Pro Ser Ser Cys His Gly Trp Ile Leu Gly 180 185 190 Glu His Gly Asp Ser Ser Val Ala Val Trp Ser Gly Val Asn Val Ala 195 200 205 Gly Val Ser Leu Gln Glu Leu Asn Pro Glu Met Gly Thr Asp Asn Asp 210 215 220 Ser Glu Asn Trp Lys Glu Val His Lys Met Val Val Asp Ser Ala Tyr 225 230 235 240 Glu Val Ile Lys Leu Lys Gly Tyr Thr Asn Trp Ala Ile Gly Leu Ser 245 250 255 Val Ala Asp Leu Ile Glu Ser Met Leu Lys Asn Leu Ser Arg Ile His 260 265 270 Pro Val Ser Thr Met Val Lys Gly Met Tyr Gly Ile Glu Asn Glu Val 275 280 285 Phe Leu Ser Leu Pro Cys Ile Leu Asn Ala Arg Gly Leu Thr Ser Val 290 295 300 Ile Asn Gln Lys Leu Lys Asp Asp Glu Val Ala Gln Leu Arg Lys Ser 305 310 315 320 Ala Asp Thr Leu Trp Asp Ile Gln Lys Asp Leu Lys Asp Leu 325 330 <210> 52 <211> 78 <212> PRT <213> Artificial Sequence<220><223> Description of Artificial Sequence: Synthetic polypeptide <400> 52 Met His Leu Leu Pro Val Leu Thr Val Ile Val Cys Pro His Phe Trp 1 5 10 15 Ile Gln Phe Leu Glu Gly Asp Ser Cys His Ile His Pro Ala Pro His 20 25 30 Ser His Thr Gly Val Ser Met Leu Ala Gln Asp Pro Ser Val Ala Ala 35 40 45 Ala Gly Met Asn Ala Lys Leu Leu Cys His Glu Val Ala Glu Ser Ser 50 55 60 Arg Ile Gln Ile Ala Ser Ala Ser Asn His Thr Val Leu Arg 65 70 75 <210> 53<211> 229<212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 53 Met Arg Ser Leu Ser Ser Gly Arg Val Arg Thr Pro Cys Gly Thr Ser 1 5 10 15 Arg Lys Thr Ser Lys Thr Cys Asp Gly Ser Asn Gln Pro Leu Asp Tyr 20 25 30 Lys Ile Cys Glu Arg Leu Thr Gly Ile Leu Asn Tyr Val Ala Pro Phe 87 ME149103561v.1 117823-35920 35 40 45 Thr Leu Cys Gly Tyr Ala Ala Leu Met Pro Leu Tyr His Ala Ile Ala 50 55 60 Ser Arg Met Ala Phe Ile Phe Ser Ser Leu Tyr Lys Ser Trp Leu Leu 65 70 75 80 Ser Leu Tyr Glu Glu Leu Trp Pro Val Val Arg Gln Arg Gly Val Val 85 90 95 Cys Thr Val Phe Ala Asp Ala Thr Pro Thr Gly Trp Gly Ile Ala Thr 100 105 110Thr Cys Gln Leu Leu Ser Gly Thr Phe Ala Phe Pro Leu Pro Ile Ala115 120 125 Thr Ala Glu Leu Ile Ala Ala Cys Leu Ala Arg Cys Trp Thr Gly Ala 130 135 140 Arg Leu Leu Gly Thr Asp Asn Ser Val Val Leu Ser Gly Lys Leu Thr 145 150 155 160 Ser Phe Pro Trp Leu Leu Ala Cys Val Ala Thr Trp Ile Leu Arg Gly 165 170 175 Thr Ser Phe Cys Tyr Val Pro Ser Ala Leu Asn Pro Ala Asp Leu Pro 180 185 190 Ser Arg Gly Leu Leu Pro Ala Leu Arg Pro Leu Pro Arg Leu Arg Asp 195 200 205 Leu Pro Arg Leu Cys Leu Leu Val Ala Ser His Leu Leu Phe Ala Pro 210 215 220 Pro Pro Cys Leu Pro 225 <210> 54 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic primer <400> 54 agtataaagc gccgtgacc 19<210> 55<211> 42 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic primer <400> 55 gggacagggc tttccatagc atatggcaac ccttaaggag aa 42 <210> 56 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic primer<400> 56 acaagtgggt atggcatgtg 20 <210> 57 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic primer <400> 57 acaattttcg gagtctggag g 21 88 ME149103561v.1 117823-35920 <210> 58 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic primer <400> 58 agcgacctca tcgtccttc 19<210> 59<211> 40 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic primer <400> 59 ccagaggttg attggatcca tcacaggtct ttgaggtctt 40 <210> 60 <400> 60 000 <210> 61 <400> 61 000 <210> 62 <400> 62 000 <210> 63 <400> 63 000 <210> 64 <400> 64 000 <210> 65<400> 65000 <210> 66 <400> 66 000 <210> 67 <400> 67 000 <210> 68 <400> 68 000 <210> 69 <400> 69 000 <210> 70<400> 70000 <210> 71 <400> 71 000 <210> 72 <400> 72 000 <210> 73 <400> 73 000 <210> 74 89 ME149103561v.1 117823-35920 <400> 74 000 <210> 75 <400> 75 000 <210> 76 <400> 76 000 <210> 77<400> 77000 <210> 78 <400> 78 000 <210> 79 <400> 79 000 <210> 80 <400> 80 000 <210> 81 <400> 81 000 <210> 82 <400> 82 000 <210> 83 <400> 83 000 <210> 84 <400> 84 000 <210> 85 <400> 85000<210> 86 <400> 86 000 <210> 87 <400> 87 000 <210> 88 <400> 88 000 <210> 89 <400> 89 000 <210> 90 <400> 90000<210> 91 <400> 91 000 <210> 92 <400> 92 000 <210> 93 <400> 93 000 <210> 94 <400> 94 90 ME149103561v.1 117823-35920 000 <210> 95 <400> 95 000 <210> 96 <400> 96 000 <210> 97 <400> 97000<210> 98 <400> 98 000 <210> 99 <400> 99 000 <210> 100 <400> 100 000 <210> 101 <211> 2905 <212> DNA <213> Homo sapiens <400> 101 aaactaaccc ctctttttct ccaaaggagt gcttgtggag atcggatctt ttctccagca 60 attgggggaa agaaggcttt ttctctgaat tagcttagtg taaccagcgg cgtatatttt 120 ttaggcgcct tttcgaaaac ctagtagtta atattcattt gtttaaatct tattttattt 180 ttaagctcaa actgcttaag aataccttaa ttccttaaag tgaaataatt ttttgcaaag 240 gggtttcctc gatttggagc tttttttttc ttccaccgtc atttctaact cttaaaacca 300 actcagttcc atcatggtga tgttcaagaa gatcaagtct tttgaggtgg tctttaacga 360 ccctgaaaag gtgtacggca gtggcgagaa ggtggctggc cgggtgatag tggaggtgtg 420 tgaagttact cgtgtcaaag ccgttaggat cctggcttgc ggagtggcta aagtgctttg 480 gatgcaggga tcccagcagt gcaaacagac ttcggagtac ctgcgctatg aagacacgct 540 tcttctggaa gaccagccaa caggtgagaa tgagatggtg atcatgagac ctggaaacaa 600atatgagtac aagttcggct ttgagcttcc tcaggggcct ctgggaacat ccttcaaagg 660aaaatatggg tgtgtagact actgggtgaa ggcttttctt gaccgcccga gccagccaac 720 tcaagagaca aagaaaaact ttgaagtagt ggatctggtg gatgtcaata cccctgattt 780 aatggcacct gtgtctgcta aaaaagaaaa gaaagtttcc tgcatgttca ttcctgatgg 840 gcgggtgtct gtctctgctc gaattgacag aaaaggattc tgtgaaggtg atgagatttc 900 catccatgct gactttgaga atacatgttc ccgaattgtg gtccccaaag ctgccattgt 960 ggcccgccac acttaccttg ccaatggcca gaccaaggtg ctgactcaga agttgtcatc 1020 agtcagaggc aatcatatta tctcagggac atgcgcatca tggcgtggca agagccttcg 1080 ggttcagaag atcaggcctt ctatcctggg ctgcaacatc cttcgagttg aatattcctt 1140 actgatctat gttagcgttc ctggatccaa gaaggtcatc cttgacctgc ccctggtaat 1200 tggcagcaga tcaggtctaa gcagcagaac atccagcatg gccagccgaa ccagctctga 1260 gatgagttgg gtagatctga acatccctga taccccagaa gctcctccct gctatatgga 1320 tgtcattcct gaagatcacc gattggagag cccaaccact cctctgctag atgacatgga 1380 tggctctcaa gacagcccta tctttatgta tgcccctgag ttcaagttca tgccaccacc 1440 gacttatact gaggtggatc cctgcatcct caacaacaat gtgcagtgag catgtggaag 1500aaaagaagca gctttaccta cttgtttctt tttgtctctc ttcctggaca ctcacttttt 1560cagagactca acagtctctg caatggagtg tgggtccacc ttagcctctg acttcctaat 1620 gtaggaggtg gtcagcaggc aatctcctgg gccttaaagg atgcggactc atcctcagcc 1680 agcgcccatg ttgtgataca ggggtgtttg ttggatgggt ttaaaaataa ctagaaaaac 1740 tcaggcccat ccattttctc agatctcctt gaaaattgag gccttttcga tagtttcggg 1800 tcaggtaaaa atggcctcct ggcgtaagct tttcaaggtt ttttggaggc tttttgtaaa 1860 ttgtgatagg aactttggac cttgaactta cgtatcatgt ggagaagagc caatttaaca 1920 aactaggaag atgaaaaggg aaattgtggc caaaactttg ggaaaaggag gttcttaaaa 1980 tcagtgtttc ccctttgtgc acttgtagaa aaaaaagaaa aaccttctag agctgatttg 2040 atggacaatg gagagagctt tccctgtgat tataaaaaag gaagctagct gctctacggt 2100 catctttgct tagagtatac tttaacctgg cttttaaagc agtagtaact gccccaccaa 2160 aggtcttaaa agccattttt ggagcctatt gcactgtgtt ctcctactgc aaatattttc 2220 91 ME149103561v.1 117823-35920 atatgggagg atggttttct cttcatgtaa gtccttggaa ttgattctaa ggtgatgttc 2280 ttagcacttt aattcctgtc aaattttttg ttctcccctt ctgccatctt aaatgtaagc 2340 tgaaactggt ctactgtgtc tctagggtta agccaaaaga caaaaaaaat tttactactt 2400 ttgagattgc cccaatgtac agaattatat aattctaacg cttaaatcat gtgaaagggt 2460 tgctgctgtc agccttgccc actgtgactt caaacccaag gaggaactct tgatcaagat 2520 gcccaaccct gtgatcagaa cctccaaata ctgccatgag aaactagagg gcaggtcttc 2580 ataaaagccc tttgaacccc cttcctgccc tgtgttagga gatagggata ttggcccctc 2640 actgcagctg ccagcacttg gtcagtcact ctcagccata gcactttgtt cactgtcctg 2700 tgtcagagca ctgagctcca cccttttctg agagttatta cagccagaaa gtgtgggctg 2760aagatggttg gtttcatgtt tttgtattat gtatcttttt gtatggtaaa gactatattt 2820tgtacttaac cagatatatt tttaccccag atggggatat tctttgtaaa aaatgaaaat 2880 aaagtttttt taatggaaaa aaaaa 2905 <210> 102 <211> 2610 <212> DNA <213> Homo sapiens <400> 102 attctttgtc tacttcctat ttgagatgtt agtagagaac tgtcctgggt gaatctttca 60 gtattgcagg gcttggcaac ttgctgcccg acaaaataca tcagaatttc tctttaagaa 120 caatatggga tggattaaaa aatatatata tgggatgaaa ttgggggtac ttcaatacct 180 tgcatgccac ccaagcattc cttatcacac agatgcattt taagtgtaac agcaagccta 240 atggctactc gattttcttt cccttcaggt gagaatgaga tggtgatcat gagacctgga 300 aacaaatatg agtacaagtt cggctttgag cttcctcagg ggcctctggg aacatccttc 360 aaaggaaaat atgggtgtgt agactactgg gtgaaggctt ttcttgaccg cccgagccag 420 ccaactcaag agacaaagaa aaactttgaa gtagtggatc tggtggatgt caatacccct 480 gatttaatgg cacctgtgtc tgctaaaaaa gaaaagaaag tttcctgcat gttcattcct 540 gatgggcggg tgtctgtctc tgctcgaatt gacagaaaag gattctgtga aggtgatgag 600 atttccatcc atgctgactt tgagaataca tgttcccgaa ttgtggtccc caaagctgcc 660 attgtggccc gccacactta ccttgccaat ggccagacca aggtgctgac tcagaagttg 720 tcatcagtca gaggcaatca tattatctca gggacatgcg catcatggcg tggcaagagc 780 cttcgggttc agaagatcag gccttctatc ctgggctgca acatccttcg agttgaatat 840 tccttactga tctatgttag cgttcctgga tccaagaagg tcatccttga cctgcccctg 900 gtaattggca gcagatcagg tctaagcagc agaacatcca gcatggccag ccgaaccagc 960 tctgagatga gttgggtaga tctgaacatc cctgataccc cagaagctcc tccctgctat 1020atggatgtca ttcctgaaga tcaccgattg gagagcccaa ccactcctct gctagatgac 1080atggatggct ctcaagacag ccctatcttt atgtatgccc ctgagttcaa gttcatgcca 1140 ccaccgactt atactgaggt ggatccctgc atcctcaaca acaatgtgca gtgagcatgt 1200 ggaagaaaag aagcagcttt acctacttgt ttctttttgt ctctcttcct ggacactcac 1260 tttttcagag actcaacagt ctctgcaatg gagtgtgggt ccaccttagc ctctgacttc 1320 ctaatgtagg aggtggtcag caggcaatct cctgggcctt aaaggatgcg gactcatcct 1380 cagccagcgc ccatgttgtg atacaggggt gtttgttgga tgggtttaaa aataactaga 1440 aaaactcagg cccatccatt ttctcagatc tccttgaaaa ttgaggcctt ttcgatagtt 1500 tcgggtcagg taaaaatggc ctcctggcgt aagcttttca aggttttttg gaggcttttt 1560 gtaaattgtg ataggaactt tggaccttga acttacgtat catgtggaga agagccaatt 1620 taacaaacta ggaagatgaa aagggaaatt gtggccaaaa ctttgggaaa aggaggttct 1680 taaaatcagt gtttcccctt tgtgcacttg tagaaaaaaa agaaaaacct tctagagctg 1740 atttgatgga caatggagag agctttccct gtgattataa aaaaggaagc tagctgctct 1800 acggtcatct ttgcttagag tatactttaa cctggctttt aaagcagtag taactgcccc 1860 accaaaggtc ttaaaagcca tttttggagc ctattgcact gtgttctcct actgcaaata 1920ttttcatatg ggaggatggt tttctcttca tgtaagtcct tggaattgat tctaaggtga 1980tgttcttagc actttaattc ctgtcaaatt ttttgttctc cccttctgcc atcttaaatg 2040 taagctgaaa ctggtctact gtgtctctag ggttaagcca aaagacaaaa aaaattttac 2100 tacttttgag attgccccaa tgtacagaat tatataattc taacgcttaa atcatgtgaa 2160 agggttgctg ctgtcagcct tgcccactgt gacttcaaac ccaaggagga actcttgatc 2220 aagatgccca accctgtgat cagaacctcc aaatactgcc atgagaaact agagggcagg 2280 tcttcataaa agccctttga acccccttcc tgccctgtgt taggagatag ggatattggc 2340 ccctcactgc agctgccagc acttggtcag tcactctcag ccatagcact ttgttcactg 2400 tcctgtgtca gagcactgag ctccaccctt ttctgagagt tattacagcc agaaagtgtg 2460 ggctgaagat ggttggtttc atgtttttgt attatgtatc tttttgtatg gtaaagacta 2520 tattttgtac ttaaccagat atatttttac cccagatggg gatattcttt gtaaaaaatg 2580 aaaataaagt ttttttaatg gaaaaaaaaa 2610 92 ME149103561v.1 117823-35920 <210> 103 <211> 2801 <212> DNA <213> Mus musculus <400> 103 gacactctcc tcctctggtc tcggggtttc cagagtttct ccagttgcgg aagacagctg 60 ttatttttct cctgaaagct tttggcacag ccggcaggct gaaacttcca ggcacctttt 120 ggaaaagttg ttagggtttg tttgaagctt tctttacatt ttcgtttggg ttttcaagcc 180 ctgactttac ggaggcgagc tcttcgtttg ctttgaaggg ttcttaaaga tttttttcct 240ctccggcttt cgtttttctt gaacccactc ggctcaatca tggtgatgtt caagaagatc 300aagtcttttg aggtggtctt caacgacccc gagaaggtgt acggcagcgg ggagaaggtg 360 gccggacggg taatagtgga agtgtgtgaa gttacccgag tcaaagccgt caggatcctg 420 gcttgcggcg tggccaaggt cctgtggatg caagggtctc agcagtgcaa acagactttg 480 gactacttgc gctatgaaga cacacttctc ctagaagagc agcctacagc aggtgagaac 540 gagatggtga tcatgaggcc tggaaacaaa tatgagtaca agttcggctt cgagcttcct 600 caagggcccc tgggaacatc ctttaaagga aaatatggtt gcgtagacta ctgggtgaag 660 gcttttctcg atcgccccag ccagccaact caagaggcaa agaaaaactt cgaagtgatg 720 gatctagtgg atgtcaatac ccctgaccta atggcaccag tgtctgccaa aaaggagaag 780 aaagtttcct gcatgttcat tcctgatgga cgtgtgtcag tctctgctcg aattgacaga 840 aaaggattct gtgaaggtga tgacatctcc atccatgctg actttgagaa cacgtgttcc 900 cgaatcgtgg tccccaaagc ggctattgtg gcccgacaca cttaccttgc caatggccag 960 accaaagtgt tcactcagaa gctgtcctca gtcagaggca atcacattat ctcagggact 1020 tgcgcatcgt ggcgtggcaa gagcctcaga gtgcagaaga tcagaccatc catcctgggc 1080 tgcaacatcc tcaaagtcga atactccttg ctgatctacg tcagtgtccc tggctccaag 1140 aaagtcatcc ttgatctgcc cctagtgatt ggcagcaggt ctggtctgag cagccggaca 1200 tccagcatgg ccagccggac gagctctgag atgagctgga tagacctaaa catcccagat 1260 accccagaag ctcctccttg ctatatggac atcattcctg aagatcacag actagagagc 1320 cccaccaccc ctctgctgga cgatgtggac gactctcaag acagccctat ctttatgtac 1380 gcccctgagt tccagttcat gcccccaccc acttacactg aggtggatcc gtgcgtcctt 1440 aacaacaaca acaacaacaa caacgtgcag tgagcctgca ggaaatgaag catctgtatt 1500 agcgcatttc tttctgcctc tctgcttgaa ctccagtgtt tcagagactc agtctctaca 1560 gcggggaacg ggtacacccc agccgctgac tcctcaagat gggtggcaat cagtaggcgg 1620 gtctccggct tcaagtggtg cagaccagtg cccgcactgt ggcataggag tgtttgctgg 1680 gtggatgtca gaacactctt agaaaaattg agacctgacc actttctcgg atgttggaaa 1740tgaagaactt gtttgtgttg actgagtcag ggcactgctg accttctggc gttgtctttc 1800caaggttttt gttttaaagg gacttttaaa ttgtctaaaa tatcagtaga ccatcatctg 1860 tgccatgggg gacagagcca atttcaagtc atggccaaaa ttttgtaaga ggagtgtttt 1920 tgtgtgtttt ttaaagtcag tgttcctttt ttatatcttt acaaagaaaa gaccttccac 1980 ggctggtgag cacgcagcct gtgaaattcg gggcagctgc tccaagttga cttcaccctg 2040 ggagcagtag tagctgtgcc cactgacggc cataaaagcc attttacagc cagttgcact 2100 gtgttctctt gtaagcataa tcagatggga gaatctgtta tttccctgta accccttgga 2160 attgattcta aggtgatgtt cttagcactt tagcttgtca attttgtttt agtctccgtt 2220 atagatgtaa gctccaccag tctcttaagg attaagccca gtgacttgga gggtgggggt 2280 tagggtctct atccctgaac attgtagacc caggctggcc tgagagatcc acctgcctct 2340 gcctcctgag tgctgcgatc aaaggcccag cttggttatt gcttttgagg ctttctccca 2400 acgcacagac ttgtgtaatt ctaacactaa tcctgtgaag ggttgtggtt gacagctgga 2460 gcctgggtga cattctacat tgagatgccc cagcactgat cggggcacag aagcccccag 2520 accccatttc ctgtccagtg ttgggagaaa gtgctgcttt cactgtggcc tcagccctgg 2580 ctcggaagct cactaagcct tagcactttg tcctgtgtca gctccacctg agaactgtgc 2640agccagaatg tctgcgagct gatggaggtt tcggttttgt tgtttttgta ttttgtgtat 2700ctttttgtat gattaaaaac tatattttct acttatccaa atatattttc accccaaagt 2760 ggggttatcc tttgtaaaaa aaaataaagt tttttaatga c 2801 <210> 104 <211> 2798 <212> DNA <213> Mus musculus <400> 104 gacactctcc tcctctggtc tcggggtttc cagagtttct ccagttgcgg aagacagctg 60 ttatttttct cctgaaagct tttggcacag ccggcaggct gaaacttcca ggcacctttt 120 ggaaaagttg ttagggtttg tttgaagctt tctttacatt ttcgtttggg ttttcaagcc 180 ctgactttac ggaggcgagc tcttcgtttg ctttgaaggg ttcttaaaga tttttttcct 240 93 ME149103561v.1 117823-35920 ctccggcttt cgtttttctt gaacccactc ggctcaatca tggtgatgtt caagaagatc 300 aagtcttttg aggtggtctt caacgacccc gagaaggtgt acggcagcgg ggagaaggtg 360 gccggacggg taatagtgga agtgtgtgaa gttacccgag tcaaagccgt caggatcctg 420 gcttgcggcg tggccaaggt cctgtggatg caagggtctc agcagtgcaa acagactttg 480 gactacttgc gctatgaaga cacacttctc ctagaagagc agcctacagg tgagaacgag 540 atggtgatca tgaggcctgg aaacaaatat gagtacaagt tcggcttcga gcttcctcaa 600 gggcccctgg gaacatcctt taaaggaaaa tatggttgcg tagactactg ggtgaaggct 660 tttctcgatc gccccagcca gccaactcaa gaggcaaaga aaaacttcga agtgatggat 720 ctagtggatg tcaatacccc tgacctaatg gcaccagtgt ctgccaaaaa ggagaagaaa 780gtttcctgca tgttcattcc tgatggacgt gtgtcagtct ctgctcgaat tgacagaaaa 840ggattctgtg aaggtgatga catctccatc catgctgact ttgagaacac gtgttcccga 900 atcgtggtcc ccaaagcggc tattgtggcc cgacacactt accttgccaa tggccagacc 960 aaagtgttca ctcagaagct gtcctcagtc agaggcaatc acattatctc agggacttgc 1020 gcatcgtggc gtggcaagag cctcagagtg cagaagatca gaccatccat cctgggctgc 1080 aacatcctca aagtcgaata ctccttgctg atctacgtca gtgtccctgg ctccaagaaa 1140 gtcatccttg atctgcccct agtgattggc agcaggtctg gtctgagcag ccggacatcc 1200 agcatggcca gccggacgag ctctgagatg agctggatag acctaaacat cccagatacc 1260 ccagaagctc ctccttgcta tatggacatc attcctgaag atcacagact agagagcccc 1320 accacccctc tgctggacga tgtggacgac tctcaagaca gccctatctt tatgtacgcc 1380 cctgagttcc agttcatgcc cccacccact tacactgagg tggatccgtg cgtccttaac 1440 aacaacaaca acaacaacaa cgtgcagtga gcctgcagga aatgaagcat ctgtattagc 1500 gcatttcttt ctgcctctct gcttgaactc cagtgtttca gagactcagt ctctacagcg 1560 gggaacgggt acaccccagc cgctgactcc tcaagatggg tggcaatcag taggcgggtc 1620 tccggcttca agtggtgcag accagtgccc gcactgtggc ataggagtgt ttgctgggtg 1680 gatgtcagaa cactcttaga aaaattgaga cctgaccact ttctcggatg ttggaaatga 1740 agaacttgtt tgtgttgact gagtcagggc actgctgacc ttctggcgtt gtctttccaa 1800 ggtttttgtt ttaaagggac ttttaaattg tctaaaatat cagtagacca tcatctgtgc 1860 catgggggac agagccaatt tcaagtcatg gccaaaattt tgtaagagga gtgtttttgt 1920 gtgtttttta aagtcagtgt tcctttttta tatctttaca aagaaaagac cttccacggc 1980 tggtgagcac gcagcctgtg aaattcgggg cagctgctcc aagttgactt caccctggga 2040 gcagtagtag ctgtgcccac tgacggccat aaaagccatt ttacagccag ttgcactgtg 2100 ttctcttgta agcataatca gatgggagaa tctgttattt ccctgtaacc ccttggaatt 2160 gattctaagg tgatgttctt agcactttag cttgtcaatt ttgttttagt ctccgttata 2220 gatgtaagct ccaccagtct cttaaggatt aagcccagtg acttggaggg tgggggttag 2280ggtctctatc cctgaacatt gtagacccag gctggcctga gagatccacc tgcctctgcc 2340tcctgagtgc tgcgatcaaa ggcccagctt ggttattgct tttgaggctt tctcccaacg 2400 cacagacttg tgtaattcta acactaatcc tgtgaagggt tgtggttgac agctggagcc 2460 tgggtgacat tctacattga gatgccccag cactgatcgg ggcacagaag cccccagacc 2520 ccatttcctg tccagtgttg ggagaaagtg ctgctttcac tgtggcctca gccctggctc 2580 ggaagctcac taagccttag cactttgtcc tgtgtcagct ccacctgaga actgtgcagc 2640 cagaatgtct gcgagctgat ggaggtttcg gttttgttgt ttttgtattt tgtgtatctt 2700 tttgtatgat taaaaactat attttctact tatccaaata tattttcacc ccaaagtggg 2760 gttatccttt gtaaaaaaaa ataaagtttt ttaatgac 2798 <210> 105 <211> 391 <212> PRT <213> Homo sapiens <400> 105 Met Val Met Phe Lys Lys Ile Lys Ser Phe Glu Val Val Phe Asn Asp1 5 10 15Pro Glu Lys Val Tyr Gly Ser Gly Glu Lys Val Ala Gly Arg Val Ile 20 25 30 Val Glu Val Cys Glu Val Thr Arg Val Lys Ala Val Arg Ile Leu Ala 35 40 45 Cys Gly Val Ala Lys Val Leu Trp Met Gln Gly Ser Gln Gln Cys Lys 50 55 60 Gln Thr Ser Glu Tyr Leu Arg Tyr Glu Asp Thr Leu Leu Leu Glu Asp 65 70 75 80 Gln Pro Thr Gly Glu Asn Glu Met Val Ile Met Arg Pro Gly Asn Lys 85 90 95 Tyr Glu Tyr Lys Phe Gly Phe Glu Leu Pro Gln Gly Pro Leu Gly Thr 94 ME149103561v.1 117823-35920 100 105 110 Ser Phe Lys Gly Lys Tyr Gly Cys Val Asp Tyr Trp Val Lys Ala Phe 115 120 125 Leu Asp Arg Pro Ser Gln Pro Thr Gln Glu Thr Lys Lys Asn Phe Glu 130 135 140 Val Val Asp Leu Val Asp Val Asn Thr Pro Asp Leu Met Ala Pro Val 145 150 155 160 Ser Ala Lys Lys Glu Lys Lys Val Ser Cys Met Phe Ile Pro Asp Gly 165 170 175Arg Val Ser Val Ser Ala Arg Ile Asp Arg Lys Gly Phe Cys Glu Gly180 185 190 Asp Glu Ile Ser Ile His Ala Asp Phe Glu Asn Thr Cys Ser Arg Ile 195 200 205 Val Val Pro Lys Ala Ala Ile Val Ala Arg His Thr Tyr Leu Ala Asn 210 215 220 Gly Gln Thr Lys Val Leu Thr Gln Lys Leu Ser Ser Val Arg Gly Asn 225 230 235 240 His Ile Ile Ser Gly Thr Ser Ala Ser Trp Arg Gly Lys Ser Leu Arg 245 250 255 Val Gln Lys Ile Arg Pro Ser Ile Leu Gly Cys Asn Ile Leu Arg Val 260 265 270 Glu Tyr Ser Leu Leu Ile Tyr Val Ser Val Pro Gly Ser Lys Lys Val 275 280 285 Ile Leu Asp Leu Pro Leu Val Ile Gly Ser Arg Ser Gly Leu Ser Ser 290 295 300 Arg Thr Ser Ser Met Ala Ser Arg Thr Ser Ser Glu Met Ser Trp Val 305 310 315 320 Asp Leu Asn Ile Pro Asp Thr Pro Glu Ala Pro Pro Cys Tyr Met Asp 325 330 335 Val Ile Pro Glu Asp His Arg Leu Glu Ser Pro Thr Thr Pro Leu Leu 340 345 350 Asp Asp Met Asp Gly Ser Gln Asp Ser Pro Ile Phe Met Tyr Ala Pro 355 360 365 Glu Phe Lys Phe Met Pro Pro Pro Thr Tyr Thr Glu Val Asp Pro Cys 370 375 380Ile Leu Asn Asn Asn Val Gln 385 390 <210> 106 <211> 336 <212> PRT <213> Homo sapiens <400> 106 Met Pro Pro Lys His Ser Leu Ser His Arg Cys Ile Leu Ser Val Thr 1 5 10 15 Ala Ser Leu Met Ala Thr Arg Phe Ser Phe Pro Ser Gly Glu Asn Glu 20 25 30 Met Val Ile Met Arg Pro Gly Asn Lys Tyr Glu Tyr Lys Phe Gly Phe 35 40 45 Glu Leu Pro Gln Gly Pro Leu Gly Thr Ser Phe Lys Gly Lys Tyr Gly 50 55 60Cys Val Asp Tyr Trp Val Lys Ala Phe Leu Asp Arg Pro Ser Gln Pro 65 70 75 80 Thr Gln Glu Thr Lys Lys Asn Phe Glu Val Val Asp Leu Val Asp Val 85 90 95 Asn Thr Pro Asp Leu Met Ala Pro Val Ser Ala Lys Lys Glu Lys Lys 100 105 110 Val Ser Cys Met Phe Ile Pro Asp Gly Arg Val Ser Val Ser Ala Arg 115 120 125 Ile Asp Arg Lys Gly Phe Cys Glu Gly Asp Glu Ile Ser Ile His Ala 130 135 140 Asp Phe Glu Asn Thr Cys Ser Arg Ile Val Val Pro Lys Ala Ala Ile 95 ME149103561v.1 117823-35920 145 150 155 160 Val Ala Arg His Thr Tyr Leu Ala Asn Gly Gln Thr Lys Val Leu Thr 165 170 175 Gln Lys Leu Ser Ser Val Arg Gly Asn His Ile Ile Ser Gly Thr Ser 180 185 190 Ala Ser Trp Arg Gly Lys Ser Leu Arg Val Gln Lys Ile Arg Pro Ser 195 200 205 Ile Leu Gly Cys Asn Ile Leu Arg Val Glu Tyr Ser Leu Leu Ile Tyr 210 215 220Val Ser Val Pro Gly Ser Lys Lys Val Ile Leu Asp Leu Pro Leu Val225 230 235 240 Ile Gly Ser Arg Ser Gly Leu Ser Ser Arg Thr Ser Ser Met Ala Ser 245 250 255 Arg Thr Ser Ser Glu Met Ser Trp Val Asp Leu Asn Ile Pro Asp Thr 260 265 270 Pro Glu Ala Pro Pro Cys Tyr Met Asp Val Ile Pro Glu Asp His Arg 275 280 285 Leu Glu Ser Pro Thr Thr Pro Leu Leu Asp Asp Met Asp Gly Ser Gln 290 295 300 Asp Ser Pro Ile Phe Met Tyr Ala Pro Glu Phe Lys Phe Met Pro Pro 305 310 315 320 Pro Thr Tyr Thr Glu Val Asp Pro Cys Ile Leu Asn Asn Asn Val Gln 325 330 335 <210> 107 <211> 397 <212> PRT <213> Mus musculus <400> 107 Met Val Met Phe Lys Lys Ile Lys Ser Phe Glu Val Val Phe Asn Asp 1 5 10 15 Pro Glu Lys Val Tyr Gly Ser Gly Glu Lys Val Ala Gly Arg Val Ile 20 25 30 Val Glu Val Cys Glu Val Thr Arg Val Lys Ala Val Arg Ile Leu Ala 35 40 45Cys Gly Val Ala Lys Val Leu Trp Met Gln Gly Ser Gln Gln Cys Lys50 55 60 Gln Thr Leu Asp Tyr Leu Arg Tyr Glu Asp Thr Leu Leu Leu Glu Glu 65 70 75 80 Gln Pro Thr Ala Gly Glu Asn Glu Met Val Ile Met Arg Pro Gly Asn 85 90 95 Lys Tyr Glu Tyr Lys Phe Gly Phe Glu Leu Pro Gln Gly Pro Leu Gly 100 105 110 Thr Ser Phe Lys Gly Lys Tyr Gly Cys Val Asp Tyr Trp Val Lys Ala 115 120 125 Phe Leu Asp Arg Pro Ser Gln Pro Thr Gln Glu Ala Lys Lys Asn Phe 130 135 140 Glu Val Met Asp Leu Val Asp Val Asn Thr Pro Asp Leu Met Ala Pro 145 150 155 160 Val Ser Ala Lys Lys Glu Lys Lys Val Ser Cys Met Phe Ile Pro Asp 165 170 175Gly Arg Val Ser Val Ser Ala Arg Ile Asp Arg Lys Gly Phe Cys Glu 180 185 190 Gly Asp Asp Ile Ser Ile His Ala Asp Phe Glu Asn Thr Cys Ser Arg 195 200 205 Ile Val Val Pro Lys Ala Ala Ile Val Ala Arg His Thr Tyr Leu Ala 210 215 220 Asn Gly Gln Thr Lys Val Phe Thr Gln Lys Leu Ser Ser Val Arg Gly 225 230 235 240 Asn His Ile Ile Ser Gly Thr Ser Ala Ser Trp Arg Gly Lys Ser Leu 245 250 255 Arg Val Gln Lys Ile Arg Pro Ser Ile Leu Gly Cys Asn Ile Leu Lys 96 ME149103561v.1 117823-35920 260 265 270 Val Glu Tyr Ser Leu Leu Ile Tyr Val Ser Val Pro Gly Ser Lys Lys 275 280 285 Val Ile Leu Asp Leu Pro Leu Val Ile Gly Ser Arg Ser Gly Leu Ser 290 295 300 Ser Arg Thr Ser Ser Met Ala Ser Arg Thr Ser Ser Glu Met Ser Trp 305 310 315 320 Ile Asp Leu Asn Ile Pro Asp Thr Pro Glu Ala Pro Pro Cys Tyr Met 325 330 335Asp Ile Ile Pro Glu Asp His Arg Leu Glu Ser Pro Thr Thr Pro Leu340 345 350 Leu Asp Asp Val Asp Asp Ser Gln Asp Ser Pro Ile Phe Met Tyr Ala 355 360 365 Pro Glu Phe Gln Phe Met Pro Pro Pro Thr Tyr Thr Glu Val Asp Pro 370 375 380 Cys Val Leu Asn Asn Asn Asn Asn Asn Asn Asn Val Gln 385 390 395 <210> 108 <211> 396 <212> PRT <213> Mus musculus <400> 108 Met Val Met Phe Lys Lys Ile Lys Ser Phe Glu Val Val Phe Asn Asp 1 5 10 15 Pro Glu Lys Val Tyr Gly Ser Gly Glu Lys Val Ala Gly Arg Val Ile 20 25 30 Val Glu Val Cys Glu Val Thr Arg Val Lys Ala Val Arg Ile Leu Ala 35 40 45 Cys Gly Val Ala Lys Val Leu Trp Met Gln Gly Ser Gln Gln Cys Lys 50 55 60 Gln Thr Leu Asp Tyr Leu Arg Tyr Glu Asp Thr Leu Leu Leu Glu Glu 65 70 75 80 Gln Pro Thr Gly Glu Asn Glu Met Val Ile Met Arg Pro Gly Asn Lys 85 90 95Tyr Glu Tyr Lys Phe Gly Phe Glu Leu Pro Gln Gly Pro Leu Gly Thr100 105 110 Ser Phe Lys Gly Lys Tyr Gly Cys Val Asp Tyr Trp Val Lys Ala Phe 115 120 125 Leu Asp Arg Pro Ser Gln Pro Thr Gln Glu Ala Lys Lys Asn Phe Glu 130 135 140 Val Met Asp Leu Val Asp Val Asn Thr Pro Asp Leu Met Ala Pro Val 145 150 155 160 Ser Ala Lys Lys Glu Lys Lys Val Ser Cys Met Phe Ile Pro Asp Gly 165 170 175 Arg Val Ser Val Ser Ala Arg Ile Asp Arg Lys Gly Phe Cys Glu Gly 180 185 190 Asp Asp Ile Ser Ile His Ala Asp Phe Glu Asn Thr Cys Ser Arg Ile 195 200 205 Val Val Pro Lys Ala Ala Ile Val Ala Arg His Thr Tyr Leu Ala Asn 210 215 220Gly Gln Thr Lys Val Phe Thr Gln Lys Leu Ser Ser Val Arg Gly Asn 225 230 235 240 His Ile Ile Ser Gly Thr Ser Ala Ser Trp Arg Gly Lys Ser Leu Arg 245 250 255 Val Gln Lys Ile Arg Pro Ser Ile Leu Gly Cys Asn Ile Leu Lys Val 260 265 270 Glu Tyr Ser Leu Leu Ile Tyr Val Ser Val Pro Gly Ser Lys Lys Val 275 280 285 Ile Leu Asp Leu Pro Leu Val Ile Gly Ser Arg Ser Gly Leu Ser Ser 290 295 300 Arg Thr Ser Ser Met Ala Ser Arg Thr Ser Ser Glu Met Ser Trp Ile 97 ME149103561v.1 117823-35920 305 310 315 320 Asp Leu Asn Ile Pro Asp Thr Pro Glu Ala Pro Pro Cys Tyr Met Asp 325 330 335 Ile Ile Pro Glu Asp His Arg Leu Glu Ser Pro Thr Thr Pro Leu Leu 340 345 350 Asp Asp Val Asp Asp Ser Gln Asp Ser Pro Ile Phe Met Tyr Ala Pro 355 360 365 Glu Phe Gln Phe Met Pro Pro Pro Thr Tyr Thr Glu Val Asp Pro Cys 370 375 380Val Leu Asn Asn Asn Asn Asn Asn Asn Asn Val Gln385 390 395 <210> 109 <400> 109 000 <210> 110 <400> 110 000 <210> 111 <211> 2905 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 111 aaactaaccc ctctttttct ccaaaggagt gcttgtggag atcggatctt ttctccagca 60 attgggggaa agaaggcttt ttctctgaat tagcttagtg taaccagcgg cgtatatttt 120 ttaggcgcct tttcgaaaac ctagtagtta atattcattt gtttaaatct tattttattt 180 ttaagctcaa actgcttaag aataccttaa ttccttaaag tgaaataatt ttttgcaaag 240 gggtttcctc gatttggagc tttttttttc ttccaccgtc atttctaact cttaaaacca 300 actcagttcc atcatggtga tgttcaagaa gatcaagtct tttgaggtgg tctttaacga 360 ccctgaaaag gtgtacggca gtggcgagaa ggtggctggc cgggtgatag tggaggtgtg 420 tgaagttact cgtgtcaaag ccgttaggat cctggcttgc ggagtggcta aagtgctttg 480 gatgcaggga tcccagcagt gcaaacagac ttcggagtac ctgcgctatg aagacacgct 540tcttctggaa gaccagccaa caggtgagaa tgagatggtg atcatgagac ctggaaacaa 600atatgagtac aagttcggct ttgagcttcc tcaggggcct ctgggaacat ccttcaaagg 660 aaaatatggg tgtgtagact actgggtgaa ggcttttctt gaccgcccga gccagccaac 720 tcaagagaca aagaaaaact ttgaagtagt ggatctggtg gatgtcaata cccctgattt 780 aatggcacct gtgtctgcta aaaaagaaaa gaaagtttcc tgcatgttca ttcctgatgg 840 gcgggtgtct gtctctgctc gaattgacag aaaaggattc tgtgaaggtg atgagatttc 900 catccatgct gactttgaga atacatgttc ccgaattgtg gtccccaaag ctgccattgt 960 ggcccgccac acttaccttg ccaatggcca gaccaaggtg ctgactcaga agttgtcatc 1020 agtcagaggc aatcatatta tctcagggac aagcgcatca tggcgtggca agagccttcg 1080 ggttcagaag atcaggcctt ctatcctggg ctgcaacatc cttcgagttg aatattcctt 1140 actgatctat gttagcgttc ctggatccaa gaaggtcatc cttgacctgc ccctggtaat 1200 tggcagcaga tcaggtctaa gcagcagaac atccagcatg gccagccgaa ccagctctga 1260 gatgagttgg gtagatctga acatccctga taccccagaa gctcctccct gctatatgga 1320 tgtcattcct gaagatcacc gattggagag cccaaccact cctctgctag atgacatgga 1380 tggctctcaa gacagcccta tctttatgta tgcccctgag ttcaagttca tgccaccacc 1440gacttatact gaggtggatc cctgcatcct caacaacaat gtgcagtgag catgtggaag 1500aaaagaagca gctttaccta cttgtttctt tttgtctctc ttcctggaca ctcacttttt 1560 cagagactca acagtctctg caatggagtg tgggtccacc ttagcctctg acttcctaat 1620 gtaggaggtg gtcagcaggc aatctcctgg gccttaaagg atgcggactc atcctcagcc 1680 agcgcccatg ttgtgataca ggggtgtttg ttggatgggt ttaaaaataa ctagaaaaac 1740 tcaggcccat ccattttctc agatctcctt gaaaattgag gccttttcga tagtttcggg 1800 tcaggtaaaa atggcctcct ggcgtaagct tttcaaggtt ttttggaggc tttttgtaaa 1860 ttgtgatagg aactttggac cttgaactta cgtatcatgt ggagaagagc caatttaaca 1920 aactaggaag atgaaaaggg aaattgtggc caaaactttg ggaaaaggag gttcttaaaa 1980 tcagtgtttc ccctttgtgc acttgtagaa aaaaaagaaa aaccttctag agctgatttg 2040 atggacaatg gagagagctt tccctgtgat tataaaaaag gaagctagct gctctacggt 2100 catctttgct tagagtatac tttaacctgg cttttaaagc agtagtaact gccccaccaa 2160 98 ME149103561v.1 117823-35920 aggtcttaaa agccattttt ggagcctatt gcactgtgtt ctcctactgc aaatattttc 2220 atatgggagg atggttttct cttcatgtaa gtccttggaa ttgattctaa ggtgatgttc 2280 ttagcacttt aattcctgtc aaattttttg ttctcccctt ctgccatctt aaatgtaagc 2340 tgaaactggt ctactgtgtc tctagggtta agccaaaaga caaaaaaaat tttactactt 2400 ttgagattgc cccaatgtac agaattatat aattctaacg cttaaatcat gtgaaagggt 2460 tgctgctgtc agccttgccc actgtgactt caaacccaag gaggaactct tgatcaagat 2520 gcccaaccct gtgatcagaa cctccaaata ctgccatgag aaactagagg gcaggtcttc 2580 ataaaagccc tttgaacccc cttcctgccc tgtgttagga gatagggata ttggcccctc 2640 actgcagctg ccagcacttg gtcagtcact ctcagccata gcactttgtt cactgtcctg 2700tgtcagagca ctgagctcca cccttttctg agagttatta cagccagaaa gtgtgggctg 2760aagatggttg gtttcatgtt tttgtattat gtatcttttt gtatggtaaa gactatattt 2820 tgtacttaac cagatatatt tttaccccag atggggatat tctttgtaaa aaatgaaaat 2880 aaagtttttt taatggaaaa aaaaa 2905 <210> 112 <211> 2610 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 112 attctttgtc tacttcctat ttgagatgtt agtagagaac tgtcctgggt gaatctttca 60 gtattgcagg gcttggcaac ttgctgcccg acaaaataca tcagaatttc tctttaagaa 120 caatatggga tggattaaaa aatatatata tgggatgaaa ttgggggtac ttcaatacct 180 tgcatgccac ccaagcattc cttatcacac agatgcattt taagtgtaac agcaagccta 240 atggctactc gattttcttt cccttcaggt gagaatgaga tggtgatcat gagacctgga 300 aacaaatatg agtacaagtt cggctttgag cttcctcagg ggcctctggg aacatccttc 360 aaaggaaaat atgggtgtgt agactactgg gtgaaggctt ttcttgaccg cccgagccag 420 ccaactcaag agacaaagaa aaactttgaa gtagtggatc tggtggatgt caatacccct 480 gatttaatgg cacctgtgtc tgctaaaaaa gaaaagaaag tttcctgcat gttcattcct 540 gatgggcggg tgtctgtctc tgctcgaatt gacagaaaag gattctgtga aggtgatgag 600 atttccatcc atgctgactt tgagaataca tgttcccgaa ttgtggtccc caaagctgcc 660 attgtggccc gccacactta ccttgccaat ggccagacca aggtgctgac tcagaagttg 720 tcatcagtca gaggcaatca tattatctca gggacaagcg catcatggcg tggcaagagc 780cttcgggttc agaagatcag gccttctatc ctgggctgca acatccttcg agttgaatat 840tccttactga tctatgttag cgttcctgga tccaagaagg tcatccttga cctgcccctg 900 gtaattggca gcagatcagg tctaagcagc agaacatcca gcatggccag ccgaaccagc 960 tctgagatga gttgggtaga tctgaacatc cctgataccc cagaagctcc tccctgctat 1020 atggatgtca ttcctgaaga tcaccgattg gagagcccaa ccactcctct gctagatgac 1080 atggatggct ctcaagacag ccctatcttt atgtatgccc ctgagttcaa gttcatgcca 1140 ccaccgactt atactgaggt ggatccctgc atcctcaaca acaatgtgca gtgagcatgt 1200 ggaagaaaag aagcagcttt acctacttgt ttctttttgt ctctcttcct ggacactcac 1260 tttttcagag actcaacagt ctctgcaatg gagtgtgggt ccaccttagc ctctgacttc 1320 ctaatgtagg aggtggtcag caggcaatct cctgggcctt aaaggatgcg gactcatcct 1380 cagccagcgc ccatgttgtg atacaggggt gtttgttgga tgggtttaaa aataactaga 1440 aaaactcagg cccatccatt ttctcagatc tccttgaaaa ttgaggcctt ttcgatagtt 1500 tcgggtcagg taaaaatggc ctcctggcgt aagcttttca aggttttttg gaggcttttt 1560 gtaaattgtg ataggaactt tggaccttga acttacgtat catgtggaga agagccaatt 1620 taacaaacta ggaagatgaa aagggaaatt gtggccaaaa ctttgggaaa aggaggttct 1680taaaatcagt gtttcccctt tgtgcacttg tagaaaaaaa agaaaaacct tctagagctg 1740atttgatgga caatggagag agctttccct gtgattataa aaaaggaagc tagctgctct 1800 acggtcatct ttgcttagag tatactttaa cctggctttt aaagcagtag taactgcccc 1860 accaaaggtc ttaaaagcca tttttggagc ctattgcact gtgttctcct actgcaaata 1920 ttttcatatg ggaggatggt tttctcttca tgtaagtcct tggaattgat tctaaggtga 1980 tgttcttagc actttaattc ctgtcaaatt ttttgttctc cccttctgcc atcttaaatg 2040 taagctgaaa ctggtctact gtgtctctag ggttaagcca aaagacaaaa aaaattttac 2100 tacttttgag attgccccaa tgtacagaat tatataattc taacgcttaa atcatgtgaa 2160 agggttgctg ctgtcagcct tgcccactgt gacttcaaac ccaaggagga actcttgatc 2220 aagatgccca accctgtgat cagaacctcc aaatactgcc atgagaaact agagggcagg 2280 tcttcataaa agccctttga acccccttcc tgccctgtgt taggagatag ggatattggc 2340 ccctcactgc agctgccagc acttggtcag tcactctcag ccatagcact ttgttcactg 2400 99 ME149103561v.1 117823-35920 tcctgtgtca gagcactgag ctccaccctt ttctgagagt tattacagcc agaaagtgtg 2460 ggctgaagat ggttggtttc atgtttttgt attatgtatc tttttgtatg gtaaagacta 2520 tattttgtac ttaaccagat atatttttac cccagatggg gatattcttt gtaaaaaatg 2580 aaaataaagt ttttttaatg gaaaaaaaaa 2610 <210> 113 <211> 2801 <212> DNA <213> Artificial Sequence <220><223> Description of Artificial Sequence: Syntheticpolynucleotide <400> 113 gacactctcc tcctctggtc tcggggtttc cagagtttct ccagttgcgg aagacagctg 60 ttatttttct cctgaaagct tttggcacag ccggcaggct gaaacttcca ggcacctttt 120 ggaaaagttg ttagggtttg tttgaagctt tctttacatt ttcgtttggg ttttcaagcc 180 ctgactttac ggaggcgagc tcttcgtttg ctttgaaggg ttcttaaaga tttttttcct 240 ctccggcttt cgtttttctt gaacccactc ggctcaatca tggtgatgtt caagaagatc 300 aagtcttttg aggtggtctt caacgacccc gagaaggtgt acggcagcgg ggagaaggtg 360 gccggacggg taatagtgga agtgtgtgaa gttacccgag tcaaagccgt caggatcctg 420 gcttgcggcg tggccaaggt cctgtggatg caagggtctc agcagtgcaa acagactttg 480 gactacttgc gctatgaaga cacacttctc ctagaagagc agcctacagc aggtgagaac 540 gagatggtga tcatgaggcc tggaaacaaa tatgagtaca agttcggctt cgagcttcct 600 caagggcccc tgggaacatc ctttaaagga aaatatggtt gcgtagacta ctgggtgaag 660 gcttttctcg atcgccccag ccagccaact caagaggcaa agaaaaactt cgaagtgatg 720 gatctagtgg atgtcaatac ccctgaccta atggcaccag tgtctgccaa aaaggagaag 780 aaagtttcct gcatgttcat tcctgatgga cgtgtgtcag tctctgctcg aattgacaga 840 aaaggattct gtgaaggtga tgacatctcc atccatgctg actttgagaa cacgtgttcc 900 cgaatcgtgg tccccaaagc ggctattgtg gcccgacaca cttaccttgc caatggccag 960 accaaagtgt tcactcagaa gctgtcctca gtcagaggca atcacattat ctcagggact 1020 agcgcatcgt ggcgtggcaa gagcctcaga gtgcagaaga tcagaccatc catcctgggc 1080 tgcaacatcc tcaaagtcga atactccttg ctgatctacg tcagtgtccc tggctccaag 1140 aaagtcatcc ttgatctgcc cctagtgatt ggcagcaggt ctggtctgag cagccggaca 1200 tccagcatgg ccagccggac gagctctgag atgagctgga tagacctaaa catcccagat 1260 accccagaag ctcctccttg ctatatggac atcattcctg aagatcacag actagagagc 1320cccaccaccc ctctgctgga cgatgtggac gactctcaag acagccctat ctttatgtac 1380gcccctgagt tccagttcat gcccccaccc acttacactg aggtggatcc gtgcgtcctt 1440 aacaacaaca acaacaacaa caacgtgcag tgagcctgca ggaaatgaag catctgtatt 1500 agcgcatttc tttctgcctc tctgcttgaa ctccagtgtt tcagagactc agtctctaca 1560 gcggggaacg ggtacacccc agccgctgac tcctcaagat gggtggcaat cagtaggcgg 1620 gtctccggct tcaagtggtg cagaccagtg cccgcactgt ggcataggag tgtttgctgg 1680 gtggatgtca gaacactctt agaaaaattg agacctgacc actttctcgg atgttggaaa 1740 tgaagaactt gtttgtgttg actgagtcag ggcactgctg accttctggc gttgtctttc 1800 caaggttttt gttttaaagg gacttttaaa ttgtctaaaa tatcagtaga ccatcatctg 1860 tgccatgggg gacagagcca atttcaagtc atggccaaaa ttttgtaaga ggagtgtttt 1920 tgtgtgtttt ttaaagtcag tgttcctttt ttatatcttt acaaagaaaa gaccttccac 1980 ggctggtgag cacgcagcct gtgaaattcg gggcagctgc tccaagttga cttcaccctg 2040 ggagcagtag tagctgtgcc cactgacggc cataaaagcc attttacagc cagttgcact 2100 gtgttctctt gtaagcataa tcagatggga gaatctgtta tttccctgta accccttgga 2160 attgattcta aggtgatgtt cttagcactt tagcttgtca attttgtttt agtctccgtt 2220atagatgtaa gctccaccag tctcttaagg attaagccca gtgacttgga gggtgggggt 2280tagggtctct atccctgaac attgtagacc caggctggcc tgagagatcc acctgcctct 2340 gcctcctgag tgctgcgatc aaaggcccag cttggttatt gcttttgagg ctttctccca 2400 acgcacagac ttgtgtaatt ctaacactaa tcctgtgaag ggttgtggtt gacagctgga 2460 gcctgggtga cattctacat tgagatgccc cagcactgat cggggcacag aagcccccag 2520 accccatttc ctgtccagtg ttgggagaaa gtgctgcttt cactgtggcc tcagccctgg 2580 ctcggaagct cactaagcct tagcactttg tcctgtgtca gctccacctg agaactgtgc 2640 agccagaatg tctgcgagct gatggaggtt tcggttttgt tgtttttgta ttttgtgtat 2700 ctttttgtat gattaaaaac tatattttct acttatccaa atatattttc accccaaagt 2760 ggggttatcc tttgtaaaaa aaaataaagt tttttaatga c 2801 <210> 114 <211> 2798 100 ME149103561v.1 117823-35920 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 114 gacactctcc tcctctggtc tcggggtttc cagagtttct ccagttgcgg aagacagctg 60 ttatttttct cctgaaagct tttggcacag ccggcaggct gaaacttcca ggcacctttt 120 ggaaaagttg ttagggtttg tttgaagctt tctttacatt ttcgtttggg ttttcaagcc 180ctgactttac ggaggcgagc tcttcgtttg ctttgaaggg ttcttaaaga tttttttcct 240ctccggcttt cgtttttctt gaacccactc ggctcaatca tggtgatgtt caagaagatc 300 aagtcttttg aggtggtctt caacgacccc gagaaggtgt acggcagcgg ggagaaggtg 360 gccggacggg taatagtgga agtgtgtgaa gttacccgag tcaaagccgt caggatcctg 420 gcttgcggcg tggccaaggt cctgtggatg caagggtctc agcagtgcaa acagactttg 480 gactacttgc gctatgaaga cacacttctc ctagaagagc agcctacagg tgaga...

Claims

117823-35920 We claim:

1. A composition, comprising an adeno-associated virus (AAV) expression cassette, the expression cassette comprising a promoter and a nucleic acid molecule encoding a thioredoxin- interacting 5 protein (TXNIP) variant protein, wherein the nucleic acid molecule is selected from the group consisting of (a) a nucleic acid molecule encoding amino acid residues 149-397 of a C247S variant TXNIP, or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 149-397 of the C247S variant TXNIP; (b) a nucleic acid molecule encoding amino acid residues 149-397 of a a C247S .LL351.352AA variant TXNIP, or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 149-397 of the a C247S .LL351.352AA variant TXNIP; (c) a nucleic acid molecule encoding amino acid residues 1-228 of TXNIP, or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 1-228 of TXNIP; (d) a nucleic acid molecule encoding amino acid residues 1-301 of TXNIP, or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 1-301 of TXNIP; (e) a nucleic acid molecule encoding amino acid residues 1-320 of TXNIP, or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 1-320 of TXNIP; or (f) a nucleic acid molecule encoding amino acid residues 255-397 of TXNIP, or a nucleic acid molecule having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% nucleotide sequence identity to the entire nucleotide sequence of the nucleic acid molecule encoding amino acid residues 255-397 of TXNIP.

2. The composition of claim 1, wherein the promoter is a ubiquitous promoter.

3. The composition of claim 1, wherein the promoter is an ocular specific promoter.

4. The composition of claim 1, wherein the promoter is a photoreceptor specific (PR-specific) promoter. 138 ME149103561v.1117823-35920 5. The composition of claim 4, wherein the PR-specific promoter is a human red opsin (hRedO) promoter.

6. The composition of claim 4, wherein the PR-specific promoter is a human bestrophin 1 (hBest1) promoter.

7. A composition, comprising an adeno-associated virus (AAV) expression cassette, the expression cassette comprising a promoter and a short hairpin RNA (shRNA) targeting heat shock protein 90 alpha family class B member 1 (HSP90AB1).

8. The composition of claim 7, wherein the promoter is a ubiquitous promoter.

9. The composition of claim 7, wherein the promoter is an ocular specific promoter.

10. The composition of claim 7, wherein the promoter is a photoreceptor specific (PR-specific) promoter.

11. The composition of claim 10, wherein the PR-specific promoter is a human red opsin (hRedO) promoter.

12. The composition of any one of claims 1-11, wherein the expression cassette is present in a vector.

13. The composition of any one of claims 1-12, wherein the expression cassette is present in an AAV vector.

14. The composition of claim 13, wherein the vector is an AAV vector selected from the group consisting of AAV2, AAV 8, AAV2 / 5, and AAV 2 / 8.

15. An AAV vector particle comprising the composition of any one of claims 1-14.

16. An isolated cell comprising the AAV particle of claim 15.

17. A pharmaceutical composition comprising the AAV composition of any one of claims 1-14 or the particle of claim 15. 139 ME149103561v.1117823-35920 18. A method for prolonging the viability of a photoreceptor cell compromised by a degenerative ocular disorder, comprising contacting said cell with the composition of any one or more of claims 1- 14, the AAV viral particle of claim 15, the cell of claims 16, or the pharmaceutical composition of claim 17, thereby prolonging the viability of the photoreceptor cell compromised by the degenerative ocular disorder.

19. A method for treating or preventing a degenerative ocular disorder in a subject, comprising administering to said subject a therapeutically effective amount of any one or more of the compositions of claims 1-14, the AAV viral particle of claim 15, the cell of claims 16, or the pharmaceutical composition of claim 17, thereby treating or preventing said degenerative ocular disorder.

20. A method for delaying loss of functional vision in a subject having a degenerative ocular disorder, comprising administering to said subject a therapeutically effective amount of the composition of any one or more of claims 1-14, the AAV viral particle of claim 15, the cell of claims 16, or the pharmaceutical composition of claim 17, thereby treating or preventing said degenerative ocular disorder.

21. The method of any one of claims 18-20, wherein the degenerative ocular disorder is associated with decreased viability of cone cells and / or decreased viability of rod cells.

22. The method of any one of claims 18-21, wherein the degenerative ocular disorder is selected from the group consisting of retinitis pigmentosa, age related macular 5 degeneration, cone rod dystrophy, and rod cone dystrophy.

23. The method of any one of claims 18-22, wherein the degenerative ocular disorder is a genetic disorder.

24. The method of any one of claims 18-23, wherein the degenerative ocular disorder is not associated with blood vessel leakage and / or growth.

25. The method of any one of claims 18-24, wherein the degenerative ocular disorder is retinitis pigmentosa.

26. A method for treating or preventing retinitis pigmentosa in a subject, comprising administering to the subject a therapeutically effective amount of the composition of any one or more of claims 1-14, 140 ME149103561v.1117823-35920 the AAV viral particle of claim 15, the cell of claims 16, or the pharmaceutical composition of claim 17, thereby treating or preventing retinitis pigmentosa in said subject.

27. The method of any one of claims 18-26, wherein the promoter is a ubiquitous promoter.

28. The method of any one of claims 18-26, wherein the promoter is an ocular specific promoter.

29. The method of any one of claims 18-26, wherein the promoter is a photoreceptor specific (PR- specific) promoter.

30. The method of claim 29, wherein the PR-specific promoter is a human red opsin (hRedO) promoter.

31. The method of claim 29, wherein the PR-specific promoter is a human bestrophin 1 (hBest1) promoter.

32. The method of any one of claims 18-31, wherein the method further comprises administering to the subject a therapeutically effective amount of a composition comprising an adeno-associated virus (AAV) expression cassette, the expression cassette comprising a photoreceptor-specific (PR- specific) promoter and a short hairpin RNA (shRNA) targeting heat shock protein 90 alpha family class B member 1 (HSP90AB1).

33. A method for prolonging the viability of a photoreceptor cell compromised by a degenerative ocular disorder, comprising contacting said cell with a composition, comprising an adeno-associated virus (AAV) expression cassette, the expression cassette comprising a photoreceptor-specific (PR- specific) promoter and a short hairpin RNA (shRNA) targeting heat shock protein 90 alpha family class B member 1 (HSP90AB1), thereby prolonging the viability of the photoreceptor cell compromised by the degenerative ocular disorder.

34. A method for treating or preventing a degenerative ocular disorder in a subject, comprising administering to said subject a therapeutically effective amount of a composition, comprising an adeno-associated virus (AAV) expression cassette, the expression cassette comprising a photoreceptor-specific (PR- specific) promoter and a short hairpin RNA (shRNA) targeting heat shock protein 90 alpha family class B member 1 (HSP90AB1), thereby treating or preventing said degenerative ocular disorder. 141 ME149103561v.1117823-35920 35. A method for delaying loss of functional vision in a subject having a degenerative ocular disorder, comprising administering to said subject a therapeutically effective amount of a composition, comprising an adeno-associated virus (AAV) expression cassette, the expression cassette comprising a photoreceptor-specific (PR- specific) promoter and a short hairpin RNA (shRNA) targeting heat shock protein 90 alpha family class B member 1 (HSP90AB1), thereby treating or preventing said degenerative ocular disorder.

36. The method of any one of claims 33-35, wherein the degenerative ocular disorder is associated with decreased viability of cone cells and / or decreased viability of rod cells.

37. The method of any one of claims 33-36, wherein the degenerative ocular disorder is selected from the group consisting of retinitis pigmentosa, age related macular 5 degeneration, cone rod dystrophy, and rod cone dystrophy.

38. The method of any one of claims 33-37, wherein the degenerative ocular disorder is a genetic disorder.

39. The method of any one of claims 33-38, wherein the degenerative ocular disorder is not associated with blood vessel leakage and / or growth.

40. The method of any one of claims 33-39, wherein the degenerative ocular disorder is retinitis pigmentosa.

41. The method of any one of claims 33-40, wherein the promoter is a ubiquitous promoter.

42. The method of any one of claims 33-40, wherein the promoter is an ocular specific promoter.

43. The method of any one of claims 33-42, wherein the promoter is a photoreceptor specific (PR- specific) promoter.

44. The method of claim 43, wherein the PR-specific promoter is a human red opsin (hRedO) promoter.

45. The method of claim 43, wherein the PR-specific promoter is a human bestrophin 1 (hBest1) promoter. 142 ME149103561v.1117823-35920 46. A method for treating or preventing retinitis pigmentosa in a subject, comprising administering to the subject a therapeutically effective amount of a composition, comprising an adeno-associated virus (AAV) expression cassette, the expression cassette comprising a promoter and a short hairpin RNA (shRNA) targeting heat shock protein 90 alpha family class B member 1 (HSP90AB1).

47. The method of claim 46, wherein the promoter is a ubiquitous promoter.

48. The method of claim 46, wherein the promoter is an ocular specific promoter.

49. The method of claim 46, wherein the promoter is a photoreceptor specific (PR-specific) promoter.

50. The method of claim 49, wherein the PR-specific promoter is a human red opsin (hRedO) promoter.

51. The method of claim 49, wherein the PR-specific promoter is a human bestrophin 1 (hBest1) promoter.

52. The method of any one of claims 33-51, wherein the method further comprises administering to the subject a therapeutically effective amount of a composition, comprising an adeno-associated virus (AAV) expression cassette, the expression cassette comprising a photoreceptor-specific (PR- specific) promoter and a nucleic acid molecule encoding a C247S variant thioredoxin-interacting 5 protein (TXNIP). 143 ME149103561v.1