Combinatorial gene therapy approaches

Abstract

Provided herein is a mutant JP2 protein comprising a deletion of a calpain cleavage site and methods of using the same.

Description

[0001]24028 / / SLW 875.245WO1 COMBINATORIAL GENE THERAPY APPROACHES PRIORITY This application claims the benefit of the filing date of U.S. Application No.63 / 643,766, filed on May 7, 2024, the disclosure of which is incorporated by reference herein. GOVERNMENT SUPPORT This invention was made with government support under HL130346 awarded by the National Institutes of Health. The government has certain rights in the invention. INCORPORATION BY REFERENCE OF SEQUENCE LISTING This application contains a Sequence Listing which has been submitted electronically in ST26 format and hereby incorporated by reference in its entirety. Said ST26 file, created on May 7, 2025, is named 875245WO1.xml and is 191,196 bytes in size. BACKGROUND Heart failure (HF), a pathophysiologic state in which the heart fails to pump sufficient blood to meet the needs of the body, is a global pandemic affecting at least 26 million people worldwide and will increase dramatically with the aging population. New approaches for prevention and treatment of HF are still urgently needed to reduce morbidity and mortality, which lags that of other prevalent diseases. SUMMARY HF is a complex disease and usually has no single cause. HF is currently treated through pharmacological and lifestyle approaches. Although new drug interventions have been developed over the last few decades, the mortality rate of HF within 5 years of diagnosis remains high. The development of novel therapies, including gene therapy, are in great demand. The present disclosure relates generally to gene therapy for a disease or disorder, e.g., a cardiac disease or disorder, using a vector expressing a mutant JP2 (an abbreviation of junctophilin-2; JPH2, JPH-2 or JP-2 are used interchangeably for junctophilin-2) in which the calpain cleavage site at amino acids R572 and T573 of SEQ ID NO: 1 has been deleted or otherwise altered so that cleavage no longer occurs. One embodiment provides a mutated JP2 protein in which the calpain cleavage site at amino acids R572 and T573 of SEQ ID NO: 1 has been deleted or otherwise altered (e.g., mutation), which mutant protein has at least 80%, 85%, 87%, 90%, 92%, 93%, 94%, 95%, 98%, 99% or more amino acid identity to SEQ ID NO:4. 1 24028 / / SLW 875.245WO1 In one aspect, the disclosure provides a gene therapy vector, comprising the polynucleotide as described in the present disclosure. In some embodiments, the gene therapy vector is an AAV9 or a functional variant thereof. One embodiment provides a polynucleotide, comprising an expression cassette and optionally flanking adeno-associated virus (AAV) inverted terminal repeats (ITRs), wherein the polynucleotide comprises a polynucleotide sequence encoding SEQ ID NO: 3 or a functional variant thereof, operatively linked to a promoter. In some embodiments, the promoter is a cardiomyocyte-specific promoter (e.g., cardiac troponin-T (TNNT2), myosin light chain-2v (MLC-2v), and alpha myosin heavy chain-6 (MYH6, also αMHC)). In some embodiments, the promoter is a striated muscle specific promoter (e.g., myosin creatine kinase (MCK), desmin (DES), and synthetic SPc5-12). In some embodiments, the promoter is a ubiquitously recognized / expressed promoter (e.g., cytomegalovirus (CMV), beta-actin (CAG), phosphoglycerate kinase (PGK), elongation factor 1α (EF1α), ubiquitin C (UbC), or micropromoters-84 (MP-84) or -135 (MP-135)), but not limited to these listed here. In one embodiment, a pharmaceutical composition is provided that includes a mutated JP2 protein in which a calpain cleavage site has been deleted or rendered nonfunctional, which mutant protein has at least 80%, 85%, 87%, 90%, 92%, 93%, 94%, 95%, 98%, 99% or more amino acid identity to SEQ ID NO:4. One embodiment provides a method to prevent, inhibit or treat a cardiac disease or condition, e.g., cardiac hypertrophy, cardiac fibrosis, cardiac inflammation, heart failure, or myocardial infarction, in a mammal is provided. The method includes administering to a mammal in need thereof, e.g., a mammal at risk of a cardiac condition or a mammal having a cardiac condition, an effective amount of a composition comprising the mutated protein or a nucleic acid vector coding for the mutated protein, or a particle having the protein or nucleic acid vector coding for the mutated protein. In one embodiment, the composition is locally administered. In one embodiment, the composition is systemically administered. In one embodiment, the administration reverses cardiac hypertrophy in a mammal. In one embodiment, the administration inhibits progression of heart failure. Previous and current clinical gene therapy trials involve the delivery of single genes. While some diseases can arise from single gene mutations, complex diseases such as heart failure are typically multifactorial in nature and involve different molecular processes. In some aspects, provided herein is the delivery of two or more gene products that are aimed at restoring different disease mechanisms in affected tissue. For example, heart failure and other cardiac diseases are 2 24028 / / SLW 875.245WO1 known to arise from pathological proteolysis of cardiac proteins, disruption of normal intracellular calcium homeostasis, and prolonged maladaptive gene expression changes. Provided herein is a combinatorial gene expression approach that targets one or more of these mechanisms that together provides better cardiac outcomes than when they are targeted separately. Provided herein is a combinatorial gene expression method in which a nucleotide sequence encoding a mutated JP2 protein in which a calpain cleavage site has been deleted or rendered nonfunctional, which mutant protein has at least 80%, 85%, 87%, 90%, 92%, 93%, 94%, 95%, 98%, 99% or more amino acid identity to SEQ ID NO:4 is administered along with second therapeutic polynucleotide sequence. In one embodiment, the second therapeutic polynucleotide sequence comprises one or more of JP2NT, CaV1.2, SERC2a, RyR2, DMD, DES, UTRN, SPTBN2, ITBG3, ANK2, ACTN2, PPP3CA, CAMK2D, PRKCA, PTK2, TNNI3, TNNT2, MYBPC3, LAMP2, or AIFM1 (SEQ ID NOs: 7 to 44 (odd numbered)). In one embodiment, the second active therapeutic polynucleotide sequence comprises JP2NT (SEQ ID NO: 5). In some embodiments, the subject is a mammal. In some embodiments, the subject is a primate. In some embodiments, the subject is a human. In some embodiments, the vector is administered by intravenous administration, intracardiac administration, intracoronary administration, intracardiac administration, and / or cardiac catheterization. In certain embodiments, any of the routes of administration may be performed by infusion or injection. Various other aspects and embodiments are disclosed in the detailed description that follows. The disclosure is limited solely by the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1A-1F. JP2CR knock-in prohibits calpain-mediated cleavage of JP2 and degradation of T-tubules. A, Schematic of the junctophilin-2 (JP2) knock-in (JP2CR) mouse model (SEQ ID NOS: 51-53). Top, Linear representation of the mouse JP2 protein indicating the relative position of the R565 / T566 calpain cleavage site. Middle, Mouse Jph2 gene locus in the antisense (−) orientation. Bottom, Alignment of DNA sequencing results from wild-type (WT) and JP2CRCRISPR-Cas9–targeted founders. B, Western blots of ventricular lysate cleavage assays (5 minutes) using purified human calpain-1 and 2 mmol / L Ca2+ in the absence or presence of 10 μmol / L MDL-28170 (calpain inhibitor). C, Confocal immunofluorescence images of freshly isolated adult cardiomyocytes or cultured cardiomyocytes treated for 24 hours with vehicle (Veh) or 1 μmol / L isoproterenol (ISO)+5 mmol / L Ca2+. D, Summary data of JP2power, a measure of JP2 regularity (n=24–27 cells from n=3 mice per group). E and F, Representative images of cardiomyocyte transverse tubule (T-tubules) stained with Di-8-ANNEPS (E) and quantified for T- 3 24028 / / SLW 875.245WO1 tubule regularity (TTpower; n=24 cells from 3 mice per group; F). Cardiomyocytes were isolated and treated as in C. Scale bars=20 μm. D and F, Bonferroni procedure after a global test based on a linear mixed-effects model was performed for multiple-group comparisons (NCSS, Kaysville, UT). A compound symmetry correlation structure was assumed for linear mixed-effects model tests. n.s. indicates not significant. FIGS. 2A-2J. JP2CRprovides protection against TAC-induced cardiac dysfunction. A, Kaplan-Meier survival curve for wild-type (WT) and junctophilin-2 knock-in (JP2CR) mice after sham and transverse aortic constriction (TAC) surgery (n= 6, 6, 40, and 26, respectively). B through D, Echocardiography analysis of left ventricular ejection fraction (LVEF; B), left ventricular end-diastolic volume (LVEDV; C), and left ventricular end-systolic volume (LVESV; D) in mice 5 weeks (5W) after sham or TAC surgery. E and F, Ex vivo heart weight–to–body weight ratio (HW / BW; E) and lung weight–to–body weight ratio (LW / BW; F) for sham and TAC mice 5 weeks after surgery. G and H, Representative images of hematoxylin-eosin–stained heart sections (G) quantified for myocytes cross-sectional area (CSA; H). Black scale bars=1 mm; blue scale bars=50 μm. I and J, Representative images of Masson trichrome–stained heart sections (I) quantified for percentage of the fibrotic area in sham and TAC groups (n=5 mice for each group). Black scale bars=1 mm; Yellow scale bars=100 μm. A, Statistical significance of survival was determined with the Gehan-Breslow-Wilcoxon test. B through J, Analyses were performed by 2- way ANOVA and Tukey multiple-comparisons test. FIGS 3A-3M. JP2CRhearts maintain E-C coupling function after pressure-overload stress. A, Representative in situ images and summary data of intact hearts stained with the lipophilic marker MM 4-64. Images were acquired from left ventricle (LV) and right ventricle (RV) 5 weeks (5W) after surgery. Scale bars=20 μm. B and C, Summary data of transverse tubule regularity (TTpower) from MM 4-64–stained images acquired from the LV (B) and RV (C) 5 weeks after sham or transverse aortic constriction (TAC) surgery (n=3 for each sham group, n=6–9 for each TAC group). D, Representative cytosolic Ca2+ confocal images (top) and quantified Ca2+dynamic traces (F / F0; bottom) in the LV of intact hearts under autonomous beating from wild- type (WT) and junctophilin-2 knock-in (JP2CR) mice 5 weeks after sham or TAC surgery. E through G, Average Ca2+transient amplitude (E), time to peak (F), and 50%, 75%, and 90% Ca2+ transient decay times (G). n=122 to 138 cardiomyocytes from n=4 to 5 mice per group. H through L, Representative confocal line scan images (H) and quantification of Ca2+spark parameters (I through L) from quiescent cardiomyocytes isolated from WT and JP2CRmice after TAC or sham surgery. Ca2+ sparks were assessed for frequency (I), amplitude (F / F0; J) full duration at half- maximum (FDHM; K), and full width at half-maximum (FWHM; L). WT: sham, n=130 cells 4 24028 / / SLW 875.245WO1 from 5 hearts; JP2CR: sham, n=96 cells from 5 hearts; WT: TAC / 5W, n=79 cells from 5 hearts; JP2CR: TAC / 5W, n=102 cells from 5 hearts. M, Quantification of diastolic Ca2+levels in Fura-2– loaded adult ventricular cardiomyocytes isolated from JP2CRand WT mice 5 weeks after TAC or sham surgery. E through M, Bonferroni procedure after a global test based on a linear mixed- effects model was performed for multiple-group comparisons (NCSS, Kaysville, UT). A compound symmetry correlation structure was assumed for linear mixed-effects model tests. E-C indicates excitation-contraction; and n.s., not significant. FIGS.4A-4L. JP2CRameliorates TAC-induced downregulation of E-C coupling proteins and upregulation of hypertrophic and fibrotic markers. A, Representative immunoblots of Ca2+handling (junctophilin-2 [JP2], type 2 ryanodine receptor [RyR2], sarcoplasmic reticulum calcium-ATPase 2 [SERCA2], voltage gated L-type calcium channel [CaV1.2], calsequestrin-2 [CSQ2], total and phospho-phospholamban [PLN]) and hypertrophic (ANP [atrial natriuretic peptide]) and fibrotic (FN1) proteins from left ventricular lysates of wild-type (WT) and JP2 knock-in (JP2CR) littermates 5 weeks (5W) after sham or transverse aortic constriction (TAC) surgery. Panels for sham and TAC sample in A were from the same immunoblot and exposure but separated by other samples. B through J, Quantitative assessment of immunoblotted proteins normalized to GAPDH protein expression. K and L, Quantitative assessment of phosphorylated PLN on Ser16 (K) and Thr17 (L) normalized to GAPDH. Data are presented as mean±SEM. B through L, Analyses performed by 2-way ANOVA and Tukey multiple-comparisons test. E-C indicates excitation-contraction. FIGS. 5A-5I. TAC-induced calpain activity is attenuated in JP2CRhearts, potentially contributing to improved RyR2, SERCA2a, and CaV1.2 protein levels. A through F, Calpain (CAPN) activity (A) and immunoblot quantification of calpain subunit protein levels (B through F) measured in left ventricular tissue homogenates from wild-type (WT) and junctophilin-2 knock-in (JP2CR) mice 5 weeks (5W) after sham or transverse aortic constriction (TAC) surgery. n=6 per group. Data are presented as mean±SEM. Two-way ANOVA was used for multiple comparisons. Panels for sham and TAC sample in B were from the same immunoblot and exposure but separated by other samples. G through I, Representative Western blots of calpain cleavage assays. HEK293T cells were transfected with type 2 ryanodine receptor (RyR2; G), sarcoplasmic reticulum calcium-ATPase 2 (SERCA2A; H), or voltage gated L-type calcium channel (CaV1.2; I) with and without calpain-1 or calpain-2. Reactions were conducted in lysates with or without Ca2+ and 10 μmol / L MDL28170 as indicated. A through F, Analyses performed by 2-way ANOVA and Tukey multiplecomparisons test. 5 24028 / / SLW 875.245WO1 FIGS. 6A-6F. RNA-sequencing analysis indicates that TAC-induced transcriptional changes are modestly attenuated in JP2CRhearts. A, Heat map of significant differentially expressed genes (DEGs; 1.5-fold change [absolute log2FC<0.585], PAdj<0.05,) determined by RNAsequencing (RNA-seq) analysis comparing sham and transverse aortic constriction (TAC) groups in wild-type (WT) and junctophilin-2 knock-in (JP2CR) hearts. B, Volcano plot of RNA- seq results comparing WT sham and JP2CRsham (purple), WT sham and WT TAC (gray scale), and JP2CRsham and JP2CRTAC (orange) groups. Darker symbols represent DEGs meeting significance thresholds (PAdj<0.05 and >1.5-fold change). Nonsignificant genes are plotted as light symbols. Example genes are indicated to show relative changes in response to TAC between genotypes. C, Venn diagram of sham vs TAC DEGs (PAdj<0.05, >1.5-fold changes) for each genotype. D, Bubble plot of cardiovascular related signaling pathways from Ingenuity Pathway Analysis. PAdj=0.01 (-log PAdj=2) is indicated for reference. E and F, Bubble plots of enriched KEGG terms for upregulated (E) and downregulated (F) DEGs using gProfiler (biit.cs.ut.ee / gprofiler / gost). Enriched terms related to experimental findings for JPCRmice are indicated in red. FIGS.7A-7J. JP2CR gene therapy attenuates HF progression in mice with pre-established cardiac dysfunction. A, Maps of cytomegalovirus promoter (CMV)–driven junctophilin-2 (JP2), JP2 knock-in (JP2CR), and GFP (green fluorescent protein) adenoassociated virus (AAV) constructs. B, Western blot analysis of Flag-tagged JP2 and JP2CRorgan distribution in mice tail vein injected with AAVs at 2 weeks after transverse aortic constriction (TAC) surgery and harvested 6 weeks later. C through F, Echocardiography analysis of left ventricular ejection fraction (LVEF; C), left ventricular end-systolic volume (LVESV; D), left ventricular end-diastolic volume (LVEDV; E), and LV mass (F) in animals at 2, 5, and 8 weeks after TAC or sham surgery. G, Heart weight–to–body weight ratio (HW / BW) for baseline and TAC mice 8 weeks after surgery. H, Lung weight–to–body weight ratio (W / BW) for baseline and TAC mice 8 weeks after surgery. n=5 to 8 mice for each group (sham [5], AAV-GFP [8], AAV-JP2 [8], AAV-JP2CR[7]). I, Representative images of hematoxylin-eosin (H&E)–stained heart sections quantified for myocytes cross-sectional area (CSA; n=5 mice for each group). J, Representative images of Masson trichrome–stained heart sections quantified for percentage of the fibrotic area in sham and TAC groups (n=5 mice for each group). C through J, Analyses performed by one-way ANOVA and Tukey multiple comparisons test. HF indicates heart failure. FIG. 8. Model for how JP2CR protects E-C coupling and heart function under cardiac stress. Left, In a healthy cardiomyocyte, normal Ca2+ handling and efficient excitation- contraction (E-C) coupling depend on stable cardiac dyad junctions formed between plasma 6 24028 / / SLW 875.245WO1 membrane transverse tubules (T-tubules) and sarcoplasmic reticular (SR) terminal cisternae. Junctophilin-2 (JP2) stabilizes dyads containing voltage gated L-type calcium channels (CaV1.2s), L-type Ca2+ channels (LTCCs), and type 2 ryanodine release channels (RyR2s). The SR clears cytosolic Ca2+ during diastole through SR Ca2+-ATPase 2a (SERCA2a). Middle, Cardiac stress promotes cytosolic Ca2+ overload and calpain activation (scissors), leading to the proteolysis of JP2, RyR2, CaV1.2, and SERCA2a. As a result, dyad junctions and T-tubules degenerate, leading to E-C uncoupling and heart failure. Right, Cleavage-resistant JP2 (junctophilin-2 knock-in [JP2CR]; represented by the purple segment in JP2) cannot be cleaved by calpain and preserves the ultrastructure of cardiac dyads and T-tubules. Preventing JP2 cleavage blocks the vicious cycle by prohibiting excessive Ca2+overload and inhibiting further calpain activation, thereby sustaining E-C coupling, which cumulatively improves cardiac outcomes. FIGS. 9A-9D depict the cloning strategy for inserting JP2 gene fragments into parental AAV shuttle vectors. A and B. Linear map (A) and sequence of the multiple cloning site (B) of the parental AAV vector (#G0692); SEQ ID NOS: 54-55). SalI and BamHI restriction sites are boxed. C. JP2 gene fragments generated by PCR using forward primers containing a SacI site, Kozak sequence, and N-terminal FLAG-tag and reverse primers containing a C-terminal HA-tag and BamHI site. D. Sequence of cloned JP2 inserts near the SacI insertion site (SEQ ID NOS: 56-59). FIGS.10A-10C demonstrates that in vivo AAV2 / 9-JP2 administration provides long-term JP2 expression in cardiomyocytes. A. Administration time course. B. Western blots of mouse tissues 8 weeks after AAV injection. C. Immunofluorescent images of cardiac tissue sections for AAV mediated GFP (green) and HA-tagged JP2 (red) expression. Cardiac DNA is stained with To-pro-3 (blue). FIGS.11A-11C demonstrate that AAV-JP2NT preventatively inhibits the development of HF. AAV was injected into 3-day-old mice before sham or TAC surgery at 8 weeks of age and analysis 5 weeks later. A. Western blot of heart lysates showing stable expression of JP2NT from AAV administration. B. Echocardiography results measuring left ventricular ejection fraction (LVEF). C. Ex vivo heart weight to body weight ratios (HW / BW). FIGS. 12A-12G show that AAV-JP2NT therapeutically inhibits the development of HF. A. Outline of therapeutic testing of AAV-JP2NT in which 9-10 wk old mice were subjective to TAC and injected with AAV (tail vein) 2 weeks later. B. Inclusion criteria and treatment based on modest TAC-induced decrease in heart function (40%>EF>60%). C-G. Evaluation of AAV- JP2NT vs AAV-GFP outcomes 8 weeks after surgery. C. Western blots. D. LVEF measured by echocardiography. E and F. Ex vivo heart weight (HW, E) and lung weight (LW, F) to body weight 7 24028 / / SLW 875.245WO1 ratios. G. Quantification of cardiac fibrosis by Masson’s trichrome staining of cardiac tissue sections. FIGS. 13A-13F show that AAV-JP2CRtherapeutically inhibits the development of established HF. A. Outline of therapeutic testing of AAV-JP2CRin which 9-10 wk old mice were subjective to TAC and injected with AAV (tail vein) 2 weeks later. B. Inclusion criteria based on modest TAC-induced decrease in heart function (40%>EF>60%) after 2 weeks. C-F. Echocardiography evaluation of AAV-dependent outcomes after surgery measuring ejection fractions (C), left ventricular end systolic volume (LVESV), end diastolic volume (LVEDV), and mass (LV mass). FIG.14 demonstrates that combined JP2CRand JP2NT expression in mice synergistically improves TAC-induced transcriptional changes. Volcano plots of RNA-sequencing data comparing Sham vs. TAC gene expression changes in WT, JP2CR, and JP2CR+ JP2NT-OE (OE – overexpressing) genetic mouse models. DEGs: differentially expressed genes (pAdj<0.05, absolute Log2 fold change <0.585 (1.5-fold)). FIGS. S1A-S1C. Validation of the JP2CRknock in model. A, Genomic exon organization of the Jph2 gene in mice (minus strand orientation) (SEQ ID NOS: 60-63). The genomic region containing Jph2 exons 3-5 is expanded in the middle panel and further expanded at the nucleotide level in the bottom panel for Exon 4 codons encoding the calpain cleavage site. gRNAs with PAM sequences used in the generation of KI mice are shown. B, DNA sequencing results spanning the Jph2 calpain cleavage region from WT and JP2CRmice. C, Agarose gel of genotyping PCR reactions for JP2WT / WT(WT), and JP2WT / CR(Hete) and JP2CR / CR(Homo) mice using primers specific for Exon 4 of Jph2. FIG. S2. JP2CRknock-in mice have normal JP2 localization at baseline. Immunohistochemistry micrographs of myocardial sections from 3-month-old WT and JP2CRmice. Scale bar, 20 μm. To-Pro-3 (blue), a high-affinity nucleic acid stain. Both WT and JP2CRmyocardium display similar organized striation pattern of JP2 (white) at baseline condition. FIGS. S3A-S3B. Ejection fraction, heart weight, heart weight (HW) to body weight (BW), lung weight to BW of wildtype (WT) mice and JP2CRmice at 3- and 6-months age. (A) EF (%), body weight, HW / BW and LW / BW ratio of WT and JP2CRmice. (3 months of age). N=7 mice / genotype. (B) EF (%), body weight, HW / BW and LW / BW ratio of WT and JP2CRmice. (6 months of age). N=7 for WT, 6 for JP2CRmice. Data are represented as mean ± SEM. Data are analyzed by unpaired t-test. P-values of comparisons are shown in the graph. FIGS. S4A-S4N. JP2CRand WT mice have similar heart function at baseline. A, Representative cardiac pressure-volume (P-V) loops from 6-month-old JP2CRand WT mice. B-J, 8 24028 / / SLW 875.245WO1 Quantitation of P-V loop analysis. LV maximum and minimum ascending rates of pressure (+dp / dt and –dp / dt), heart rate (HR), LV end-diastolic pressure (LVEDP), LV development pressure (LVDP), LV end-systolic volume (LVESV), LV end-diastolic volume (LVEDV), LV relaxation time (Tau), left ventricle ejection fraction (LVEF). n^=^5 for each group. A' indicates tissue Doppler velocity from atrial contraction; E', early diastolic tissue Doppler velocity. K, Representative images of hematoxylin & eosin (H&E) (left) and Masson’s trichrome stained heart sections (middle and right). Red scale bar, 1 mm; Yellow scale bar, 50 μm. L, Quantification of percent fibrotic area in 6-month-old WT and JP2CRmice hearts from Masson’s trichrome staining (n=5 mice for each group). M-N, Serum samples from WT mice with heart failure collected at 5 weeks after TAC surgery or from 6-month-old WT and JP2CR mice at baseline. Levels of NT-proANP (M) and TNNT2 (N) in plasma samples were analyzed by ELISA. Data are mean±SEM. P values were analyzed by one-way ANOVA and Tukey’s post hoc analysis. ANP, atrial natriuretic peptide; TNNT2, Troponin T2. FIGS. S5A-S5B. JP2CRprevents JP2NT production in isoproterenol - high extracellular [Ca2+]otreated cardiomyocytes. A. Confocal immunofluorescence images of cultured adult cardiomyocytes showing JP2 disorganization and nuclear enrichment of JP2NT in WT, but to a less extent in JP2CRcells after treatment with 1 μM Isoproterenol + 5 mM Ca2+for 24 hrs. Yellow boxes in left panels are enlarged to the right with nuclei outlined in red. Anti-JP2 (green, left; white, right); To-pro-3-stained DNA (blue) B. Summary data of relative nuclear vs membrane JP2(NT) intensity (n=24-27 cardiomyocytes from 3 hearts per group). Data are represented as mean ± SEM. Data were analyzed by linear mixed model analyses with Bonferroni correction. FIGS. S6A-S6D. JP2CRpreserves the colocalization between RyR2 and CaV1.2 in response to pressure overload. A, Adult ventricular cardiomyocytes isolated from JP2CRand WT mice 5 weeks after TAC or Sham surgery were immunostained for RyR2 (ryanodine receptor-2; green channel - right column) and LTCC α1C subunit (red channel - middle column). The overlay of green and red channels is depicted in the left column. B, Colocalization percentage of RyR2 with CaV1.2. C-D, Average CaV1.2 (C) and RyR2 (D) distribution regularity (Fourier transformed power) in cardiomyocytes isolated from JP2CRand WT mice 5 weeks after TAC or Sham surgery. Power index determined by AutoTT. Data are shown as mean±SEM from N=3 hearts / 30 cells per group. FIG. S7. Heatmap of significant differentially expressed genes (DEGs) within select enriched cardiovascular disease signaling pathways. Ingenuity Pathway Analysis (QIAGEN) was performed on DEGs and queried for enriched Canonical Pathways. DEGs lying within pathways 9 24028 / / SLW 875.245WO1 annotated for select cardiovascular disease signaling pathways are indicated. TAC, trans-aortic constriction; WT, wildtype; CR, calpain resistant junctophilin-2. FIG. S8. JP2CRdoes not affect the mRNA expression of major calcium handling genes at baseline and under stressed condition. TPM, transcripts per million (TPM) values obtained from RNA-seq analysis of ventricular tissue from WT and JP2CRhearts 5 weeks after sham and TAC surgery. N=4 hearts / group. FIG. S9. Enriched gene otology (GO) terms for downregulated genes in JP2CRhearts in response to TAC are less significant than in WT. Enriched GO terms determined by gProfiler after separately analyzing significantly upregulated versus downregulated DEGs (Log2FC <-0.58 or >0.58; pAdj <0.05; Sham vs. TAC). Data are plotted for the 20 terms with lowest pAdj values for both WT and JP2CR. FIGS. S10A-S10C. Protocol used to induce moderate cardiac dysfunction to evaluate AAV-JP2CRvs. AAV-JP2 and AAV-eGFP gene therapy. A-B. The experimental workflow (A) and flow chart of sequential inclusion criteria (B) used to obtain a cohort of mice with similar levels of moderate heart failure that were then randomized to receive AAV-eGFP, AAV-JP2 and AAV- JP2CR. The TAC model was performed on 9-10-week-old C57BL / 6N male mice. Mice with ejection fractions (EF) ranging from 40% - 60% 2 weeks post-TAC were selected for gene therapy administration. Heart function was assessed by echocardiography 3 and 6 weeks after AAV injection. Mice were euthanized for collecting heart tissue after the last echocardiography measurement. C. Graph showing distribution of individual mouse EF assessed by echo at 2 weeks post TAC. The dotted red lines represent the group of mice that were included for randomization. Each black dot represents one mouse. FIGS. S11A-S11B. AAV-mediated exogenous JP2CRexpression in different mouse organs. A, Western blot for heart lysates from mice infected with AAV2 / 9-eGFP or AAV2 / 9-JP2CRfor 8- weeks beginning at 9-10 weeks of age. B, IF staining of AAV-mediated exogenous JP2CRexpression in different organs. Slides from mice tail-vein-infected with AAV2 / 9-eGFP or AAV2 / 9- JP2CRfor 8-weeks beginning at 9-10 weeks of age. Yellow scale bar, 1 mm; Red scale bar, 50 μm. FIG. S12. Viral transduction of mice with JP2CRmodestly increases total JP2 levels in the heart. Western blot comparing different protein loading amounts from samples after transduction with AAV-GFP and AAV-JP2CR; IB: Flag and JP2, GAPDH (0.1μg, 0.3μg, 1μg, 3μg, 10μg, 30μg). ABBREVIATIONS AAV Adeno-associated virus Ca2+Calcium CICR Calcium induced calcium release 10 24028 / / SLW 875.245WO1 DEGs Differentially expressed genes E-C Excitation-Contraction (coupling) EF Ejection fraction GFP Green fluorescent protein HF Heart failure ISO Isoproterenol JP2 Junctophillin-2 JP2CRCleavage-resistant Junctophilin-2 JP2NT N-terminal fragment of JP2 LTCC L-type calcium channel LVEDV Left ventricular end-diastolic volume LVESV Left ventricular end-systolic volume NLS Nuclear localization signal or sequence PLN Phospholamban RNA-seq RNA sequencing RyR2 Ryanodine receptor 2 SERCA2a Sarcoplasmic reticulum calcium ATPase 2a SR Sarcoplasmic reticulum TAB Transverse or trans-aortic banding TAC Transverse or trans-aortic constriction T-tubule Transverse tubule WT Wild type DETAILED DESCRIPTION OF THE INVENTION Cardiac gene therapy involves the introduction of recombinant genetic material to patients with cardiac disease. One goal is to alter the levels of specific gene products that will either directly or indirectly alter mechanisms that contribute to HF, including abnormalities in adrenergic signaling, maladaptive transcriptional activity, alterations in calcium handling, activation of proteolytic pathways that result in cell death, and stimulation of pathways that lead to deposition of extracellular matrix within the myocardium, among others. Changes in the levels or activity of molecules that play roles in these pathways have been identified. Adeno-associated viral vectors (AAV) can efficiently deliver genetic material to the myocardium in vivo and are being tested clinically for their effectiveness in treating patients with HF. Provided herein, JP2 represents a unique nodal point in HF progression as JP2 lies at the crossroads of several HF-related 11 24028 / / SLW 875.245WO1 mechanisms including dysregulated E-C coupling, Ca2+-dependent proteolysis, and maladaptive gene expression. Calpain specifically cleaves JP2 within its C-terminus generating a nuclear localized JP2NT fragment. The primary calpain cleavage site of JP2 was mapped to its C-terminus between residues R565 / T566 (Guo 2015; Wang 2021). The major proteolytic fragments are mimicked by constructs expressing residues 1-565 (Flag-JP2NT) and 566-end (JP2CT-HA) and prevented in a cleavage resistant deletion mutant of JP2 (JP2CR). It was unexpectedly observed EGFP-tagged JP2NT localizes to the nucleus of cells and subsequently the nuclear localization signal was identified (NLS, residues 488-492: KRPRP) (Guo 2018). JP2NT also contains a putative evolutionarily conserved helix-turn-helix DNA binding domain within its alanine-rich region (ARR) and its deletion (Δ 367-402) permits nuclear localization but prohibits co-localization with DNA. JP2NT is a direct transducer of excitation-transcription (E-T) coupling that reports E-C coupling dysfunction to the nucleus. It was found that cardiomyocyte nuclei in human ischemic cardiomyopathy (ICM) tissue and in mice after myocardial infarction (MI) are significantly enriched with JP2 species using antibodies against internal epitope that detects JP2 and JP2NT (Guo 2018). As the full-length JP2 is exclusively localized outside nuclei and JP2NT is concentrated in nuclei (Guo 2018), these results, with similar findings in hearts from mice subjected to transverse aortic banding (TAB, also known as transverse aortic constriction (TAC)) induced pressure overload (Guo 2018), indicate that pathological stresses promote the generation and nuclear accumulation of JP2NT. These data indicate that JP2NT, as a consequence of stress- induced calpain cleavage, serves as a novel regulator of stress-responsive pathological gene expression. Indeed, adenoviral transduction of adult isolated cardiomyocytes with JP2NT leads to dramatic changes in differentially expressed (DE) genes (1996 down, 574 up; pAdj<0.05) compared to empty virus that is an order of magnitude greater than for full length JP2 (264 down, 96 up). These data are interpreted to mean that the JP2NT proteolytic fragment functions as a transcriptional repressor. To investigate its function in vivo, cardiac specific JP2NT transgenic overexpressing (JP2NT-OE) mice were generated. At baseline, JP2NT-OE mice are phenotypically normal without changes in survival or cardiac function with only modest changes in cardiac gene expression (220 DE genes). However, in response to five weeks of TAB-induced pressure overload stress, JP2NT-OE mice were able to maintain cardiac ejection fraction and have attenuated cardiac hypertrophy compared to littermate controls (Guo 2018). Using RNA-seq and chromatin immunoprecipitation coupled deep sequencing (ChIP-seq), it was found that overexpressed 12 24028 / / SLW 875.245WO1 JP2NT inhibits overall transcriptional reprogramming by TAB by 54% (1653 DE genes vs.3580 in controls; pAdj<0.05) (Guo 2018) enriching at gene promoters (Guo 2018). Canonical stress- responsive pathways (e.g., hypertrophic (ERK1 / 2 MAPK), fibrotic (TGF-β, FGF2) and hypoxic (HIF1α) signaling) are strongly attenuated after TAB when comparing DE genes in JP2NT-OE mice against those in WT animals (Guo 2018). Parallel experiments using the novel JP2ΔNLS knock-in mice, in which JP2NT produced by stress cannot translocate to the nucleus, resulted in exacerbated TAB-induced cardiac dysfunction (Guo 2018), further demonstrating that JP2NT confers cardiac protection in stressed hearts by repressing stress-induced maladaptive transcriptional remodeling. Cumulatively, these data indicate that JP2 is tightly regulated through subcellular localization and proteolytic processing to uniquely mediate E-C and E-T coupling mechanisms. E-T coupling is the process whereby depolarization dependent Ca2+influx promotes changes in gene expression. It was found that JP2, an E-C coupling constituent, serves as a direct calpain substrate liberating its self-protective, nuclear translocating N-terminal fragment to directly repress stress-induced gene expression. JP2 is not only a structural protein for normal E-C coupling function and Ca2+homeostasis in healthy cardiomyocytes, but also functions to transduce mechanical information into salutary transcriptional reprogramming in stressed hearts. Stress-induced cardiac dysfunction is attenuated by inhibiting calpain-dependent JP2 cleavage. It was previously reported that human ischemic and dilated cardiomyopathy samples have increased calpain activities and decreased JP2 levels similar to failing murine hearts after TAB-induced pressure overload, MI, and isoproterenol (ISO) infusion (Wang 2018). Inhibiting calpain activity with i.p. injection of 10 mg / kg / day MDL-21870 in TAB-, MI-, and ISO-stressed mice improved left ventricular ejection fraction (LVEF) as determined by echocardiography, mitigated JP2 loss and maintained dyad junctions as measured by T-tubular integrity. This signifies that inhibition of JP2 cleavage has therapeutic benefits. However, it was also found that MDL administration also prevents the generation and nuclear localization of the cardioprotective JP2NT fragment in failing hearts after TAB and MI surgery (Wang 2018). JP2CRmice are protected from stress-induced HF and cardiomyocyte calcium handling dysfunction. To dissect the specific contribution of calpain cleavage of JP2 in the context of the cardiac benefits provided by MDL-28170 treatment, a calpain-resistant mutant JP2 knockin mouse model was generated (JP2CR). JP2CRmice are healthy at baseline indicating the CR mutation has little to no effect in healthy animals. Both in vitro calpain cleavage assays and confocal imaging assays confirm that mutant JP2 (JP2CR, Δ563-568) is indeed resistant to cleavage by calpain and in response to ISO treatment. 13 24028 / / SLW 875.245WO1 To determine whether JP2CRis cardioprotective in vivo, cardiac responses were measured in mice subjected to sham or transaortic constriction (TAC) surgery. It was found that a significantly larger fraction of JP2CRmice (18 of 26, 69.2%) survived from 5 weeks of pressure overload stress compared to WT (19 of 38, 50%, p<0.05) mice. Cardiac function was evaluated in surviving animals via echocardiographic assessments of left ventricular ejection fraction (LVEF), end-diastolic volume (LVEDV), end-systolic volume (LVESV). In sham operated groups, WT and JP2CRmice had similar cardiac function and other HF parameters including cardiac hypertrophy (heart weight / body weight ratio (HW / BW)), lung edema (lung weight to body weight (LW / BW)), cardiomyocyte hypertrophy (cross-sectional area (CSA)), and the area of cardiac fibrosis. Such findings indicate JP2CRdoes not dramatically affect the heart under normal conditions. Under pressure overload conditions that promote cardiac hypertrophy and HF, JP2CRmice showed significantly improved cardiac outcomes for all these measures and demonstrates that JP2CRprotects the heart against TAC-induced pathological remodeling. Since a function of intact JP2 is to stabilize cardiac dyad junctions and maintain normal calcium homeostasis and E-C coupling, it was investigated whether dyad associated intracellular calcium transients or T-tubular organization are altered in JP2CRmice at baseline and after TAC. By contrast, JP2CRmice had significantly better organized T-tubule structures following pressure overload compared to WT mice. Using confocal microscopy to record intracellular Ca2+transients from intact hearts under spontaneous beating revealed there was no difference in Ca2+handling properties in sham-operated WT and JP2CRhearts, suggesting that and JP2CRalso has no influence on CICR at baseline. WT hearts have markedly impaired Ca2+handling after TAC as indicated by a significant decrease in Ca2+transient amplitude, an increase in Ca2+transient time to peak (Tpeak), and a prolongation in the 50 Ca2+transient decay time (T50). Consistent with attenuated T-tubule remodeling after TAC, JP2CRhearts had a significantly higher Ca2+transient amplitude with shorter time to peak and decay rates as compared to WT TAC hearts. Consistent with improved CICR, it was found that cardiac dyad regularity not as disorganized in JP2CRhearts after TAC compared to WT TAC hearts when measuring the T-tubules organization. These results indicate JP2CRpreserves T-tubule remodeling and Ca2+handling during pressure overload stress. JP2CRlimits the feedback activation of calpain and the cleavage of calpain substrates during HF stress. Mechanisms of JP2CRcardioprotection were investigated by Western blotting known E-C coupling proteins and hypertrophic markers. There is a downregulation in E-C coupling proteins in WT hearts after TAC including JP2, RyR2, sarco-endoplasmic reticulum calcium ATPase-2a (SERCA2a), and CaV1.2. As demonstrated above, the JP2 R565 / T566 cleavage site is required for in vivo JP2 proteolysis. Here, the data shows the increase in the 75 14 24028 / / SLW 875.245WO1 kD JP2NT proteolytic fragment and a concomitant decrease in the full-length protein occurs in WT hearts but not in JP2CRhearts. While no significant differences were found in the expression levels of E-C coupling proteins in sham samples when comparing WT and JP2CRmice, the TAC- induced downregulation of RyR2, CaV1.2, and SERCA2a was significantly reduced in JP2CRLV lysates. With respect to pathology, the expression of atrial natriuretic protein (ANP) and Fibronectin-1 (FN1) were induced by TAC in both genotypes, but their changes were less dramatic in JP2CRhearts and support the attenuated cardiac fibrosis and hypertrophy phenotype of JP2CRmice. In addition to JP2, calpain has been reported to cleave other proteins in the heart that are involved in E-C coupling (e.g., RyR2, Serca2a, CaV1.2), structural integrity (e.g., dystrophin (DMD), desmin (DES), utrophin (UTRN), β2-spectrin (SPTBN2), integrin-β3 (ITGB3), ankyrin- B (ANK2), sarcomeric actinin (ACTN2)), signaling (e.g., calcineurin (PPP3CA), calcium- calmodulin dependent kinase-IIδ (CAMK2D) protein kinase-Cα (PRKCA), focal adhesion kinase (PTK2)), contraction (e.g., cardiac troponin-I (TNNI3), cardiac troponin-T (TNNT2), cardiac myosin binding protein-C (MYBPC3)), and lysis / apoptosis (e.g., lysosomal associated membrane protein 2 (LAMP2), apoptosis inducing factor mitochondria associated 1 (AIFM1)) (PubMed citations include 21817165, 37456811, 37768438); incorporated herein by reference). SEQ ID NO: 7 (RyR2 nt, human) ACTTGCTCGGAGGAGCCGGGGCCGAGCGGACCGCCGGCTGCAGGCAGCGAGCGCGGCTGGGCTGCGGGGCTGCTTCC CCGCGTCCTCCGGGCCCGGGCCGCCCTCCTCCCGCACAGTGCGGAGCAGGGAGGCCCCGCGCCTCGACCACCCGCGC CCGAGCGTCCGCGCCTCCTCCTCCGCTCTGCAGGCGGGGACCGCCCGGCGCTCGGCACCCGGCAGCGCGGCCCCCTC CAGCCCCCGGCTCCCGGCAGCAGAAGCAGAAGGCAGCGCCAGGGGCCGCCGCCGCCGCCGAGCTCCGCGGGGCTCGG GAGCCGGCCCCGGCGAGGAGGCGCGGAACCATGGCCGATGGGGGCGAGGGCGAAGACGAGATCCAGTTCCTGCGAAC TGATGATGAAGTGGTTCTGCAGTGCACCGCAACCATCCACAAAGAACAACAGAAGCTATGCTTGGCAGCAGAAGGAT TTGGCAACAGACTTTGTTTCTTGGAGTCCACTTCCAATTCCAAGAATGTGCCCCCAGACCTCTCCATCTGCACCTTT GTGCTGGAGCAGTCCCTCTCTGTCCGGGCGCTGCAGGAGATGCTGGCTAACACCGTGGAGAAATCAGAAGGGCAAGT TGATGTGGAAAAATGGAAATTCATGATGAAGACTGCTCAAGGTGGTGGTCATCGAACACTCCTCTACGGACATGCCA TATTGCTGCGCCATTCCTATAGTGGCATGTATCTGTGCTGCCTGTCCACCTCCCGGTCTTCAACTGATAAGCTGGCT TTTGATGTTGGCTTGCAAGAGGACACCACAGGGGAGGCTTGTTGGTGGACCATACACCCTGCCTCTAAGCAGCGATC AGAAGGAGAAAAAGTACGAGTTGGAGATGACCTCATCTTAGTTAGCGTGTCCTCTGAAAGGTACTTGCACTTGTCTT ATGGCAACGGCAGCTTACACGTGGATGCCGCTTTCCAGCAGACTCTCTGGAGCGTGGCCCCAATCAGCTCAGGAAGT GAGGCAGCCCAAGGGTATCTCATTGGTGGTGATGTCCTCAGGTTGCTGCATGGACACATGGACGAGTGTCTCACTGT CCCTTCAGGAGAACATGGTGAAGAGCAGCGGAGAACTGTTCATTATGAAGGTGGCGCTGTGTCTGTTCATGCACGTT CCCTTTGGAGACTAGAGACGCTAAGAGTTGCGTGGAGTGGAAGCCACATAAGATGGGGACAGCCATTCCGACTACGC CATGTCACAACAGGAAAATACTTGAGTCTCATGGAAGACAAAAACCTTCTACTCATGGACAAAGAGAAAGCTGATGT AAAATCAACAGCATTTACCTTCCGGTCTTCCAAGGAAAAATTGGATGTAGGGGTGAGAAAAGAAGTAGATGGCATGG GAACATCTGAAATAAAATACGGTGACTCAGTATGCTATATACAACATGTAGACACAGGCCTATGGCTTACTTACCAG TCTGTGGACGTGAAATCCGTGAGAATGGGATCTATACAACGTAAGGCTATTATGCATCATGAAGGCCACATGGATGA TGGCATAAGTTTGTCGAGATCCCAGCATGAAGAATCACGCACAGCCCGAGTTATCCGGAGCACAGTCTTCCTTTTCA ATAGATTTATAAGGGGCCTTGATGCTCTCAGCAAGAAAGCGAAGGCTTCCACAGTCGATTTGCCTATAGAGTCCGTA AGCCTAAGTCTGCAGGATCTCATTGGCTACTTCCACCCCCCAGATGAGCATTTAGAGCATGAAGACAAACAGAACAG ACTACGAGCCCTGAAGAATCGGCAAAATCTCTTCCAGGAAGAGGGAATGATCAACCTCGTGCTTGAGTGCATAGACC GTTTGCACGTCTACAGCAGTGCAGCACACTTTGCTGATGTTGCTGGGCGAGAAGCAGGAGAGTCTTGGAAATCCATT CTGAATTCTCTGTATGAGTTGCTGGCGGCTCTAATTAGAGGAAATCGTAAAAACTGTGCTCAATTTTCTGGCTCCCT CGACTGGTTGATCAGCAGATTGGAAAGACTGGAAGCTTCTTCAGGCATTCTGGAAGTTTTACACTGTGTTTTAGTAG 15 24028 / / SLW 875.245WO1 AAAGTCCAGAAGCTCTAAATATTATTAAAGAAGGACATATTAAATCTATTATCTCACTTTTAGACAAACATGGAAGA AATCACAAGGTTCTGGATGTCTTGTGCTCACTCTGTGTTTGCCACGGGGTTGCAGTCCGTTCTAACCAGCATCTCAT CTGTGACAATCTCCTACCAGGAAGAGACTTGTTATTGCAGACACGTCTTGTGAACCATGTCAGCAGCATGAGACCCA ATATTTTTCTGGGCGTCAGTGAAGGTTCTGCTCAGTATAAGAAATGGTACTATGAATTGATGGTGGACCACACAGAG CCCTTTGTGACAGCTGAAGCAACTCACCTGCGAGTGGGCTGGGCTTCCACTGAAGGATATTCTCCCTACCCTGGAGG GGGCGAAGAGTGGGGTGGAAATGGTGTTGGAGATGATCTCTTCTCCTATGGATTTGATGGCCTTCATCTCTGGTCAG GTTGTATTGCTCGTACTGTAAGCTCACCAAACCAACATCTGTTAAGAACTGATGATGTCATCAGTTGCTGTTTAGAT CTGAGTGCCCCAAGCATCTCGTTCCGAATTAATGGACAACCTGTTCAAGGAATGTTTGAGAATTTCAACATCGATGG CCTCTTCTTTCCAGTCGTTAGTTTCTCTGCAGGAATAAAAGTACGCTTTCTGCTTGGAGGGCGACATGGAGAATTCA AATTTCTTCCTCCACCTGGGTATGCTCCTTGTTATGAAGCTGTTCTGCCAAAAGAAAAGTTGAAAGTGGAACACAGC CGAGAGTACAAGCAAGAAAGAACTTACACACGCGACCTGCTGGGCCCCACAGTTTCCCTGACGCAAGCTGCCTTCAC ACCCATCCCTGTGGATACCAGCCAGATCGTGTTGCCTCCTCATCTAGAAAGAATAAGAGAAAAACTGGCAGAGAATA TCCATGAACTCTGGGTTATGAATAAAATTGAGCTTGGCTGGCAGTATGGTCCGGTTAGAGATGACAACAAGAGACAA CACCCATGCCTGGTGGAGTTCTCCAAGCTGCCTGAACAGGAGCGCAATTACAACTTACAAATGTCGCTTGAGACCCT GAAGACTTTGTTGGCATTAGGATGTCATGTGGGTATATCAGATGAACATGCTGAAGACAAGGTGAAAAAAATGAAGC TACCCAAGAATTACCAGCTGACAAGTGGATACAAGCCTGCCCCTATGGACCTGAGCTTTATCAAACTCACCCCATCA CAAGAAGCAATGGTGGACAAGTTGGCAGAAAATGCACATAATGTGTGGGCGCGGGATCGAATCCGGCAGGGCTGGAC TTATGGCATCCAACAGGACGTAAAGAACAGAAGAAATCCTCGCCTTGTTCCCTACACTCTTCTGGATGACCGAACCA AGAAATCCAACAAGGACAGCCTCCGCGAGGCTGTGCGCACGCTGCTGGGGTACGGCTACAACTTGGAAGCACCAGAT CAAGATCATGCAGCCAGAGCCGAAGTGTGCAGCGGCACCGGGGAAAGGTTCCGAATCTTCCGTGCCGAGAAGACCTA TGCAGTGAAGGCCGGACGGTGGTATTTTGAATTTGAGACGGTCACTGCTGGAGACATGAGGGTTGGTTGGAGTCGTC CTGGTTGTCAACCGGATCAGGAGCTTGGCTCAGATGAACGTGCCTTTGCCTTTGATGGCTTCAAGGCCCAGCGGTGG CATCAGGGCAATGAACACTATGGGCGCTCTTGGCAAGCAGGCGATGTCGTGGGGTGTATGGTTGACATGAACGAACA CACCATGATGTTCACACTGAATGGTGAAATCCTTCTTGATGATTCAGGCTCAGAACTGGCTTTCAAGGACTTTGATG TTGGCGATGGATTCATACCTGTGTGTAGCCTTGGAGTGGCTCAAGTGGGTAGGATGAACTTTGGAAAGGATGTCAGC ACCTTGAAATATTTCACCATCTGTGGCTTACAAGAGGGCTATGAACCATTTGCCGTTAATACAAACAGGGATATTAC CATGTGGCTGAGCAAGAGGCTTCCTCAGTTTCTTCAAGTTCCATCAAACCATGAACATATAGAGGTGACCAGAATAG ACGGCACCATAGACAGTTCCCCATGTTTAAAGGTCACTCAGAAGTCTTTTGGTTCTCAGAACAGCAACACTGATATC ATGTTTTATCGCCTGAGCATGCCGATCGAGTGCGCGGAGGTCTTCTCCAAGACGGTGGCTGGAGGGCTCCCTGGGGC TGGCCTTTTTGGGCCCAAGAATGACTTGGAAGATTATGATGCTGATTCTGACTTTGAGGTTCTGATGAAGACAGCTC ATGGCCATCTAGTGCCCGATCGTGTTGACAAAGACAAAGAAGCTACTAAACCAGAGTTTAACAACCACAAAGATTAT GCCCAGGAAAAGCCCTCTCGTCTGAAACAAAGATTTTTGCTTAGAAGAACAAAGCCAGATTACAGCACAAGCCATTC TGCAAGACTCACCGAAGATGTCCTTGCTGATGATCGGGATGACTATGATTTCTTGATGCAAACGTCCACGTACTATT ACTCAGTGAGAATCTTTCCTGGACAAGAACCTGCTAATGTCTGGGTGGGCTGGATTACATCAGATTTCCATCAGTAT GACACAGGCTTTGACTTGGACAGAGTTCGCACAGTAACAGTTACTCTAGGAGATGAAAAAGGAAAAGTGCATGAAAG CATCAAACGCAGCAACTGCTATATGGTATGTGCGGGTGAGAGCATGAGCCCCGGGCAAGGACGCAACAATAATGGAC TGGAGATTGGCTGTGTGGTGGATGCTGCCAGCGGGCTGCTCACATTCATTGCCAATGGCAAGGAACTGAGCACATAC TATCAGGTGGAACCGAGTACAAAATTATTTCCTGCGGTTTTTGCACAAGCTACAAGTCCCAATGTTTTCCAGTTTGA GTTGGGAAGAATAAAGAATGTGATGCCTCTCTCGGCGGGATTATTCAAGAGTGAGCACAAGAACCCCGTGCCGCAGT GCCCCCCGCGCCTCCACGTGCAGTTCCTGTCACACGTCCTGTGGAGCAGAATGCCCAACCAGTTTTTGAAGGTAGAT GTGTCTCGAATAAGTGAACGCCAAGGCTGGTTGGTGCAGTGTTTGGATCCTCTGCAGTTCATGTCTCTTCATATCCC TGAGGAAAACAGATCTGTTGACATCTTAGAGTTGACAGAGCAGGAGGAATTGCTGAAATTTCACTATCACACTCTCC GGCTCTACTCAGCCGTCTGTGCTCTTGGGAACCACCGGGTGGCCCATGCCCTGTGCAGCCATGTGGATGAACCTCAG CTCCTCTATGCCATTGAGAACAAGTACATGCCTGGTTTGCTGCGTGCTGGCTACTATGACCTGCTGATTGACATCCA CCTGAGCTCCTATGCCACTGCCAGGCTCATGATGAACAACGAGTACATTGTCCCCATGACGGAGGAGACGAAGAGCA TCACCCTGTTCCCTGATGAGAACAAAAAACACGGCCTTCCAGGGATCGGCCTCAGCACCTCCCTCAGGCCACGGATG CAGTTTTCCTCCCCCAGTTTTGTAAGCATTAGTAATGAATGTTACCAGTACAGTCCAGAGTTCCCACTGGACATCCT CAAGTCCAAAACCATACAGATGCTGACAGAAGCTGTTAAAGAGGGCAGTCTTCATGCCCGGGACCCAGTTGGAGGGA CTACTGAATTCCTCTTTGTACCTCTCATCAAGCTTTTCTATACCCTGCTGATCATGGGCATCTTTCACAACGAGGAC TTGAAGCACATCTTGCAGTTGATTGAGCCCAGTGTGTTTAAAGAAGCTGCCACTCCGGAGGAGGAGAGTGACACGCT GGAGAAAGAGCTCAGTGTGGACGATGCAAAGCTGCAAGGAGCTGGTGAGGAAGAAGCCAAGGGGGGCAAGCGGCCCA AGGAAGGCCTGCTCCAAATGAAACTGCCAGAGCCAGTTAAATTGCAGATGTGCCTACTGCTTCAGTACCTCTGTGAC TGCCAGGTCCGGCACCGGATAGAAGCCATTGTAGCCTTTTCAGATGATTTTGTGGCTAAGCTCCAAGACAATCAACG TTTCCGATACAACGAAGTCATGCAAGCCTTAAACATGTCAGCTGCACTCACAGCCAGGAAGACAAAGGAATTTAGAT CACCACCTCAAGAACAGATCAATATGCTTCTCAATTTTAAGGATGACAAAAGTGAATGTCCATGTCCAGAAGAAATT CGTGACCAACTATTGGATTTCCATGAAGATTTGATGACACATTGTGGAATTGAGCTGGATGAAGATGGGTCTCTGGA TGGAAACAGTGATTTAACAATTAGAGGGCGTCTGCTATCCCTGGTAGAAAAGGTGACATATCTGAAGAAGAAGCAAG CAGAAAAACCAGTTGAGAGTGACTCCAAAAAGTCCTCCACTCTGCAGCAGCTGATTTCTGAGACCATGGTCCGATGG 16 24028 / / SLW 875.245WO1 GCTCAGGAGTCTGTCATTGAAGACCCCGAGCTGGTGAGGGCCATGTTTGTGTTGCTCCATCGGCAGTATGACGGCAT TGGGGGTCTTGTTCGGGCCCTGCCAAAGACCTACACGATAAATGGTGTGTCCGTGGAGGACACCATCAACCTGCTGG CATCCCTTGGTCAGATTCGGTCCCTGCTGAGTGTGAGAATGGGCAAAGAAGAAGAGAAGCTCATGATTCGTGGATTA GGGGATATTATGAATAACAAAGTGTTTTACCAGCACCCTAATCTCATGAGGGCACTGGGGATGCACGAGACTGTGAT GGAGGTCATGGTGAACGTCCTTGGAGGTGGAGAGTCCAAGGAAATCACCTTTCCCAAGATGGTGGCCAACTGTTGCC GTTTTCTCTGTTACTTCTGTCGTATAAGTAGGCAGAATCAAAAAGCTATGTTTGATCATCTCAGTTATTTACTGGAA AACAGCAGTGTTGGTCTTGCCTCCCCAGCTATGAGAGGTTCAACACCACTGGATGTGGCTGCAGCTTCGGTGATGGA TAATAATGAACTAGCATTAGCTCTGCGTGAGCCGGATCTAGAAAAGGTAGTTCGTTATTTGGCTGGTTGTGGACTGC AAAGTTGCCAGATGCTGGTGTCTAAGGGCTATCCAGACATTGGGTGGAACCCAGTTGAAGGAGAGAGATATCTTGAC TTTCTTAGATTTGCTGTCTTCTGTAATGGGGAGAGTGTGGAGGAAAATGCAAATGTCGTGGTGAGATTGCTCATTCG GAGGCCTGAGTGTTTTGGTCCTGCTTTGAGAGGAGAAGGTGGGAATGGGCTTCTTGCAGCAATGGAAGAAGCCATCA AAATCGCCGAGGATCCTTCCCGAGATGGTCCCTCACCAAATAGCGGATCCAGTAAAACACTTGACACAGAGGAGGAG GAAGATGACACTATCCACATGGGGAACGCGATCATGACCTTCTATTCAGCTTTGATTGACCTCTTGGGACGCTGTGC TCCTGAGATGCATTTGATTCATGCCGGGAAGGGAGAAGCCATCAGAATTAGGTCCATTTTGAGATCCCTCATTCCCC TGGGAGATTTGGTGGGCGTTATCAGCATCGCTTTTCAGATGCCAACAATAGCCAAAGATGGGAATGTGGTGGAACCT GACATGTCTGCGGGGTTTTGCCCAGATCACAAGGCAGCCATGGTTTTATTCCTTGACAGGGTCTATGGGATTGAGGT TCAAGACTTCCTCCTCCATCTTCTTGAGGTTGGCTTTCTGCCAGATCTCCGGGCGGCTGCTTCTTTAGATACGGCAG CTTTGAGTGCTACAGACATGGCCTTGGCCCTCAATCGGTACCTTTGCACAGCCGTCTTGCCATTGTTAACAAGATGT GCTCCTCTCTTTGCTGGCACAGAGCACCACGCTTCTCTCATTGACTCATTACTTCATACTGTGTATAGACTTTCTAA GGGCTGTTCACTTACCAAAGCTCAGCGGGATTCCATAGAAGTTTGTTTACTCTCTATTTGTGGACAACTGAGACCTT CTATGATGCAGCACTTACTCAGAAGATTAGTATTTGATGTTCCATTATTAAATGAACACGCAAAGATGCCTCTTAAA CTGCTGACAAATCATTATGAAAGATGCTGGAAATATTACTGCCTGCCTGGAGGGTGGGGAAACTTTGGTGCTGCCTC AGAAGAAGAACTTCATTTATCAAGAAAGTTGTTCTGGGGCATTTTTGATGCCCTGTCTCAAAAGAAATATGAACAAG AACTTTTCAAACTGGCACTGCCTTGCCTGAGTGCAGTTGCGGGAGCTTTGCCTCCAGACTACATGGAGTCAAATTAT GTCAGTATGATGGAAAAACAGTCATCAATGGATTCTGAAGGGAACTTTAACCCACAACCTGTTGATACCTCAAATAT TACAATTCCTGAGAAATTGGAATACTTCATTAACAAATATGCAGAACACTCCCATGACAAATGGTCAATGGACAAGT TGGCAAATGGATGGATTTATGGAGAAATATATTCAGACTCTTCTAAGGTTCAGCCATTAATGAAGCCATATAAGCTA TTGTCTGAAAAGGAAAAAGAAATTTATCGCTGGCCAATCAAAGAATCTTTAAAAACTATGCTGGCTTGGGGCTGGAG AATTGAAAGAACTCGGGAGGGAGACAGCATGGCCCTTTACAACCGGACTCGTCGTATTTCTCAGACAAGCCAGGTTT CTGTGGACGCTGCCCATGGTTACAGTCCCCGGGCCATTGACATGAGCAATGTTACACTATCTAGAGACCTGCATGCT ATGGCAGAAATGATGGCTGAAAACTACCATAATATATGGGCAAAGAAAAAGAAAATGGAGTTGGAGTCCAAAGGAGG AGGAAACCATCCTCTGCTGGTGCCCTATGATACACTGACAGCCAAAGAGAAAGCCAAGGATAGAGAAAAAGCACAGG ACATCCTCAAGTTCTTGCAGATCAATGGATATGCTGTATCCAGAGGATTTAAGGACCTGGAACTGGACACGCCTTCT ATTGAGAAACGATTTGCCTATAGTTTCCTCCAACAACTCATTCGCTATGTGGATGAAGCCCATCAGTATATCCTGGA GTTTGATGGTGGCAGCAGAGGCAAAGGAGAACATTTCCCTTATGAACAAGAAATCAAGTTCTTTGCAAAAGTCGTTC TTCCTTTAATTGATCAGTATTTCAAAAACCATCGTTTATACTTCTTATCTGCAGCAAGCAGACCTCTCTGCTCTGGA GGACATGCTTCCAACAAAGAGAAAGAAATGGTGACTAGCCTATTCTGCAAACTTGGAGTTCTTGTCAGGCATAGGAT TTCACTATTTGGCAATGATGCAACATCAATTGTCAACTGTCTTCATATTTTGGGTCAGACTTTGGATGCAAGGACAG TGATGAAGACTGGCCTGGAGAGTGTTAAAAGTGCACTCAGAGCTTTTCTGGACAACGCTGCAGAGGATCTGGAGAAG ACCATGGAAAACCTCAAGCAGGGCCAGTTCACTCACACCCGAAACCAGCCCAAAGGGGTTACTCAGATTATCAATTA CACCACAGTGGCCCTGCTGCCAATGCTGTCTTCATTATTTGAACATATTGGCCAGCATCAGTTCGGAGAAGACCTAA TATTGGAAGATGTCCAGGTGTCTTGTTATAGAATTCTGACTAGCTTATATGCTTTGGGAACCAGCAAGAGTATTTAC GTGGAGAGGCAACGTTCTGCATTAGGAGAATGTCTAGCTGCCTTTGCTGGTGCTTTTCCTGTAGCATTTTTGGAAAC TCATCTGGACAAACATAATATTTACTCCATCTACAATACCAAGTCTTCACGAGAAAGAGCAGCTCTCAGTTTGCCAA CTAATGTGGAAGATGTTTGTCCAAACATACCGTCTTTGGAGAAACTCATGGAAGAAATCGTGGAATTAGCCGAGTCC GGCATTCGCTACACTCAAATGCCACATGTCATGGAAGTCATACTGCCCATGCTTTGCAGCTACATGTCTCGTTGGTG GGAGCATGGACCTGAGAACAATCCAGAACGGGCCGAGATGTGCTGCACAGCCCTGAACTCAGAGCACATGAACACAC TTCTAGGGAACATATTGAAAATCATATATAATAACTTGGGGATTGATGAGGGAGCCTGGATGAAGAGGCTAGCAGTG TTTTCCCAGCCTATAATAAATAAAGTGAAACCTCAGCTCTTGAAAACTCATTTCTTGCCGTTAATGGAGAAACTCAA GAAAAAGGCAGCTACGGTGGTGTCTGAGGAAGACCACCTGAAAGCTGAGGCCAGGGGGGACATGTCGGAGGCAGAAC TCCTCATCCTAGATGAGTTCACCACACTGGCCAGAGATCTCTATGCCTTCTACCCTCTCTTGATTAGATTTGTGGAC TATAACAGGGCAAAGTGGCTAAAGGAGCCTAACCCAGAAGCAGAGGAGCTCTTCCGCATGGTGGCTGAAGTGTTTAT CTACTGGTCGAAGTCCCATAATTTCAAAAGAGAAGAGCAGAACTTCGTTGTACAGAATGAAATCAACAATATGTCTT TCCTTATTACTGATACCAAGTCAAAGATGTCAAAGGCAGCTGTTTCTGATCAGGAAAGGAAGAAAATGAAGCGCAAA GGAGATCGGTATTCCATGCAGACCTCTCTGATTGTAGCAGCTCTGAAGCGGTTACTGCCCATTGGGTTGAACATCTG TGCCCCTGGGGACCAGGAGCTCATTGCTCTGGCCAAAAATCGATTTAGCCTGAAAGATACCGAGGATGAAGTACGAG ATATAATCCGCAGCAATATTCATTTACAAGGCAAGTTGGAGGATCCTGCTATTAGATGGCAAATGGCTCTTTACAAA GACTTACCAAACAGGACTGATGATACCTCAGATCCAGAGAAGACGGTAGAAAGAGTATTGGATATAGCAAATGTGCT 17 24028 / / SLW 875.245WO1 TTTTCATCTTGAACAGAAGTCTAAACGTGTGGGTCGGAGACATTACTGTCTGGTGGAACATCCTCAGAGATCTAAAA AGGCTGTATGGCATAAACTACTGTCCAAGCAGAGGAAAAGGGCTGTTGTAGCCTGCTTCCGGATGGCCCCCTTATAT AATCTGCCAAGGCATCGGGCTGTCAATCTCTTTCTTCAGGGATATGAAAAGTCTTGGATTGAAACAGAAGAACATTA CTTTGAAGATAAACTGATAGAAGATTTAGCAAAACCTGGGGCTGAACCTCCAGAAGAAGATGAAGGCACTAAGAGAG TTGATCCTCTACATCAGCTGATCCTTCTGTTTAGTCGGACAGCTTTAACAGAGAAATGCAAACTGGAGGAAGATTTT TTATATATGGCCTATGCAGATATTATGGCAAAGAGTTGTCATGATGAGGAAGATGACGATGGTGAAGAGGAAGTGAA GAGTTTTGAAGAAAAAGAAATGGAAAAGCAAAAGCTTCTATACCAGCAAGCCCGACTCCACGATCGTGGCGCGGCTG AGATGGTGCTACAGACAATCAGTGCCAGCAAAGGTGAAACTGGACCAATGGTAGCAGCTACTCTGAAACTTGGAATT GCTATTTTAAATGGTGGGAACTCCACAGTACAGCAGAAAATGCTTGACTACCTCAAGGAGAAAAAGGATGTGGGCTT CTTTCAGAGCCTGGCCGGCCTGATGCAGTCATGTAGTGTCCTTGACCTAAATGCATTTGAGCGACAAAACAAAGCTG AAGGTCTTGGGATGGTGACAGAGGAAGGATCAGGAGAAAAGGTTCTGCAGGACGATGAGTTCACCTGTGACCTCTTC CGATTCCTGCAACTACTCTGTGAGGGACACAACTCAGATTTTCAGAATTATCTGAGAACTCAGACTGGCAATAATAC AACTGTCAACATAATTATCTCCACTGTAGACTACCTACTGAGAGTTCAGGAATCAATTAGTGACTTTTATTGGTATT ACTCTGGGAAAGATGTTATTGATGAACAAGGACAACGGAATTTCTCCAAAGCTATCCAAGTGGCAAAACAAGTCTTT AACACTCTTACAGAGTATATTCAGGGTCCTTGCACTGGGAATCAACAGAGTTTGGCACACAGCAGGCTGTGGGATGC TGTGGTCGGCTTTCTTCATGTGTTTGCCCATATGCAGATGAAGCTGTCGCAGGATTCCAGTCAAATTGAGCTATTAA AAGAATTAATGGATCTGCAGAAGGATATGGTGGTCATGTTGCTGTCCATGTTAGAAGGTAATGTTGTTAATGGAACG ATTGGCAAACAGATGGTGGATATGCTTGTGGAATCTTCCAACAACGTGGAGATGATTCTCAAATTTTTTGACATGTT CTTAAAACTAAAGGATTTGACGTCGTCTGATACTTTTAAAGAATATGACCCCGATGGCAAGGGAGTCATTTCCAAGA GGGACTTCCACAAAGCGATGGAGAGCCATAAGCACTACACGCAGTCAGAAACGGAATTTCTTTTGTCTTGTGCGGAG ACGGATGAGAATGAAACCCTCGACTACGAAGAGTTCGTCAAACGCTTCCACGAACCTGCGAAGGACATCGGCTTCAA CGTCGCCGTCCTTCTGACAAACCTCTCTGAGCACATGCCCAACGATACCCGACTTCAGACTTTTCTGGAATTAGCAG AGAGCGTCCTGAATTATTTCCAGCCCTTTCTGGGCCGCATCGAAATCATGGGAAGCGCCAAACGCATCGAGAGGGTC TATTTTGAAATCAGTGAGTCCAGCCGAACCCAGTGGGAGAAGCCCCAGGTCAAGGAGTCCAAAAGACAGTTCATATT TGACGTGGTCAACGAAGGCGGAGAGAAAGAGAAGATGGAACTCTTTGTGAACTTCTGCGAGGACACCATCTTTGAAA TGCAGCTGGCGGCTCAGATCTCGGAGTCGGACTTGAACGAGAGGTCAGCGAATAAGGAAGAAAGCGAGAAGGAGAGG CCGGAAGAGCAGGGGCCGAGGATGGCTTTCTTCTCCATTCTGACGGTCAGGTCGGCCCTGTTTGCGCTCAGGTACAA TATCTTGACCCTTATGCGAATGCTCAGTCTGAAGAGCCTGAAGAAGCAGATGAAAAAAGTAAAAAAGATGACCGTGA AGGACATGGTCACGGCCTTCTTTTCATCCTACTGGAGTATTTTCATGACCCTCTTGCACTTCGTGGCCAGCGTTTTC AGAGGCTTTTTCCGCATCATTTGCAGCCTGCTGCTTGGGGGAAGCCTCGTCGAAGGTGCTAAAAAGATCAAAGTTGC AGAACTGTTAGCCAACATGCCAGACCCCACTCAGGATGAGGTTAGAGGAGATGGGGAGGAGGGAGAGAGGAAACCCC TGGAAGCCGCCCTGCCCTCCGAGGATCTGACCGACTTAAAGGAGCTGACAGAGGAAAGTGACCTTCTTTCGGACATC TTTGGCCTGGATCTGAAGAGAGAAGGAGGACAGTACAAACTGATTCCTCATAATCCAAATGCTGGGCTCAGTGACCT CATGAGCAACCCAGTCCCCATGCCTGAGGTGCAGGAAAAATTTCAGGAACAGAAGGCAAAAGAAGAAGAAAAGGAAG AAAAAGAAGAAACCAAATCTGAACCTGAAAAAGCCGAGGGAGAAGATGGAGAAAAAGAAGAGAAAGCCAAGGAAGAC AAGGGCAAACAAAAGTTGAGGCAGCTTCACACACACAGATACGGAGAACCAGAAGTGCCAGAGTCAGCATTCTGGAA GAAAATCATAGCATATCAACAGAAACTTCTAAACTATTTTGCTCGCAACTTTTACAACATGAGAATGTTAGCCTTAT TTGTCGCATTTGCTATCAATTTCATCTTGCTCTTTTATAAGGTCTCCACTTCTTCTGTGGTTGAAGGAAAGGAGCTC CCCACGAGAAGTTCAAGTGAAAATGCCAAAGTGACAAGCCTGGACAGCAGCTCCCATAGAATCATCGCAGTTCACTA TGTACTAGAGGAGAGCAGCGGCTACATGGAGCCCACGTTGCGTATCTTAGCTATTCTGCACACGGTCATTTCTTTCT TCTGCATCATTGGATACTACTGCTTGAAAGTCCCATTGGTTATTTTTAAGCGAGAAAAGGAAGTGGCACGGAAATTG GAATTTGATGGGCTTTATATTACAGAACAGCCTTCAGAAGATGATATTAAAGGCCAGTGGGATAGACTCGTAATCAA CACACAGTCATTTCCCAACAACTACTGGGACAAATTTGTTAAAAGAAAGGTTATGGATAAATATGGAGAGTTCTACG GCCGAGACAGAATCAGTGAATTACTTGGCATGGACAAGGCAGCTCTGGACTTCAGTGATGCCAGAGAAAAGAAGAAG CCAAAGAAAGACAGCTCCTTATCAGCTGTACTGAACTCCATTGATGTGAAGTATCAGATGTGGAAACTAGGAGTCGT TTTCACTGACAACTCCTTCCTCTACCTAGCCTGGTATATGACTATGTCTGTTCTTGGACACTATAACAACTTTTTTT TTGCCGCTCACCTTCTCGACATTGCTATGGGATTCAAGACATTAAGAACCATCTTGTCCTCAGTAACTCACAATGGC AAACAGCTCGTATTAACCGTTGGCTTATTAGCTGTTGTTGTATACCTATACACTGTGGTGGCATTCAATTTTTTCCG AAAATTCTACAATAAAAGTGAAGATGGTGATACACCAGATATGAAATGTGACGATATGCTAACATGCTATATGTTCC ACATGTATGTTGGAGTTCGTGCTGGAGGAGGGATCGGGGATGAAATCGAAGACCCAGCAGGAGATGAATATGAGATC TATCGAATCATCTTTGACATCACTTTCTTCTTCTTTGTTATTGTCATTCTCTTGGCCATAATACAAGGTCTAATTAT TGATGCTTTTGGAGAACTAAGAGACCAACAGGAACAAGTCAAAGAAGACATGGAGACCAAATGCTTCATCTGTGGGA TAGGCAATGATTACTTCGACACAGTGCCACATGGCTTTGAAACCCACACTTTACAGGAGCACAACTTGGCTAATTAC TTGTTTTTTCTGATGTATCTTATAAACAAAGATGAAACAGAACACACAGGACAGGAATCTTATGTCTGGAAGATGTA TCAAGAAAGGTGTTGGGAATTTTTCCCAGCAGGGGATTGCTTCCGGAAACAGTATGAAGACCAGCTAAATTAA SEQ ID NO: 8 (RyR2 aa, human) 18 24028 / / SLW 875.245WO1 LLGGAGAERTAGCRQRARLGCGAASPRPPGPGRPPPAQCGAGRPRASTTRARASAPPPPLCRRGPPGARHPAARPPP APGSRQQKQKAAPGAAAAAELRGAREPAPARRRGTMADGGEGEDEIQFLRTDDEVVLQCTATIHKEQQKLCLAAEGF GNRLCFLESTSNSKNVPPDLSICTFVLEQSLSVRALQEMLANTVEKSEGQVDVEKWKFMMKTAQGGGHRTLLYGHAI LLRHSYSGMYLCCLSTSRSSTDKLAFDVGLQEDTTGEACWWTIHPASKQRSEGEKVRVGDDLILVSVSSERYLHLSY GNGSLHVDAAFQQTLWSVAPISSGSEAAQGYLIGGDVLRLLHGHMDECLTVPSGEHGEEQRRTVHYEGGAVSVHARS LWRLETLRVAWSGSHIRWGQPFRLRHVTTGKYLSLMEDKNLLLMDKEKADVKSTAFTFRSSKEKLDVGVRKEVDGMG TSEIKYGDSVCYIQHVDTGLWLTYQSVDVKSVRMGSIQRKAIMHHEGHMDDGISLSRSQHEESRTARVIRSTVFLFN RFIRGLDALSKKAKASTVDLPIESVSLSLQDLIGYFHPPDEHLEHEDKQNRLRALKNRQNLFQEEGMINLVLECIDR LHVYSSAAHFADVAGREAGESWKSILNSLYELLAALIRGNRKNCAQFSGSLDWLISRLERLEASSGILEVLHCVLVE SPEALNIIKEGHIKSIISLLDKHGRNHKVLDVLCSLCVCHGVAVRSNQHLICDNLLPGRDLLLQTRLVNHVSSMRPN IFLGVSEGSAQYKKWYYELMVDHTEPFVTAEATHLRVGWASTEGYSPYPGGGEEWGGNGVGDDLFSYGFDGLHLWSG CIARTVSSPNQHLLRTDDVISCCLDLSAPSISFRINGQPVQGMFENFNIDGLFFPVVSFSAGIKVRFLLGGRHGEFK FLPPPGYAPCYEAVLPKEKLKVEHSREYKQERTYTRDLLGPTVSLTQAAFTPIPVDTSQIVLPPHLERIREKLAENI HELWVMNKIELGWQYGPVRDDNKRQHPCLVEFSKLPEQERNYNLQMSLETLKTLLALGCHVGISDEHAEDKVKKMKL PKNYQLTSGYKPAPMDLSFIKLTPSQEAMVDKLAENAHNVWARDRIRQGWTYGIQQDVKNRRNPRLVPYTLLDDRTK KSNKDSLREAVRTLLGYGYNLEAPDQDHAARAEVCSGTGERFRIFRAEKTYAVKAGRWYFEFETVTAGDMRVGWSRP GCQPDQELGSDERAFAFDGFKAQRWHQGNEHYGRSWQAGDVVGCMVDMNEHTMMFTLNGEILLDDSGSELAFKDFDV GDGFIPVCSLGVAQVGRMNFGKDVSTLKYFTICGLQEGYEPFAVNTNRDITMWLSKRLPQFLQVPSNHEHIEVTRID GTIDSSPCLKVTQKSFGSQNSNTDIMFYRLSMPIECAEVFSKTVAGGLPGAGLFGPKNDLEDYDADSDFEVLMKTAH GHLVPDRVDKDKEATKPEFNNHKDYAQEKPSRLKQRFLLRRTKPDYSTSHSARLTEDVLADDRDDYDFLMQTSTYYY SVRIFPGQEPANVWVGWITSDFHQYDTGFDLDRVRTVTVTLGDEKGKVHESIKRSNCYMVCAGESMSPGQGRNNNGL EIGCVVDAASGLLTFIANGKELSTYYQVEPSTKLFPAVFAQATSPNVFQFELGRIKNVMPLSAGLFKSEHKNPVPQC PPRLHVQFLSHVLWSRMPNQFLKVDVSRISERQGWLVQCLDPLQFMSLHIPEENRSVDILELTEQEELLKFHYHTLR LYSAVCALGNHRVAHALCSHVDEPQLLYAIENKYMPGLLRAGYYDLLIDIHLSSYATARLMMNNEYIVPMTEETKSI TLFPDENKKHGLPGIGLSTSLRPRMQFSSPSFVSISNECYQYSPEFPLDILKSKTIQMLTEAVKEGSLHARDPVGGT TEFLFVPLIKLFYTLLIMGIFHNEDLKHILQLIEPSVFKEAATPEEESDTLEKELSVDDAKLQGAGEEEAKGGKRPK EGLLQMKLPEPVKLQMCLLLQYLCDCQVRHRIEAIVAFSDDFVAKLQDNQRFRYNEVMQALNMSAALTARKTKEFRS PPQEQINMLLNFKDDKSECPCPEEIRDQLLDFHEDLMTHCGIELDEDGSLDGNSDLTIRGRLLSLVEKVTYLKKKQA EKPVESDSKKSSTLQQLISETMVRWAQESVIEDPELVRAMFVLLHRQYDGIGGLVRALPKTYTINGVSVEDTINLLA SLGQIRSLLSVRMGKEEEKLMIRGLGDIMNNKVFYQHPNLMRALGMHETVMEVMVNVLGGGESKEITFPKMVANCCR FLCYFCRISRQNQKAMFDHLSYLLENSSVGLASPAMRGSTPLDVAAASVMDNNELALALREPDLEKVVRYLAGCGLQ SCQMLVSKGYPDIGWNPVEGERYLDFLRFAVFCNGESVEENANVVVRLLIRRPECFGPALRGEGGNGLLAAMEEAIK IAEDPSRDGPSPNSGSSKTLDTEEEEDDTIHMGNAIMTFYSALIDLLGRCAPEMHLIHAGKGEAIRIRSILRSLIPL GDLVGVISIAFQMPTIAKDGNVVEPDMSAGFCPDHKAAMVLFLDRVYGIEVQDFLLHLLEVGFLPDLRAAASLDTAA LSATDMALALNRYLCTAVLPLLTRCAPLFAGTEHHASLIDSLLHTVYRLSKGCSLTKAQRDSIEVCLLSICGQLRPS MMQHLLRRLVFDVPLLNEHAKMPLKLLTNHYERCWKYYCLPGGWGNFGAASEEELHLSRKLFWGIFDALSQKKYEQE LFKLALPCLSAVAGALPPDYMESNYVSMMEKQSSMDSEGNFNPQPVDTSNITIPEKLEYFINKYAEHSHDKWSMDKL ANGWIYGEIYSDSSKVQPLMKPYKLLSEKEKEIYRWPIKESLKTMLAWGWRIERTREGDSMALYNRTRRISQTSQVS VDAAHGYSPRAIDMSNVTLSRDLHAMAEMMAENYHNIWAKKKKMELESKGGGNHPLLVPYDTLTAKEKAKDREKAQD ILKFLQINGYAVSRGFKDLELDTPSIEKRFAYSFLQQLIRYVDEAHQYILEFDGGSRGKGEHFPYEQEIKFFAKVVL PLIDQYFKNHRLYFLSAASRPLCSGGHASNKEKEMVTSLFCKLGVLVRHRISLFGNDATSIVNCLHILGQTLDARTV MKTGLESVKSALRAFLDNAAEDLEKTMENLKQGQFTHTRNQPKGVTQIINYTTVALLPMLSSLFEHIGQHQFGEDLI LEDVQVSCYRILTSLYALGTSKSIYVERQRSALGECLAAFAGAFPVAFLETHLDKHNIYSIYNTKSSRERAALSLPT NVEDVCPNIPSLEKLMEEIVELAESGIRYTQMPHVMEVILPMLCSYMSRWWEHGPENNPERAEMCCTALNSEHMNTL LGNILKIIYNNLGIDEGAWMKRLAVFSQPIINKVKPQLLKTHFLPLMEKLKKKAATVVSEEDHLKAEARGDMSEAEL LILDEFTTLARDLYAFYPLLIRFVDYNRAKWLKEPNPEAEELFRMVAEVFIYWSKSHNFKREEQNFVVQNEINNMSF LITDTKSKMSKAAVSDQERKKMKRKGDRYSMQTSLIVAALKRLLPIGLNICAPGDQELIALAKNRFSLKDTEDEVRD IIRSNIHLQGKLEDPAIRWQMALYKDLPNRTDDTSDPEKTVERVLDIANVLFHLEQKSKRVGRRHYCLVEHPQRSKK AVWHKLLSKQRKRAVVACFRMAPLYNLPRHRAVNLFLQGYEKSWIETEEHYFEDKLIEDLAKPGAEPPEEDEGTKRV DPLHQLILLFSRTALTEKCKLEEDFLYMAYADIMAKSCHDEEDDDGEEEVKSFEEKEMEKQKLLYQQARLHDRGAAE MVLQTISASKGETGPMVAATLKLGIAILNGGNSTVQQKMLDYLKEKKDVGFFQSLAGLMQSCSVLDLNAFERQNKAE GLGMVTEEGSGEKVLQDDEFTCDLFRFLQLLCEGHNSDFQNYLRTQTGNNTTVNIIISTVDYLLRVQESISDFYWYY SGKDVIDEQGQRNFSKAIQVAKQVFNTLTEYIQGPCTGNQQSLAHSRLWDAVVGFLHVFAHMQMKLSQDSSQIELLK ELMDLQKDMVVMLLSMLEGNVVNGTIGKQMVDMLVESSNNVEMILKFFDMFLKLKDLTSSDTFKEYDPDGKGVISKR DFHKAMESHKHYTQSETEFLLSCAETDENETLDYEEFVKRFHEPAKDIGFNVAVLLTNLSEHMPNDTRLQTFLELAE SVLNYFQPFLGRIEIMGSAKRIERVYFEISESSRTQWEKPQVKESKRQFIFDVVNEGGEKEKMELFVNFCEDTIFEM QLAAQISESDLNERSANKEESEKERPEEQGPRMAFFSILTVRSALFALRYNILTLMRMLSLKSLKKQMKKVKKMTVK DMVTAFFSSYWSIFMTLLHFVASVFRGFFRIICSLLLGGSLVEGAKKIKVAELLANMPDPTQDEVRGDGEEGERKPL 19 24028 / / SLW 875.245WO1 EAALPSEDLTDLKELTEESDLLSDIFGLDLKREGGQYKLIPHNPNAGLSDLMSNPVPMPEVQEKFQEQKAKEEEKEE KEETKSEPEKAEGEDGEKEEKAKEDKGKQKLRQLHTHRYGEPEVPESAFWKKIIAYQQKLLNYFARNFYNMRMLALF VAFAINFILLFYKVSTSSVVEGKELPTRSSSENAKVTSLDSSSHRIIAVHYVLEESSGYMEPTLRILAILHTVISFF CIIGYYCLKVPLVIFKREKEVARKLEFDGLYITEQPSEDDIKGQWDRLVINTQSFPNNYWDKFVKRKVMDKYGEFYG RDRISELLGMDKAALDFSDAREKKKPKKDSSLSAVLNSIDVKYQMWKLGVVFTDNSFLYLAWYMTMSVLGHYNNFFF AAHLLDIAMGFKTLRTILSSVTHNGKQLVLTVGLLAVVVYLYTVVAFNFFRKFYNKSEDGDTPDMKCDDMLTCYMFH MYVGVRAGGGIGDEIEDPAGDEYEIYRIIFDITFFFFVIVILLAIIQGLIIDAFGELRDQQEQVKEDMETKCFICGI GNDYFDTVPHGFETHTLQEHNLANYLFFLMYLINKDETEHTGQESYVWKMYQERCWEFFPAGDCFRKQYEDQLN* SEQ ID NO: 9 (CaV1.2 nt, human) ATGGTCAATGAGAATACGAGGATGTACATTCCAGAGGAAAACCACCAAGGTTCCAACTATGGGAGCCCACGCCCCGC CCATGCCAACATGAATGCCAATGCGGCAGCGGGGCTGGCCCCTGAGCACATCCCCACCCCGGGGGCTGCCCTGTCGT GGCAGGCGGCCATCGACGCAGCCCGGCAGGCTAAGCTGATGGGCAGCGCTGGCAATGCGACCATCTCCACAGTCAGC TCCACGCAGCGGAAGCGGCAGCAATATGGGAAACCCAAGAAGCAGGGCAGCACCACGGCCACACGCCCGCCCCGAGC CCTGCTCTGCCTGACCCTGAAGAACCCCATCCGGAGGGCCTGCATCAGCATTGTCGAATGGAAACCATTTGAAATAA TTATTTTACTGACTATTTTTGCCAATTGTGTGGCCTTAGCGATCTATATTCCCTTTCCAGAAGATGATTCCAACGCC ACCAATTCCAACCTGGAACGAGTGGAATATCTCTTTCTCATAATTTTTACGGTGGAAGCGTTTTTAAAAGTAATCGC CTATGGACTCCTCTTTCACCCCAATGCCTACCTCCGCAACGGCTGGAACCTACTAGATTTTATAATTGTGGTTGTGG GGCTTTTTAGTGCAATTTTAGAACAAGCAACCAAAGCAGATGGGGCAAACGCTCTCGGAGGGAAAGGGGCCGGATTT GATGTGAAGGCGCTGAGGGCCTTCCGCGTGCTGCGCCCCCTGCGGCTGGTGTCCGGAGTCCCAAGTCTCCAGGTGGT CCTGAATTCCATCATCAAGGCCATGGTCCCCCTGCTGCACATCGCCCTGCTTGTGCTGTTTGTCATCATCATCTACG CCATCATCGGCTTGGAGCTCTTCATGGGGAAGATGCACAAGACCTGCTACAACCAGGAGGGCATAGCAGATGTTCCA GCAGAAGATGACCCTTCCCCTTGTGCGCTGGAAACGGGCCACGGGCGGCAGTGCCAGAACGGCACGGTGTGCAAGCC CGGCTGGGATGGTCCCAAGCACGGCATCACCAACTTTGACAACTTTGCCTTCGCCATGCTCACGGTGTTCCAGTGCA TCACCATGGAGGGCTGGACGGACGTGCTGTACTGGGTCAATGATGCCGTAGGAAGGGACTGGCCCTGGATCTATTTT GTTACACTAATCATCATAGGGTCATTTTTTGTACTTAACTTGGTTCTCGGTGTGCTTAGCGGAGAGTTTTCCAAAGA GAGGGAGAAGGCCAAGGCCCGGGGAGATTTCCAGAAGCTGCGGGAGAAGCAGCAGCTAGAAGAGGATCTCAAAGGCT ACCTGGATTGGATCACTCAGGCCGAAGACATCGATCCTGAGAATGAGGACGAAGGCATGGATGAGGAGAAGCCCCGA AACATGAGCATGCCCACCAGTGAGACCGAGTCCGTCAACACCGAAAACGTGGCTGGAGGTGACATCGAGGGAGAAAA CTGCGGGGCCAGGCTGGCCCACCGGATCTCCAAGTCAAAGTTCAGCCGCTACTGGCGCCGGTGGAATCGGTTCTGCA GAAGGAAGTGCCGCGCCGCAGTCAAGTCTAATGTCTTCTACTGGCTGGTGATTTTCCTGGTGTTCCTCAACACGCTC ACCATTGCCTCTGAGCACTACAACCAGCCCAACTGGCTCACAGAAGTCCAAGACACGGCAAACAAGGCCCTGCTGGC CCTGTTCACGGCAGAGATGCTCCTGAAGATGTACAGCCTGGGCCTGCAGGCCTACTTCGTGTCCCTCTTCAACCGCT TTGACTGCTTCGTCGTGTGTGGCGGCATCCTGGAGACCATCCTGGTGGAGACCAAGATCATGTCCCCACTGGGCATC TCCGTGCTCAGATGCGTCCGGCTGCTGAGGATTTTCAAGATCACGAGGTACTGGAACTCCTTGAGCAACCTGGTGGC ATCCTTGCTGAACTCTGTGCGCTCCATCGCCTCCCTGCTCCTTCTCCTCTTCCTCTTCATCATCATCTTCTCCCTCC TGGGGATGCAGCTCTTTGGAGGAAAGTTCAACTTTGATGAGATGCAGACCCGGAGGAGCACATTCGATAACTTCCCC CAGTCCCTCCTCACTGTGTTTCAGATCCTGACCGGGGAGGACTGGAATTCGGTGATGTATGATGGGATCATGGCTTA TGGCGGCCCCTCTTTTCCAGGGATGTTAGTCTGTATTTACTTCATCATCCTCTTCATCTGTGGAAACTATATCCTAC TGAATGTGTTCTTGGCCATTGCTGTGGACAACCTGGCTGATGCTGAGAGCCTCACATCTGCCCAAAAGGAGGAGGAA GAGGAGAAGGAGAGAAAGAAGCTGGCCAGGACTGCCAGCCCAGAGAAGAAACAAGAGTTGGTGGAGAAGCCGGCAGT GGGGGAATCCAAGGAGGAGAAGATTGAGCTGAAATCCATCACGGCTGATGGAGAGTCTCCACCCGCCACCAAGATCA ACATGGATGACCTCCAGCCCAATGAAAATGAGGATAAGAGCCCCTACCCCAACCCAGAAACTACAGGAGAAGAGGAT GAGGAGGAGCCAGAGATGCCTGTCGGCCCTCGCCCACGACCACTCTCTGAGCTTCACCTTAAGGAAAAGGCAGTGCC CATGCCAGAAGCCAGCGCGTTTTTCATCTTCAGCTCTAACAACAGGTTTCGCCTCCAGTGCCACCGCATTGTCAATG ACACGATCTTCACCAACCTGATCCTCTTCTTCATTCTGCTCAGCAGCATTTCCCTGGCTGCTGAGGACCCGGTCCAG CACACCTCCTTCAGGAACCATATTCTGTTTTATTTTGATATTGTTTTTACCACCATTTTCACCATTGAAATTGCTCT GAAGATCCTAGGCAATGCAGACTATGTCTTCACTAGTATCTTTACATTAGAAATTATCCTTAAGATGACTGCTTATG GGGCTTTCTTGCACAAGGGTTCTTTCTGCCGGAACTACTTCAACATCCTGGACCTGCTGGTGGTCAGCGTGTCCCTC ATCTCCTTTGGCATCCAGTCCAGTGCAATCAATGTCGTGAAGATCTTGCGAGTCCTGCGAGTACTCAGGCCCCTGAG GGCCATCAACAGGGCCAAGGGGCTAAAGCATGTGGTTCAGTGTGTGTTTGTCGCCATCCGGACCATCGGGAACATCG TGATTGTCACCACCCTGCTGCAGTTCATGTTTGCCTGCATCGGGGTCCAGCTCTTCAAGGGAAAGCTGTACACCTGT TCAGACAGTTCCAAGCAGACAGAGGCGGAATGCAAGGGCAACTACATCACGTACAAAGACGGGGAGGTTGACCACCC CATCATCCAACCCCGCAGCTGGGAGAACAGCAAGTTTGACTTTGACAATGTTCTGGCAGCCATGATGGCCCTCTTCA CCGTCTCCACCTTCGAAGGGTGGCCAGAGCTGCTGTACCGCTCCATCGACTCCCACACGGAAGACAAGGGCCCCATC TACAACTACCGTGTGGAGATCTCCATCTTCTTCATCATCTACATCATCATCATCGCCTTCTTCATGATGAACATCTT CGTGGGCTTCGTCATCGTCACCTTTCAGGAGCAGGGGGAGCAGGAGTACAAGAACTGTGAGCTGGACAAGAACCAGC 20 24028 / / SLW 875.245WO1 GACAGTGCGTGGAATACGCCCTCAAGGCCCGGCCCCTGCGGAGGTACATCCCCAAGAACCAGCACCAGTACAAAGTG TGGTACGTGGTCAACTCCACCTACTTCGAGTACCTGATGTTCGTCCTCATCCTGCTCAACACCATCTGCCTGGCCAT GCAGCACTACGGCCAGAGCTGCCTGTTCAAAATCGCCATGAACATCCTCAACATGCTCTTCACTGGCCTCTTCACCG TGGAGATGATCCTGAAGCTCATTGCCTTCAAACCCAAGGGTTACTTTAGTGATCCCTGGAATGTTTTTGACTTCCTC ATCGTAATTGGCAGCATAATTGACGTCATTCTCAGTGAGACTAATCACTATTTCTGTGATGCATGGAATACATTTGA CGCCTTGATTGTTGTGGGTAGCATTGTTGATATAGCAATCACCGAGGTAAACCCAGCTGAACATACCCAATGCTCTC CCTCTATGAACGCAGAGGAAAACTCCCGCATCTCCATCACCTTCTTCCGCCTGTTCCGGGTCATGCGTCTGGTGAAG CTGCTGAGCCGTGGGGAGGGCATCCGGACGCTGCTGTGGACCTTCATCAAGTCCTTCCAGGCCCTGCCCTATGTGGC CCTCCTGATCGTGATGCTGTTCTTCATCTACGCGGTGATCGGGATGCAGGTGTTTGGGAAAATTGCCCTGAATGATA CCACAGAGATCAACCGGAACAACAACTTTCAGACCTTCCCCCAGGCCGTGCTGCTCCTCTTCAGGTGTGCCACCGGG GAGGCCTGGCAGGACATCATGCTGGCCTGCATGCCAGGCAAGAAGTGTGCCCCAGAGTCCGAGCCCAGCAACAGCAC GGAGGGTGAAACACCCTGTGGTAGCAGCTTTGCTGTCTTCTACTTCATCAGCTTCTACATGCTCTGTGCCTTCCTGA TCATCAACCTCTTTGTAGCTGTCATCATGGACAACTTTGACTACCTGACAAGGGACTGGTCCATCCTTGGTCCCCAC CACCTGGATGAGTTTAAAAGAATCTGGGCAGAGTATGACCCTGAAGCCAAGGGTCGTATCAAACACCTGGATGTGGT GACCCTCCTCCGGCGGATTCAGCCGCCACTAGGTTTTGGGAAGCTGTGCCCTCACCGCGTGGCTTGCAAACGCCTGG TCTCCATGAACATGCCTCTGAACAGCGACGGGACAGTCATGTTCAATGCCACCCTGTTTGCCCTGGTCAGGACGGCC CTGAGGATCAAAACAGAAGGGAACCTAGAACAAGCCAATGAGGAGCTGCGGGCGATCATCAAGAAGATCTGGAAGCG GACCAGCATGAAGCTGCTGGACCAGGTGGTGCCCCCTGCAGGTGATGATGAGGTCACCGTTGGCAAGTTCTACGCCA CGTTCCTGATCCAGGAGTACTTCCGGAAGTTCAAGAAGCGCAAAGAGCAGGGCCTTGTGGGCAAGCCCTCCCAGAGG AACGCGCTGTCTCTGCAGGCTGGCTTGCGCACACTGCATGACATCGGGCCTGAGATCCGACGGGCCATCTCTGGAGA TCTCACCGCTGAGGAGGAGCTGGACAAGGCCATGAAGGAGGCTGTGTCCGCTGCTTCTGAAGATGACATCTTCAGGA GGGCCGGTGGCCTGTTCGGCAACCACGTCAGCTACTACCAAAGCGACGGCCGGAGCGCCTTCCCCCAGACCTTCACC ACTCAGCGCCCGCTGCACATCAACAAGGCGGGCAGCAGCCAGGGCGACACTGAGTCGCCATCCCACGAGAAGCTGGT GGACTCCACCTTCACCCCGAGCAGCTACTCGTCCACCGGCTCCAACGCCAACATCAACAACGCCAACAACACCGCCC TGGGTCGCCTCCCTCGCCCCGCCGGCTACCCCAGCACGGTCAGCACTGTGGAGGGCCACGGGCCCCCCTTGTCCCCT GCCATCCGGGTGCAGGAGGTGGCGTGGAAGCTCAGCTCCAACAGGGAAAGGCACGTTCCGATGTGTGAGGATCTGGA GCTCAGGAGGGATTCAGGCTCAGCAGGGACTCAGGCTCACTGCCTTCTGCTCAGGAAAGCAAACCCCTCTAGGTGCC ACTCCCGGGAGAGCCAGGCAGCCATGGCGGGTCAGGAGGAGACGTCTCAGGATGAGACCTATGAAGTGAAGATGAAC CATGACACGGAGGCCTGCAGTGAGCCCAGCCTGCTCTCCACAGAGATGCTCTCCTACCAGGATGACGAAAATCGGCA ACTGACGCTCCCAGAGGAGGACAAGAGGGACATCCGGCAATCTCCGAAGAGGGGTTTCCTCCGCTCTGCCTCACTAG GTCGAAGGGCCTCCTTCCACCTGGAATGTCTGAAGCGACAGAAGGACCGAGGGGGAGACATCTCTCAGAAGACAGTC CTGCCCTTGCATCTGGTTCATCATCAGGCATTGGCAGTGGCAGGCCTGAGCCCCCTCCTCCAGAGAAGCCATTCCCC TGCCTCATTCCCTAGGCCTTTTGCCACCCCACCAGCCACACCTGGCAGCCGAGGCTGGCCCCCACAGCCCGTCCCCA CCCTGCGGCTTGAGGGGGTCGAGTCCAGTGAGAAACTCAACAGCAGCTTCCCATCCATCCACTGCGGCTCCTGGGCT GAGACCACCCCCGGTGGCGGGGGCAGCAGCGCCGCCCGGAGAGTCCGGCCCGTCTCCCTCATGGTGCCCAGCCAGGC TGGGGCCCCAGGGAGGCAGTTCCACGGCAGTGCCAGCAGCCTGGTGGAAGCGGTCTTGATTTCAGAAGGACTGGGGC AGTTTGCTCAAGATCCCAAGTTCATCGAGGTCACCACCCAGGAGCTGGCCGACGCCTGCGACATGACCATAGAGGAG ATGGAGAGCGCGGCCGACAACATCCTCAGCGGGGGCGCCCCACAGAGCCCCAATGGCGCCCTCTTACCCTTTGTGAA CTGCAGGGACGCGGGGCAGGACCGAGCCGGGGGCGAAGAGGACGCGGGCTGTGTGCGCGCGCGGGGTCGACCGAGTG AGGAGGAGCTCCAGGACAGCAGGGTCTACGTCAGCAGCCTGTAG SEQ ID NO: 10 (CaV1.2 aa, human) MVNENTRMYIPEENHQGSNYGSPRPAHANMNANAAAGLAPEHIPTPGAALSWQAAIDAARQAKLMGSAGNATISTVS STQRKRQQYGKPKKQGSTTATRPPRALLCLTLKNPIRRACISIVEWKPFEIIILLTIFANCVALAIYIPFPEDDSNA TNSNLERVEYLFLIIFTVEAFLKVIAYGLLFHPNAYLRNGWNLLDFIIVVVGLFSAILEQATKADGANALGGKGAGF DVKALRAFRVLRPLRLVSGVPSLQVVLNSIIKAMVPLLHIALLVLFVIIIYAIIGLELFMGKMHKTCYNQEGIADVP AEDDPSPCALETGHGRQCQNGTVCKPGWDGPKHGITNFDNFAFAMLTVFQCITMEGWTDVLYWVNDAVGRDWPWIYF VTLIIIGSFFVLNLVLGVLSGEFSKEREKAKARGDFQKLREKQQLEEDLKGYLDWITQAEDIDPENEDEGMDEEKPR NMSMPTSETESVNTENVAGGDIEGENCGARLAHRISKSKFSRYWRRWNRFCRRKCRAAVKSNVFYWLVIFLVFLNTL TIASEHYNQPNWLTEVQDTANKALLALFTAEMLLKMYSLGLQAYFVSLFNRFDCFVVCGGILETILVETKIMSPLGI SVLRCVRLLRIFKITRYWNSLSNLVASLLNSVRSIASLLLLLFLFIIIFSLLGMQLFGGKFNFDEMQTRRSTFDNFP QSLLTVFQILTGEDWNSVMYDGIMAYGGPSFPGMLVCIYFIILFICGNYILLNVFLAIAVDNLADAESLTSAQKEEE EEKERKKLARTASPEKKQELVEKPAVGESKEEKIELKSITADGESPPATKINMDDLQPNENEDKSPYPNPETTGEED EEEPEMPVGPRPRPLSELHLKEKAVPMPEASAFFIFSSNNRFRLQCHRIVNDTIFTNLILFFILLSSISLAAEDPVQ HTSFRNHILFYFDIVFTTIFTIEIALKILGNADYVFTSIFTLEIILKMTAYGAFLHKGSFCRNYFNILDLLVVSVSL ISFGIQSSAINVVKILRVLRVLRPLRAINRAKGLKHVVQCVFVAIRTIGNIVIVTTLLQFMFACIGVQLFKGKLYTC SDSSKQTEAECKGNYITYKDGEVDHPIIQPRSWENSKFDFDNVLAAMMALFTVSTFEGWPELLYRSIDSHTEDKGPI 21 24028 / / SLW 875.245WO1 YNYRVEISIFFIIYIIIIAFFMMNIFVGFVIVTFQEQGEQEYKNCELDKNQRQCVEYALKARPLRRYIPKNQHQYKV WYVVNSTYFEYLMFVLILLNTICLAMQHYGQSCLFKIAMNILNMLFTGLFTVEMILKLIAFKPKGYFSDPWNVFDFL IVIGSIIDVILSETNHYFCDAWNTFDALIVVGSIVDIAITEVNPAEHTQCSPSMNAEENSRISITFFRLFRVMRLVK LLSRGEGIRTLLWTFIKSFQALPYVALLIVMLFFIYAVIGMQVFGKIALNDTTEINRNNNFQTFPQAVLLLFRCATG EAWQDIMLACMPGKKCAPESEPSNSTEGETPCGSSFAVFYFISFYMLCAFLIINLFVAVIMDNFDYLTRDWSILGPH HLDEFKRIWAEYDPEAKGRIKHLDVVTLLRRIQPPLGFGKLCPHRVACKRLVSMNMPLNSDGTVMFNATLFALVRTA LRIKTEGNLEQANEELRAIIKKIWKRTSMKLLDQVVPPAGDDEVTVGKFYATFLIQEYFRKFKKRKEQGLVGKPSQR NALSLQAGLRTLHDIGPEIRRAISGDLTAEEELDKAMKEAVSAASEDDIFRRAGGLFGNHVSYYQSDGRSAFPQTFT TQRPLHINKAGSSQGDTESPSHEKLVDSTFTPSSYSSTGSNANINNANNTALGRLPRPAGYPSTVSTVEGHGPPLSP AIRVQEVAWKLSSNRERHVPMCEDLELRRDSGSAGTQAHCLLLRKANPSRCHSRESQAAMAGQEETSQDETYEVKMN HDTEACSEPSLLSTEMLSYQDDENRQLTLPEEDKRDIRQSPKRGFLRSASLGRRASFHLECLKRQKDRGGDISQKTV LPLHLVHHQALAVAGLSPLLQRSHSPASFPRPFATPPATPGSRGWPPQPVPTLRLEGVESSEKLNSSFPSIHCGSWA ETTPGGGGSSAARRVRPVSLMVPSQAGAPGRQFHGSASSLVEAVLISEGLGQFAQDPKFIEVTTQELADACDMTIEE MESAADNILSGGAPQSPNGALLPFVNCRDAGQDRAGGEEDAGCVRARGRPSEEELQDSRVYVSSL* SEQ ID NO: 11 (SERCA2a nt, human) atggagaacgcgcacaccaagacggtggaggaggtgctgggccacttcggcgtcaacgagagtacggggctgagcct ggaacaggtcaagaagcttaaggagagatggggctccaacgagttaccggctgaagaaggaaaaaccttgctggaac ttgtgattgagcagtttgaagacttgctagttaggattttattactggcagcatgtatatcttttgttttggcttgg tttgaagaaggtgaagaaacaattacagcctttgtagaaccttttgtaattttactcatattagtagccaatgcaat tgtgggtgtatggcaggaaagaaatgctgaaaatgccatcgaagcccttaaggaatatgagcctgaaatgggcaaag tgtatcgacaggacagaaagagtgtgcagcggattaaagctaaagacatagttcctggtgatattgtagaaattgct gttggtgacaaagttcctgctgatataaggttaacttccatcaaatctaccacactaagagttgaccagtcaattct cacaggtgaatctgtctctgtcatcaagcacactgatcccgtccctgacccacgagctgtcaaccaagataaaaaga acatgctgttttctggtacaaacattgctgctgggaaagctatgggagtggtggtagcaactggagttaacaccgaa attggcaagatccgggatgaaatggtggcaacagaacaggagagaacaccccttcagcaaaaactagatgaatttgg ggaacagctttccaaagtcatctcccttatttgcattgcagtctggatcataaatattgggcacttcaatgacccgg ttcatggagggtcctggatcagaggtgctatttactactttaaaattgcagtggccctggctgtagcagccattcct gaaggtctgcctgcagtcatcaccacctgcctggctcttggaactcgcagaatggcaaagaaaaatgccattgttcg aagcctcccgtctgtggaaacccttggttgtacttctgttatctgctcagacaagactggtacacttacaacaaacc agatgtcagtctgcaggatgttcattctggacagagtggaaggtgatacttgttcccttaatgagtttaccataact ggatcaacttatgcacctattggagaagtgcataaagatgataaaccagtgaattgtcaccagtatgatggtctggt agaattagcaacaatttgtgctctttgtaatgactctgctttggattacaatgaggcaaagggtgtgtatgaaaaag ttggagaagctacagagactgctctcacttgcctagtagagaagatgaatgtatttgataccgaattgaagggtctt tctaaaatagaacgtgcaaatgcctgcaactcagtcattaaacagctgatgaaaaaggaattcactctagagttttc acgtgacagaaagtcaatgtcggtttactgtacaccaaataaaccaagcaggacatcaatgagcaagatgtttgtga agggtgctcctgaaggtgtcattgacaggtgcacccacattcgagttggaagtactaaggttcctatgacctctgga gtcaaacagaagatcatgtctgtcattcgagagtggggtagtggcagcgacacactgcgatgcctggccctggccac tcatgacaacccactgagaagagaagaaatgcaccttgaggactctgccaactttattaaatatgagaccaatctga ccttcgttggctgcgtgggcatgctggatcctccgagaatcgaggtggcctcctccgtgaagctgtgccggcaagca ggcatccgggtcatcatgatcactggggacaacaagggcactgctgtggccatctgtcgccgcatcggcatcttcgg gcaggatgaggacgtgacgtcaaaagctttcacaggccgggagtttgatgaactcaacccctccgcccagcgagacg cctgcctgaacgcccgctgttttgctcgagttgaaccctcccacaagtctaaaatcgtagaatttcttcagtctttt gatgagattacagctatgactggcgatggcgtgaacgatgctcctgctctgaagaaagccgagattggcattgctat gggctctggcactgcggtggctaaaaccgcctctgagatggtcctggcggatgacaacttctccaccattgtggctg ccgttgaggaggggcgggcaatctacaacaacatgaaacagttcatccgctacctcatctcgtccaacgtcggggaa gttgtctgtattttcctgacagcagcccttggatttcccgaggctttgattcctgttcagctgctctgggtcaatct ggtgacagatggcctgcctgccactgcactggggttcaaccctcctgatctggacatcatgaataaacctccccgga acccaaaggaaccattgatcagcgggtggctctttttccgttacttggctattggctgttacgtcggcgctgctacc gtgggtgctgctgcatggtggttcattgctgctgacggtggtccaagagtgtccttctaccagctgagtcatttcct acagtgtaaagaggacaacccggactttgaaggcgtggattgtgcaatctttgaatccccatacccgatgacaatgg cgctctctgttctagtaactatagaaatgtgtaacgccctcaacagcttgtccgaaaaccagtccttgctgaggatg cccccctgggagaacatctggctcgtgggctccatctgcctgtccatgtcactccacttcctgatcctctatgtcga acccttgccactcatcttccagatcacaccgctgaacgtgacccagtggctgatggtgctgaaaatctccttgcccg tgattctcatggatgagacgctcaagtttgtggcccgcaactacctggaacctgcaatactggagtaa SEQ ID NO: 12 (SERCA2a aa, human) 22 24028 / / SLW 875.245WO1 MENAHTKTVEEVLGHFGVNESTGLSLEQVKKLKERWGSNELPAEEGKTLLELVIEQFEDLLVRILLLAACISFVLAW FEEGEETITAFVEPFVILLILVANAIVGVWQERNAENAIEALKEYEPEMGKVYRQDRKSVQRIKAKDIVPGDIVEIA VGDKVPADIRLTSIKSTTLRVDQSILTGESVSVIKHTDPVPDPRAVNQDKKNMLFSGTNIAAGKAMGVVVATGVNTE IGKIRDEMVATEQERTPLQQKLDEFGEQLSKVISLICIAVWIINIGHFNDPVHGGSWIRGAIYYFKIAVALAVAAIP EGLPAVITTCLALGTRRMAKKNAIVRSLPSVETLGCTSVICSDKTGTLTTNQMSVCRMFILDRVEGDTCSLNEFTIT GSTYAPIGEVHKDDKPVNCHQYDGLVELATICALCNDSALDYNEAKGVYEKVGEATETALTCLVEKMNVFDTELKGL SKIERANACNSVIKQLMKKEFTLEFSRDRKSMSVYCTPNKPSRTSMSKMFVKGAPEGVIDRCTHIRVGSTKVPMTSG VKQKIMSVIREWGSGSDTLRCLALATHDNPLRREEMHLEDSANFIKYETNLTFVGCVGMLDPPRIEVASSVKLCRQA GIRVIMITGDNKGTAVAICRRIGIFGQDEDVTSKAFTGREFDELNPSAQRDACLNARCFARVEPSHKSKIVEFLQSF DEITAMTGDGVNDAPALKKAEIGIAMGSGTAVAKTASEMVLADDNFSTIVAAVEEGRAIYNNMKQFIRYLISSNVGE VVCIFLTAALGFPEALIPVQLLWVNLVTDGLPATALGFNPPDLDIMNKPPRNPKEPLISGWLFFRYLAIGCYVGAAT VGAAAWWFIAADGGPRVSFYQLSHFLQCKEDNPDFEGVDCAIFESPYPMTMALSVLVTIEMCNALNSLSENQSLLRM PPWENIWLVGSICLSMSLHFLILYVEPLPLIFQITPLNVTQWLMVLKISLPVILMDETLKFVARNYLEPAILE* SEQ ID NO: 13 (DMD nt, human) ATGCTTTGGTGGGAAGAAGTAGAGGACTGTTATGAAAGAGAAGATGTTCAAAAGAAAACATTCACAAAATGGGTAAA TGCACAATTTTCTAAGTTTGGGAAGCAGCATATTGAGAACCTCTTCAGTGACCTACAGGATGGGAGGCGCCTCCTAG ACCTCCTCGAAGGCCTGACAGGGCAAAAACTGCCAAAAGAAAAAGGATCCACAAGAGTTCATGCCCTGAACAATGTC AACAAGGCACTGCGGGTTTTGCAGAACAATAATGTTGATTTAGTGAATATTGGAAGTACTGACATCGTAGATGGAAA TCATAAACTGACTCTTGGTTTGATTTGGAATATAATCCTCCACTGGCAGGTCAAAAATGTAATGAAAAATATCATGG CTGGATTGCAACAAACCAACAGTGAAAAGATTCTCCTGAGCTGGGTCCGACAATCAACTCGTAATTATCCACAGGTT AATGTAATCAACTTCACCACCAGCTGGTCTGATGGCCTGGCTTTGAATGCTCTCATCCATAGTCATAGGCCAGACCT ATTTGACTGGAATAGTGTGGTTTGCCAGCAGTCAGCCACACAACGACTGGAACATGCATTCAACATCGCCAGATATC AATTAGGCATAGAGAAACTACTCGATCCTGAAGATGTTGATACCACCTATCCAGATAAGAAGTCCATCTTAATGTAC ATCACATCACTCTTCCAAGTTTTGCCTCAACAAGTGAGCATTGAAGCCATCCAGGAAGTGGAAATGTTGCCAAGGCC ACCTAAAGTGACTAAAGAAGAACATTTTCAGTTACATCATCAAATGCACTATTCTCAACAGATCACGGTCAGTCTAG CACAGGGATATGAGAGAACTTCTTCCCCTAAGCCTCGATTCAAGAGCTATGCCTACACACAGGCTGCTTATGTCACC ACCTCTGACCCTACACGGAGCCCATTTCCTTCACAGCATTTGGAAGCTCCTGAAGACAAGTCATTTGGCAGTTCATT GATGGAGAGTGAAGTAAACCTGGACCGTTATCAAACAGCTTTAGAAGAAGTATTATCGTGGCTTCTTTCTGCTGAGG ACACATTGCAAGCACAAGGAGAGATTTCTAATGATGTGGAAGTGGTGAAAGACCAGTTTCATACTCATGAGGGGTAC ATGATGGATTTGACAGCCCATCAGGGCCGGGTTGGTAATATTCTACAATTGGGAAGTAAGCTGATTGGAACAGGAAA ATTATCAGAAGATGAAGAAACTGAAGTACAAGAGCAGATGAATCTCCTAAATTCAAGATGGGAATGCCTCAGGGTAG CTAGCATGGAAAAACAAAGCAATTTACATAGAGTTTTAATGGATCTCCAGAATCAGAAACTGAAAGAGTTGAATGAC TGGCTAACAAAAACAGAAGAAAGAACAAGGAAAATGGAGGAAGAGCCTCTTGGACCTGATCTTGAAGACCTAAAACG CCAAGTACAACAACATAAGGTGCTTCAAGAAGATCTAGAACAAGAACAAGTCAGGGTCAATTCTCTCACTCACATGG TGGTGGTAGTTGATGAATCTAGTGGAGATCACGCAACTGCTGCTTTGGAAGAACAACTTAAGGTATTGGGAGATCGA TGGGCAAACATCTGTAGATGGACAGAAGACCGCTGGGTTCTTTTACAAGACATCCTTCTCAAATGGCAACGTCTTAC TGAAGAACAGTGCCTTTTTAGTGCATGGCTTTCAGAAAAAGAAGATGCAGTGAACAAGATTCACACAACTGGCTTTA AAGATCAAAATGAAATGTTATCAAGTCTTCAAAAACTGGCCGTTTTAAAAGCGGATCTAGAAAAGAAAAAGCAATCC ATGGGCAAACTGTATTCACTCAAACAAGATCTTCTTTCAACACTGAAGAATAAGTCAGTGACCCAGAAGACGGAAGC ATGGCTGGATAACTTTGCCCGGTGTTGGGATAATTTAGTCCAAAAACTTGAAAAGAGTACAGCACAGATTTCACAGG CTGTCACCACCACTCAGCCATCACTAACACAGACAACTGTAATGGAAACAGTAACTACGGTGACCACAAGGGAACAG ATCCTGGTAAAGCATGCTCAAGAGGAACTTCCACCACCACCTCCCCAAAAGAAGAGGCAGATTACTGTGGATTCTGA AATTAGGAAAAGGTTGGATGTTGATATAACTGAACTTCACAGCTGGATTACTCGCTCAGAAGCTGTGTTGCAGAGTC CTGAATTTGCAATCTTTCGGAAGGAAGGCAACTTCTCAGACTTAAAAGAAAAAGTCAATGCCATAGAGCGAGAAAAA GCTGAGAAGTTCAGAAAACTGCAAGATGCCAGCAGATCAGCTCAGGCCCTGGTGGAACAGATGGTGAATGAGGGTGT TAATGCAGATAGCATCAAACAAGCCTCAGAACAACTGAACAGCCGGTGGATCGAATTCTGCCAGTTGCTAAGTGAGA GACTTAACTGGCTGGAGTATCAGAACAACATCATCGCTTTCTATAATCAGCTACAACAATTGGAGCAGATGACAACT ACTGCTGAAAACTGGTTGAAAATCCAACCCACCACCCCATCAGAGCCAACAGCAATTAAAAGTCAGTTAAAAATTTG TAAGGATGAAGTCAACCGGCTATCAGGTCTTCAACCTCAAATTGAACGATTAAAAATTCAAAGCATAGCCCTGAAAG AGAAAGGACAAGGACCCATGTTCCTGGATGCAGACTTTGTGGCCTTTACAAATCATTTTAAGCAAGTCTTTTCTGAT GTGCAGGCCAGAGAGAAAGAGCTACAGACAATTTTTGACACTTTGCCACCAATGCGCTATCAGGAGACCATGAGTGC CATCAGGACATGGGTCCAGCAGTCAGAAACCAAACTCTCCATACCTCAACTTAGTGTCACCGACTATGAAATCATGG AGCAGAGACTCGGGGAATTGCAGGCTTTACAAAGTTCTCTGCAAGAGCAACAAAGTGGCCTATACTATCTCAGCACC ACTGTGAAAGAGATGTCGAAGAAAGCGCCCTCTGAAATTAGCCGGAAATATCAATCAGAATTTGAAGAAATTGAGGG ACGCTGGAAGAAGCTCTCCTCCCAGCTGGTTGAGCATTGTCAAAAGCTAGAGGAGCAAATGAATAAACTCCGAAAAA TTCAGAATCACATACAAACCCTGAAGAAATGGATGGCTGAAGTTGATGTTTTTCTGAAGGAGGAATGGCCTGCCCTT 23 24028 / / SLW 875.245WO1 GGGGATTCAGAAATTCTAAAAAAGCAGCTGAAACAGTGCAGACTTTTAGTCAGTGATATTCAGACAATTCAGCCCAG TCTAAACAGTGTCAATGAAGGTGGGCAGAAGATAAAGAATGAAGCAGAGCCAGAGTTTGCTTCGAGACTTGAGACAG AACTCAAAGAACTTAACACTCAGTGGGATCACATGTGCCAACAGGTCTATGCCAGAAAGGAGGCCTTGAAGGGAGGT TTGGAGAAAACTGTAAGCCTCCAGAAAGATCTATCAGAGATGCACGAATGGATGACACAAGCTGAAGAAGAGTATCT TGAGAGAGATTTTGAATATAAAACTCCAGATGAATTACAGAAAGCAGTTGAAGAGATGAAGAGAGCTAAAGAAGAGG CCCAACAAAAAGAAGCGAAAGTGAAACTCCTTACTGAGTCTGTAAATAGTGTCATAGCTCAAGCTCCACCTGTAGCA CAAGAGGCCTTAAAAAAGGAACTTGAAACTCTAACCACCAACTACCAGTGGCTCTGCACTAGGCTGAATGGGAAATG CAAGACTTTGGAAGAAGTTTGGGCATGTTGGCATGAGTTATTGTCATACTTGGAGAAAGCAAACAAGTGGCTAAATG AAGTAGAATTTAAACTTAAAACCACTGAAAACATTCCTGGCGGAGCTGAGGAAATCTCTGAGGTGCTAGATTCACTT GAAAATTTGATGCGACATTCAGAGGATAACCCAAATCAGATTCGCATATTGGCACAGACCCTAACAGATGGCGGAGT CATGGATGAGCTAATCAATGAGGAACTTGAGACATTTAATTCTCGTTGGAGGGAACTACATGAAGAGGCTGTAAGGA GGCAAAAGTTGCTTGAACAGAGCATCCAGTCTGCCCAGGAGACTGAAAAATCCTTACACTTAATCCAGGAGTCCCTC ACATTCATTGACAAGCAGTTGGCAGCTTATATTGCAGACAAGGTGGACGCAGCTCAAATGCCTCAGGAAGCCCAGAA AATCCAATCTGATTTGACAAGTCATGAGATCAGTTTAGAAGAAATGAAGAAACATAATCAGGGGAAGGAGGCTGCCC AAAGAGTCCTGTCTCAGATTGATGTTGCACAGAAAAAATTACAAGATGTCTCCATGAAGTTTCGATTATTCCAGAAA CCAGCCAATTTTGAGCTGCGTCTACAAGAAAGTAAGATGATTTTAGATGAAGTGAAGATGCACTTGCCTGCATTGGA AACAAAGAGTGTGGAACAGGAAGTAGTACAGTCACAGCTAAATCATTGTGTGAACTTGTATAAAAGTCTGAGTGAAG TGAAGTCTGAAGTGGAAATGGTGATAAAGACTGGACGTCAGATTGTACAGAAAAAGCAGACGGAAAATCCCAAAGAA CTTGATGAAAGAGTAACAGCTTTGAAATTGCATTATAATGAGCTGGGAGCAAAGGTAACAGAAAGAAAGCAACAGTT GGAGAAATGCTTGAAATTGTCCCGTAAGATGCGAAAGGAAATGAATGTCTTGACAGAATGGCTGGCAGCTACAGATA TGGAATTGACAAAGAGATCAGCAGTTGAAGGAATGCCTAGTAATTTGGATTCTGAAGTTGCCTGGGGAAAGGCTACT CAAAAAGAGATTGAGAAACAGAAGGTGCACCTGAAGAGTATCACAGAGGTAGGAGAGGCCTTGAAAACAGTTTTGGG CAAGAAGGAGACGTTGGTGGAAGATAAACTCAGTCTTCTGAATAGTAACTGGATAGCTGTCACCTCCCGAGCAGAAG AGTGGTTAAATCTTTTGTTGGAATACCAGAAACACATGGAAACTTTTGACCAGAATGTGGACCACATCACAAAGTGG ATCATTCAGGCTGACACACTTTTGGATGAATCAGAGAAAAAGAAACCCCAGCAAAAAGAAGACGTGCTTAAGCGTTT AAAGGCAGAACTGAATGACATACGCCCAAAGGTGGACTCTACACGTGACCAAGCAGCAAACTTGATGGCAAACCGCG GTGACCACTGCAGGAAATTAGTAGAGCCCCAAATCTCAGAGCTCAACCATCGATTTGCAGCCATTTCACACAGAATT AAGACTGGAAAGGCCTCCATTCCTTTGAAGGAATTGGAGCAGTTTAACTCAGATATACAAAAATTGCTTGAACCACT GGAGGCTGAAATTCAGCAGGGGGTGAATCTGAAAGAGGAAGACTTCAATAAAGATATGAATGAAGACAATGAGGGTA CTGTAAAAGAATTGTTGCAAAGAGGAGACAACTTACAACAAAGAATCACAGATGAGAGAAAGAGAGAGGAAATAAAG ATAAAACAGCAGCTGTTACAGACAAAACATAATGCTCTCAAGGATTTGAGGTCTCAAAGAAGAAAAAAGGCTCTAGA AATTTCTCATCAGTGGTATCAGTACAAGAGGCAGGCTGATGATCTCCTGAAATGCTTGGATGACATTGAAAAAAAAT TAGCCAGCCTACCTGAGCCCAGAGATGAAAGGAAAATAAAGGAAATTGATCGGGAATTGCAGAAGAAGAAAGAGGAG CTGAATGCAGTGCGTAGGCAAGCTGAGGGCTTGTCTGAGGATGGGGCCGCAATGGCAGTGGAGCCAACTCAGATCCA GCTCAGCAAGCGCTGGCGGGAAATTGAGAGCAAATTTGCTCAGTTTCGAAGACTCAACTTTGCACAAATTCACACTG TCCGTGAAGAAACGATGATGGTGATGACTGAAGACATGCCTTTGGAAATTTCTTATGTGCCTTCTACTTATTTGACT GAAATCACTCATGTCTCACAAGCCCTATTAGAAGTGGAACAACTTCTCAATGCTCCTGACCTCTGTGCTAAGGACTT TGAAGATCTCTTTAAGCAAGAGGAGTCTCTGAAGAATATAAAAGATAGTCTACAACAAAGCTCAGGTCGGATTGACA TTATTCATAGCAAGAAGACAGCAGCATTGCAAAGTGCAACGCCTGTGGAAAGGGTGAAGCTACAGGAAGCTCTCTCC CAGCTTGATTTCCAATGGGAAAAAGTTAACAAAATGTACAAGGACCGACAAGGGCGATTTGACAGATCTGTTGAGAA ATGGCGGCGTTTTCATTATGATATAAAGATATTTAATCAGTGGCTAACAGAAGCTGAACAGTTTCTCAGAAAGACAC AAATTCCTGAGAATTGGGAACATGCTAAATACAAATGGTATCTTAAGGAACTCCAGGATGGCATTGGGCAGCGGCAA ACTGTTGTCAGAACATTGAATGCAACTGGGGAAGAAATAATTCAGCAATCCTCAAAAACAGATGCCAGTATTCTACA GGAAAAATTGGGAAGCCTGAATCTGCGGTGGCAGGAGGTCTGCAAACAGCTGTCAGACAGAAAAAAGAGGCTAGAAG AACAAAAGAATATCTTGTCAGAATTTCAAAGAGATTTAAATGAATTTGTTTTATGGTTGGAGGAAGCAGATAACATT GCTAGTATCCCACTTGAACCTGGAAAAGAGCAGCAACTAAAAGAAAAGCTTGAGCAAGTCAAGTTACTGGTGGAAGA GTTGCCCCTGCGCCAGGGAATTCTCAAACAATTAAATGAAACTGGAGGACCCGTGCTTGTAAGTGCTCCCATAAGCC CAGAAGAGCAAGATAAACTTGAAAATAAGCTCAAGCAGACAAATCTCCAGTGGATAAAGGTTTCCAGAGCTTTACCT GAGAAACAAGGAGAAATTGAAGCTCAAATAAAAGACCTTGGGCAGCTTGAAAAAAAGCTTGAAGACCTTGAAGAGCA GTTAAATCATCTGCTGCTGTGGTTATCTCCTATTAGGAATCAGTTGGAAATTTATAACCAACCAAACCAAGAAGGAC CATTTGACGTTCAGGAAACTGAAATAGCAGTTCAAGCTAAACAACCGGATGTGGAAGAGATTTTGTCTAAAGGGCAG CATTTGTACAAGGAAAAACCAGCCACTCAGCCAGTGAAGAGGAAGTTAGAAGATCTGAGCTCTGAGTGGAAGGCGGT AAACCGTTTACTTCAAGAGCTGAGGGCAAAGCAGCCTGACCTAGCTCCTGGACTGACCACTATTGGAGCCTCTCCTA CTCAGACTGTTACTCTGGTGACACAACCTGTGGTTACTAAGGAAACTGCCATCTCCAAACTAGAAATGCCATCTTCC TTGATGTTGGAGGTACCTGCTCTGGCAGATTTCAACCGGGCTTGGACAGAACTTACCGACTGGCTTTCTCTGCTTGA TCAAGTTATAAAATCACAGAGGGTGATGGTGGGTGACCTTGAGGATATCAACGAGATGATCATCAAGCAGAAGGCAA CAATGCAGGATTTGGAACAGAGGCGTCCCCAGTTGGAAGAACTCATTACCGCTGCCCAAAATTTGAAAAACAAGACC AGCAATCAAGAGGCTAGAACAATCATTACGGATCGAATTGAAAGAATTCAGAATCAGTGGGATGAAGTACAAGAACA 24 24028 / / SLW 875.245WO1 CCTTCAGAACCGGAGGCAACAGTTGAATGAAATGTTAAAGGATTCAACACAATGGCTGGAAGCTAAGGAAGAAGCTG AGCAGGTCTTAGGACAGGCCAGAGCCAAGCTTGAGTCATGGAAGGAGGGTCCCTATACAGTAGATGCAATCCAAAAG AAAATCACAGAAACCAAGCAGTTGGCCAAAGACCTCCGCCAGTGGCAGACAAATGTAGATGTGGCAAATGACTTGGC CCTGAAACTTCTCCGGGATTATTCTGCAGATGATACCAGAAAAGTCCACATGATAACAGAGAATATCAATGCCTCTT GGAGAAGCATTCATAAAAGGGTGAGTGAGCGAGAGGCTGCTTTGGAAGAAACTCATAGATTACTGCAACAGTTCCCC CTGGACCTGGAAAAGTTTCTTGCCTGGCTTACAGAAGCTGAAACAACTGCCAATGTCCTACAGGATGCTACCCGTAA GGAAAGGCTCCTAGAAGACTCCAAGGGAGTAAAAGAGCTGATGAAACAATGGCAAGACCTCCAAGGTGAAATTGAAG CTCACACAGATGTTTATCACAACCTGGATGAAAACAGCCAAAAAATCCTGAGATCCCTGGAAGGTTCCGATGATGCA GTCCTGTTACAAAGACGTTTGGATAACATGAACTTCAAGTGGAGTGAACTTCGGAAAAAGTCTCTCAACATTAGGTC CCATTTGGAAGCCAGTTCTGACCAGTGGAAGCGTCTGCACCTTTCTCTGCAGGAACTTCTGGTGTGGCTACAGCTGA AAGATGATGAATTAAGCCGGCAGGCACCTATTGGAGGCGACTTTCCAGCAGTTCAGAAGCAGAACGATGTACATAGG GCCTTCAAGAGGGAATTGAAAACTAAAGAACCTGTAATCATGAGTACTCTTGAGACTGTACGAATATTTCTGACAGA GCAGCCTTTGGAAGGACTAGAGAAACTCTACCAGGAGCCCAGAGAGCTGCCTCCTGAGGAGAGAGCCCAGAATGTCA CTCGGCTTCTACGAAAGCAGGCTGAGGAGGTCAATACTGAGTGGGAAAAATTGAACCTGCACTCCGCTGACTGGCAG AGAAAAATAGATGAGACCCTTGAAAGACTCCAGGAACTTCAAGAGGCCACGGATGAGCTGGACCTCAAGCTGCGCCA AGCTGAGGTGATCAAGGGATCCTGGCAGCCCGTGGGCGATCTCCTCATTGACTCTCTCCAAGATCACCTCGAGAAAG TCAAGGCACTTCGAGGAGAAATTGCGCCTCTGAAAGAGAACGTGAGCCACGTCAATGACCTTGCTCGCCAGCTTACC ACTTTGGGCATTCAGCTCTCACCGTATAACCTCAGCACTCTGGAAGACCTGAACACCAGATGGAAGCTTCTGCAGGT GGCCGTCGAGGACCGAGTCAGGCAGCTGCATGAAGCCCACAGGGACTTTGGTCCAGCATCTCAGCACTTTCTTTCCA CGTCTGTCCAGGGTCCCTGGGAGAGAGCCATCTCGCCAAACAAAGTGCCCTACTATATCAACCACGAGACTCAAACA ACTTGCTGGGACCATCCCAAAATGACAGAGCTCTACCAGTCTTTAGCTGACCTGAATAATGTCAGATTCTCAGCTTA TAGGACTGCCATGAAACTCCGAAGACTGCAGAAGGCCCTTTGCTTGGATCTCTTGAGCCTGTCAGCTGCATGTGATG CCTTGGACCAGCACAACCTCAAGCAAAATGACCAGCCCATGGATATCCTGCAGATTATTAATTGTTTGACCACTATT TATGACCGCCTGGAGCAAGAGCACAACAATTTGGTCAACGTCCCTCTCTGCGTGGATATGTGTCTGAACTGGCTGCT GAATGTTTATGATACGGGACGAACAGGGAGGATCCGTGTCCTGTCTTTTAAAACTGGCATCATTTCCCTGTGTAAAG CACATTTGGAAGACAAGTACAGATACCTTTTCAAGCAAGTGGCAAGTTCAACAGGATTTTGTGACCAGCGCAGGCTG GGCCTCCTTCTGCATGATTCTATCCAAATTCCAAGACAGTTGGGTGAAGTTGCATCCTTTGGGGGCAGTAACATTGA GCCAAGTGTCCGGAGCTGCTTCCAATTTGCTAATAATAAGCCAGAGATCGAAGCGGCCCTCTTCCTAGACTGGATGA GACTGGAACCCCAGTCCATGGTGTGGCTGCCCGTCCTGCACAGAGTGGCTGCTGCAGAAACTGCCAAGCATCAGGCC AAATGTAACATCTGCAAAGAGTGTCCAATCATTGGATTCAGGTACAGGAGTCTAAAGCACTTTAATTATGACATCTG CCAAAGCTGCTTTTTTTCTGGTCGAGTTGCAAAAGGCCATAAAATGCACTATCCCATGGTGGAATATTGCACTCCGA CTACATCAGGAGAAGATGTTCGAGACTTTGCCAAGGTACTAAAAAACAAATTTCGAACCAAAAGGTATTTTGCGAAG CATCCCCGAATGGGCTACCTGCCAGTGCAGACTGTCTTAGAGGGGGACAACATGGAAACTCCCGTTACTCTGATCAA CTTCTGGCCAGTAGATTCTGCGCCTGCCTCGTCCCCTCAGCTTTCACACGATGATACTCATTCACGCATTGAACATT ATGCTAGCAGGCTAGCAGAAATGGAAAACAGCAATGGATCTTATCTAAATGATAGCATCTCTCCTAATGAGAGCATA GATGATGAACATTTGTTAATCCAGCATTACTGCCAAAGTTTGAACCAGGACTCCCCCCTGAGCCAGCCTCGTAGTCC TGCCCAGATCTTGATTTCCTTAGAGAGTGAGGAAAGAGGGGAGCTAGAGAGAATCCTAGCAGATCTTGAGGAAGAAA ACAGGAATCTGCAAGCAGAATATGACCGTCTAAAGCAGCAGCACGAACATAAAGGCCTGTCCCCACTGCCGTCCCCT CCTGAAATGATGCCCACCTCTCCCCAGAGTCCCCGGGATGCTGAGCTCATTGCTGAGGCCAAGCTACTGCGTCAACA CAAAGGCCGCCTGGAAGCCAGGATGCAAATCCTGGAAGACCACAATAAACAGCTGGAGTCACAGTTACACAGGCTAA GGCAGCTGCTGGAGCAACCCCAGGCAGAGGCCAAAGTGAATGGCACAACGGTGTCCTCTCCTTCTACCTCTCTACAG AGGTCCGACAGCAGTCAGCCTATGCTGCTCCGAGTGGTTGGCAGTCAAACTTCGGACTCCATGGGTGAGGAAGATCT TCTCAGTCCTCCCCAGGACACAAGCACAGGGTTAGAGGAGGTGATGGAGCAACTCAACAACTCCTTCCCTAGTTCAA GAGGAAGAAATACCCCTGGAAAGCCAATGAGAGAGGACACAATGTAG SEQ ID NO: 14 (DMD aa, human) MLWWEEVEDCYEREDVQKKTFTKWVNAQFSKFGKQHIENLFSDLQDGRRLLDLLEGLTGQKLPKEKGSTRVHALNNV NKALRVLQNNNVDLVNIGSTDIVDGNHKLTLGLIWNIILHWQVKNVMKNIMAGLQQTNSEKILLSWVRQSTRNYPQV NVINFTTSWSDGLALNALIHSHRPDLFDWNSVVCQQSATQRLEHAFNIARYQLGIEKLLDPEDVDTTYPDKKSILMY ITSLFQVLPQQVSIEAIQEVEMLPRPPKVTKEEHFQLHHQMHYSQQITVSLAQGYERTSSPKPRFKSYAYTQAAYVT TSDPTRSPFPSQHLEAPEDKSFGSSLMESEVNLDRYQTALEEVLSWLLSAEDTLQAQGEISNDVEVVKDQFHTHEGY MMDLTAHQGRVGNILQLGSKLIGTGKLSEDEETEVQEQMNLLNSRWECLRVASMEKQSNLHRVLMDLQNQKLKELND WLTKTEERTRKMEEEPLGPDLEDLKRQVQQHKVLQEDLEQEQVRVNSLTHMVVVVDESSGDHATAALEEQLKVLGDR WANICRWTEDRWVLLQDILLKWQRLTEEQCLFSAWLSEKEDAVNKIHTTGFKDQNEMLSSLQKLAVLKADLEKKKQS MGKLYSLKQDLLSTLKNKSVTQKTEAWLDNFARCWDNLVQKLEKSTAQISQAVTTTQPSLTQTTVMETVTTVTTREQ ILVKHAQEELPPPPPQKKRQITVDSEIRKRLDVDITELHSWITRSEAVLQSPEFAIFRKEGNFSDLKEKVNAIEREK AEKFRKLQDASRSAQALVEQMVNEGVNADSIKQASEQLNSRWIEFCQLLSERLNWLEYQNNIIAFYNQLQQLEQMTT 25 24028 / / SLW 875.245WO1 TAENWLKIQPTTPSEPTAIKSQLKICKDEVNRLSGLQPQIERLKIQSIALKEKGQGPMFLDADFVAFTNHFKQVFSD VQAREKELQTIFDTLPPMRYQETMSAIRTWVQQSETKLSIPQLSVTDYEIMEQRLGELQALQSSLQEQQSGLYYLST TVKEMSKKAPSEISRKYQSEFEEIEGRWKKLSSQLVEHCQKLEEQMNKLRKIQNHIQTLKKWMAEVDVFLKEEWPAL GDSEILKKQLKQCRLLVSDIQTIQPSLNSVNEGGQKIKNEAEPEFASRLETELKELNTQWDHMCQQVYARKEALKGG LEKTVSLQKDLSEMHEWMTQAEEEYLERDFEYKTPDELQKAVEEMKRAKEEAQQKEAKVKLLTESVNSVIAQAPPVA QEALKKELETLTTNYQWLCTRLNGKCKTLEEVWACWHELLSYLEKANKWLNEVEFKLKTTENIPGGAEEISEVLDSL ENLMRHSEDNPNQIRILAQTLTDGGVMDELINEELETFNSRWRELHEEAVRRQKLLEQSIQSAQETEKSLHLIQESL TFIDKQLAAYIADKVDAAQMPQEAQKIQSDLTSHEISLEEMKKHNQGKEAAQRVLSQIDVAQKKLQDVSMKFRLFQK PANFELRLQESKMILDEVKMHLPALETKSVEQEVVQSQLNHCVNLYKSLSEVKSEVEMVIKTGRQIVQKKQTENPKE LDERVTALKLHYNELGAKVTERKQQLEKCLKLSRKMRKEMNVLTEWLAATDMELTKRSAVEGMPSNLDSEVAWGKAT QKEIEKQKVHLKSITEVGEALKTVLGKKETLVEDKLSLLNSNWIAVTSRAEEWLNLLLEYQKHMETFDQNVDHITKW IIQADTLLDESEKKKPQQKEDVLKRLKAELNDIRPKVDSTRDQAANLMANRGDHCRKLVEPQISELNHRFAAISHRI KTGKASIPLKELEQFNSDIQKLLEPLEAEIQQGVNLKEEDFNKDMNEDNEGTVKELLQRGDNLQQRITDERKREEIK IKQQLLQTKHNALKDLRSQRRKKALEISHQWYQYKRQADDLLKCLDDIEKKLASLPEPRDERKIKEIDRELQKKKEE LNAVRRQAEGLSEDGAAMAVEPTQIQLSKRWREIESKFAQFRRLNFAQIHTVREETMMVMTEDMPLEISYVPSTYLT EITHVSQALLEVEQLLNAPDLCAKDFEDLFKQEESLKNIKDSLQQSSGRIDIIHSKKTAALQSATPVERVKLQEALS QLDFQWEKVNKMYKDRQGRFDRSVEKWRRFHYDIKIFNQWLTEAEQFLRKTQIPENWEHAKYKWYLKELQDGIGQRQ TVVRTLNATGEEIIQQSSKTDASILQEKLGSLNLRWQEVCKQLSDRKKRLEEQKNILSEFQRDLNEFVLWLEEADNI ASIPLEPGKEQQLKEKLEQVKLLVEELPLRQGILKQLNETGGPVLVSAPISPEEQDKLENKLKQTNLQWIKVSRALP EKQGEIEAQIKDLGQLEKKLEDLEEQLNHLLLWLSPIRNQLEIYNQPNQEGPFDVQETEIAVQAKQPDVEEILSKGQ HLYKEKPATQPVKRKLEDLSSEWKAVNRLLQELRAKQPDLAPGLTTIGASPTQTVTLVTQPVVTKETAISKLEMPSS LMLEVPALADFNRAWTELTDWLSLLDQVIKSQRVMVGDLEDINEMIIKQKATMQDLEQRRPQLEELITAAQNLKNKT SNQEARTIITDRIERIQNQWDEVQEHLQNRRQQLNEMLKDSTQWLEAKEEAEQVLGQARAKLESWKEGPYTVDAIQK KITETKQLAKDLRQWQTNVDVANDLALKLLRDYSADDTRKVHMITENINASWRSIHKRVSEREAALEETHRLLQQFP LDLEKFLAWLTEAETTANVLQDATRKERLLEDSKGVKELMKQWQDLQGEIEAHTDVYHNLDENSQKILRSLEGSDDA VLLQRRLDNMNFKWSELRKKSLNIRSHLEASSDQWKRLHLSLQELLVWLQLKDDELSRQAPIGGDFPAVQKQNDVHR AFKRELKTKEPVIMSTLETVRIFLTEQPLEGLEKLYQEPRELPPEERAQNVTRLLRKQAEEVNTEWEKLNLHSADWQ RKIDETLERLQELQEATDELDLKLRQAEVIKGSWQPVGDLLIDSLQDHLEKVKALRGEIAPLKENVSHVNDLARQLT TLGIQLSPYNLSTLEDLNTRWKLLQVAVEDRVRQLHEAHRDFGPASQHFLSTSVQGPWERAISPNKVPYYINHETQT TCWDHPKMTELYQSLADLNNVRFSAYRTAMKLRRLQKALCLDLLSLSAACDALDQHNLKQNDQPMDILQIINCLTTI YDRLEQEHNNLVNVPLCVDMCLNWLLNVYDTGRTGRIRVLSFKTGIISLCKAHLEDKYRYLFKQVASSTGFCDQRRL GLLLHDSIQIPRQLGEVASFGGSNIEPSVRSCFQFANNKPEIEAALFLDWMRLEPQSMVWLPVLHRVAAAETAKHQA KCNICKECPIIGFRYRSLKHFNYDICQSCFFSGRVAKGHKMHYPMVEYCTPTTSGEDVRDFAKVLKNKFRTKRYFAK HPRMGYLPVQTVLEGDNMETPVTLINFWPVDSAPASSPQLSHDDTHSRIEHYASRLAEMENSNGSYLNDSISPNESI DDEHLLIQHYCQSLNQDSPLSQPRSPAQILISLESEERGELERILADLEEENRNLQAEYDRLKQQHEHKGLSPLPSP PEMMPTSPQSPRDAELIAEAKLLRQHKGRLEARMQILEDHNKQLESQLHRLRQLLEQPQAEAKVNGTTVSSPSTSLQ RSDSSQPMLLRVVGSQTSDSMGEEDLLSPPQDTSTGLEEVMEQLNNSFPSSRGRNTPGKPMREDTM* SEQ ID NO: 15 (UTRN nt, human) ATGGCCAAGTATGGAGAACATGAAGCCAGTCCTGACAATGGGCAGAACGAATTCAGTGATATCATTAAGTCCAGATC TGATGAACACAATGACGTACAGAAGAAAACCTTTACCAAATGGATAAATGCTCGATTTTCAAAGAGTGGGAAACCAC CCATCAATGATATGTTCACAGACCTCAAAGATGGAAGGAAGCTATTGGATCTTCTAGAAGGCCTCACAGGAACATCA CTGCCAAAGGAACGTGGTTCCACAAGGGTACATGCCTTAAATAACGTCAACAGAGTGCTGCAGGTTTTACATCAGAA CAATGTGGAATTAGTGAATATAGGGGGAACTGACATTGTGGATGGAAATCACAAACTGACTTTGGGGTTACTTTGGA GCATCATTTTGCACTGGCAGGTGAAAGATGTCATGAAGGATGTCATGTCGGACCTGCAGCAGACGAACAGTGAGAAG ATCCTGCTCAGCTGGGTGCGTCAGACCACCAGGCCCTACAGCCAAGTCAACGTCCTCAACTTCACCACCAGCTGGAC AGATGGACTCGCCTTTAATGCTGTCCTCCACCGACATAAACCTGATCTCTTCAGCTGGGATAAAGTTGTCAAAATGT CACCAATTGAGAGACTTGAACATGCCTTCAGCAAGGCTCAAACTTATTTGGGAATTGAAAAGCTGTTAGATCCTGAA GATGTTGCCGTTCAGCTTCCTGACAAGAAATCCATAATTATGTATTTAACATCTTTGTTTGAGGTGCTACCTCAGCA AGTCACCATAGACGCCATCCGTGAGGTAGAGACACTCCCAAGGAAATATAAAAAAGAATGTGAAGAAGAGGCAATTA ATATACAGAGTACAGCGCCTGAGGAGGAGCATGAGAGTCCCCGAGCTGAAACTCCCAGCACTGTCACTGAGGTTGAC ATGGATCTGGACAGCTATCAGATTGCGTTGGAGGAAGTGCTGACCTGGTTGCTTTCTGCTGAGGACACTTTCCAGGA GCAGGATGATATTTCTGATGATGTTGAAGAAGTCAAAGACCAGTTTGCAACCCATGAAGCTTTTATGATGGAACTGA CTGCACACCAGAGCAGTGTGGGCAGCGTCCTGCAGGCAGGCAACCAACTGATAACACAAGGAACTCTGTCAGACGAA GAAGAATTTGAGATTCAGGAACAGATGACCCTGCTGAATGCTAGATGGGAGGCTCTTAGGGTGGAGAGTATGGACAG ACAGTCCCGGCTGCACGATGTGCTGATGGAACTGCAGAAGAAGCAACTGCAGCAGCTCTCCGCCTGGTTAACACTCA CAGAGGAGCGCATTCAGAAGATGGAAACTTGCCCCCTGGATGATGATGTAAAATCTCTACAAAAGCTGCTAGAAGAA 26 24028 / / SLW 875.245WO1 CATAAAAGTTTGCAAAGTGATCTTGAGGCTGAACAGGTGAAAGTAAATTCACTAACTCACATGGTGGTCATTGTTGA TGAAAACAGTGGTGAGAGTGCTACAGCTATCCTAGAAGACCAGTTACAGAAACTTGGTGAGCGCTGGACAGCAGTAT GCCGTTGGACTGAAGAACGCTGGAATAGGTTACAAGAAATCAATATATTGTGGCAGGAATTATTGGAAGAACAGTGC TTGTTGAAAGCTTGGTTAACCGAAAAAGAAGAGGCTTTAAATAAAGTCCAGACAAGCAACTTCAAAGACCAAAAGGA ACTAAGTGTCAGTGTTCGACGTCTGGCTATTTTGAAGGAAGACATGGAAATGAAGCGTCAAACATTGGATCAGCTGA GTGAGATTGGCCAGGATGTGGGACAATTACTTGATAATTCCAAGGCATCTAAGAAGATCAACAGTGACTCAGAGGAA CTGACTCAAAGATGGGATTCTTTGGTTCAGAGACTAGAAGATTCCTCCAACCAGGTGACTCAGGCTGTAGCAAAGCT GGGGATGTCTCAGATTCCTCAGAAGGACCTTTTGGAGACTGTTCGTGTAAGAGAACAAGCAATTACAAAAAAATCTA AGCAGGAACTGCCTCCTCCTCCTCCCCCAAAGAAGAGACAGATCCATGTGGATATTGAAGCTAAGAAAAAGTTTGAT GCTATAAGTGCAGAGCTGTTGAACTGGATTTTGAAATGGAAAACTGCCATTCAGACCACAGAGATAAAAGAGTATAT GAAGATGCAAGACACTTCCGAAATGAAAAAGAAGTTGAAGGCATTAGAAAAAGAACAGAGAGAAAGAATCCCCAGAG CAGATGAATTAAACCAAACTGGACAAATCCTTGTGGAGCAAATGGGAAAAGAAGGCCTTCCTACTGAAGAAATAAAA AATGTTCTGGAGAAGGTTTCATCAGAATGGAAGAATGTATCTCAACATTTGGAAGATCTAGAAAGAAAGATTCAGCT ACAGGAAGATATAAATGCTTATTTCAAGCAGCTTGATGAGCTTGAAAAGGTCATCAAGACAAAGGAGGAGTGGGTAA AACACACTTCCATTTCTGAATCTTCCCGGCAGTCCTTGCCAAGCTTGAAGGATTCCTGTCAGCGGGAATTGACAAAT CTTCTTGGCCTTCACCCCAAAATTGAAATGGCTCGTGCAAGCTGCTCGGCCCTGATGTCTCAGCCTTCTGCCCCAGA TTTTGTCCAGCGGGGCTTCGATAGCTTTCTGGGCCGCTACCAAGCTGTACAAGAGGCTGTAGAGGATCGTCAACAAC ATCTAGAGAATGAACTGAAGGGCCAACCTGGACATGCATATCTGGAAACATTGAAAACACTGAAAGATGTGCTAAAT GATTCAGAAAATAAGGCCCAGGTGTCTCTGAATGTCCTTAATGATCTTGCCAAGGTGGAGAAGGCCCTGCAAGAAAA AAAGACCCTTGATGAAATCCTTGAGAATCAGAAACCTGCATTACATAAACTTGCAGAAGAAACAAAGGCTCTGGAGA AAAATGTTCATCCTGATGTAGAAAAATTATATAAGCAAGAATTTGATGATGTGCAAGGAAAGTGGAACAAGCTAAAG GTCTTGGTTTCCAAAGATCTACATTTGCTTGAGGAAATTGCTCTCACACTCAGAGCTTTTGAGGCCGATTCAACAGT CATTGAGAAGTGGATGGATGGCGTGAAAGACTTCTTAATGAAACAGCAGGCTGCCCAAGGAGACGACGCAGGTCTAC AGAGGCAGTTAGACCAGTGCTCTGCATTTGTTAATGAAATAGAAACAATTGAATCATCTCTGAAAAACATGAAGGAA ATAGAGACTAATCTTCGAAGTGGTCCAGTTGCTGGAATAAAAACTTGGGTGCAGACAAGACTAGGTGACTACCAAAC TCAACTGGAGAAACTTAGCAAGGAGATCGCTACTCAAAAAAGTAGGTTGTCTGAAAGTCAAGAAAAAGCTGCGAACC TGAAGAAAGACTTGGCAGAGATGCAGGAATGGATGACCCAGGCCGAGGAAGAATATTTGGAGCGGGATTTTGAGTAC AAGTCACCAGAAGAGCTTGAGAGTGCTGTGGAAGAGATGAAGAGGGCAAAAGAGGATGTGTTGCAGAAGGAGGTGAG AGTGAAGATTCTCAAGGACAACATCAAGTTATTAGCTGCCAAGGTGCCCTCTGGTGGCCAGGAGTTGACGTCTGAGC TGAATGTTGTGCTGGAGAATTACCAACTTCTTTGTAATAGAATTCGAGGAAAGTGCCACACGCTAGAGGAGGTCTGG TCTTGTTGGATTGAACTGCTTCACTATTTGGATCTTGAAACTACCTGGTTAAACACTTTGGAAGAGCGGATGAAGAG CACAGAGGTCCTGCCTGAGAAGACGGATGCTGTCAACGAAGCCCTGGAGTCTCTGGAATCTGTTCTGCGCCACCCGG CAGATAATCGCACCCAGATTCGAGAGCTTGGCCAGACTCTGATTGATGGGGGGATCCTGGATGATATAATCAGTGAG AAACTGGAGGCTTTCAACAGCCGATATGAAGATCTAAGTCACCTGGCAGAGAGCAAGCAGATTTCTTTGGAAAAGCA ACTCCAGGTGCTGCGGGAAACTGACCAGATGCTTCAAGTCTTGCAAGAGAGCTTGGGGGAGCTGGACAAACAGCTCA CCACATACCTGACTGACAGGATAGATGCTTTCCAAGTTCCACAGGAAGCTCAGAAAATCCAAGCAGAGATCTCAGCC CATGAGCTAACCCTAGAGGAGTTGAGAAGAAATATGCGTTCTCAGCCCCTGACCTCCCCAGAGAGTAGGACTGCCAG AGGAGGAAGTCAGATGGATGTGCTACAGAGGAAACTCCGAGAGGTGTCCACAAAGTTCCAGCTTTTCCAGAAGCCAG CTAACTTCGAGCAGCGCATGCTGGACTGCAAGCGTGTGCTGGATGGCGTGAAAGCAGAACTTCACGTTCTGGATGTG AAGGACGTAGACCCTGACGTCATACAGACGCACCTGGACAAGTGTATGAAACTGTATAAAACTTTGAGTGAAGTCAA ACTTGAAGTGGAAACTGTGATTAAAACAGGAAGACATATTGTCCAGAAACAGCAAACGGACAACCCAAAAGGGATGG ATGAGCAGCTGACTTCCCTGAAGGTTCTTTACAATGACCTGGGCGCACAGGTGACAGAAGGAAAACAGGATCTGGAA AGAGCATCACAGTTGGCCCGGAAAATGAAGAAAGAGGCTGCTTCTCTCTCTGAATGGCTTTCTGCTACTGAAACTGA ATTGGTACAGAAGTCCACTTCAGAAGGTCTGCTTGGTGACTTGGATACAGAAATTTCCTGGGCTAAAAATGTTCTGA AGGATCTGGAAAAGAGAAAAGCTGATTTAAATACCATCACAGAGAGTAGTGCTGCCCTGCAAAACTTGATTGAGGGC AGTGAGCCTATTTTAGAAGAGAGGCTCTGCGTCCTTAACGCTGGGTGGAGCCGAGTTCGTACCTGGACTGAAGATTG GTGCAATACCTTGATGAACCATCAGAACCAGCTAGAAATATTTGATGGGAACGTGGCTCACATAAGTACCTGGCTTT ATCAAGCTGAAGCTCTATTGGATGAAATTGAAAAGAAACCAACAAGTAAACAGGAAGAAATTGTGAAGCGTTTAGTA TCTGAGCTGGATGATGCCAACCTCCAGGTTGAAAATGTCCGCGATCAAGCCCTTATTTTGATGAATGCCCGTGGAAG CTCAAGCAGGGAGCTTGTAGAACCAAAGTTAGCTGAGCTGAATAGGAACTTTGAAAAGGTGTCTCAACATATCAAAA GTGCCAAATTGCTAATTGCTCAGGAACCATTATACCAATGTTTGGTCACCACTGAAACATTTGAAACTGGTGTGCCT TTCTCTGACTTGGAAAAATTAGAAAATGACATAGAAAATATGTTAAAATTTGTGGAAAAACACTTGGAATCCAGTGA TGAAGATGAAAAGATGGATGAGGAGAGTGCCCAGATTGAGGAAGTTCTACAAAGAGGAGAAGAAATGTTACATCAAC CTATGGAAGATAATAAAAAAGAAAAGATCCGTTTGCAATTATTACTTTTGCATACTAGATACAACAAAATTAAGGCA ATCCCTATTCAACAGAGGAAAATGGGTCAACTTGCTTCTGGAATTAGATCATCACTTCTTCCTACAGATTATCTGGT TGAAATTAACAAAATTTTACTTTGCATGGATGATGTTGAATTATCGCTTAATGTTCCAGAGCTCAACACTGCTATTT ACGAAGACTTCTCTTTTCAGGAAGACTCTCTGAAGAATATCAAAGACCAACTGGACAAACTTGGAGAGCAGATTGCA GTCATTCATGAAAAACAGCCAGATGTCATCCTTGAAGCCTCTGGACCTGAAGCCATTCAGATCAGAGATACACTTAC 27 24028 / / SLW 875.245WO1 TCAGCTGAATGCAAAATGGGACAGAATTAATAGAATGTACAGTGATCGGAAAGGTTGTTTTGACAGGGCAATGGAAG AATGGAGACAGTTCCATTGTGACCTTAATGACCTCACACAGTGGATAACAGAGGCTGAAGAATTACTGGTTGATACC TGTGCTCCAGGTGGCAGCCTGGACTTAGAGAAAGCCAGGATACATCAGCAGGAACTTGAGGTGGGCATCAGCAGCCA CCAGCCCAGTTTTGCAGCACTAAACCGAACTGGGGATGGGATTGTGCAGAAACTCTCCCAGGCAGATGGAAGCTTCT TGAAAGAAAAACTGGCAGGTTTAAACCAACGCTGGGATGCAATTGTTGCAGAAGTGAAGGATAGGCAGCCAAGGCTA AAAGGAGAAAGTAAGCAGGTGATGAAGTACAGGCATCAGCTAGATGAGATTATCTGTTGGTTAACAAAGGCTGAGCA TGCTATGCAAAAGAGATCAACCACCGAATTGGGAGAAAACCTGCAAGAATTAAGAGACTTAACTCAAGAAATGGAAG TACATGCTGAAAAACTCAAATGGCTGAATAGAACTGAATTGGAGATGCTTTCAGATAAAAGTCTGAGTTTACCTGAA AGGGATAAAATTTCAGAAAGCTTAAGGACTGTAAATATGACATGGAATAAGATTTGCAGAGAGGTGCCTACCACCCT GAAGGAATGCATCCAGGAGCCCAGTTCTGTTTCACAGACAAGGATTGCTGCTCATCCTAATGTCCAAAAGGTGGTGC TAGTATCATCTGCGTCAGATATTCCTGTTCAGTCTCATCGTACTTCGGAAATTTCAATTCCTGCTGATCTTGATAAA ACTATAACAGAACTAGCCGACTGGCTGGTATTAATCGACCAGATGCTGAAGTCCAACATTGTCACTGTTGGGGATGT AGAAGAGATCAATAAGACCGTTTCCCGAATGAAAATTACAAAGGCTGACTTAGAACAGCGCCATCCTCAGCTGGATT ATGTTTTTACATTGGCACAGAATTTGAAAAATAAAGCTTCCAGTTCAGATATGAGAACAGCAATTACAGAAAAATTG GAAAGGGTCAAGAACCAGTGGGATGGCACCCAGCATGGCGTTGAGCTAAGACAGCAGCAGCTTGAGGACATGATTAT TGACAGTCTTCAGTGGGATGACCATAGGGAGGAGACTGAAGAACTGATGAGAAAATATGAGGCTCGACTCTATATTC TTCAGCAAGCCCGACGGGATCCACTCACCAAACAAATTTCTGATAACCAAATACTGCTTCAAGAACTGGGTCCTGGA GATGGTATCGTCATGGCGTTCGATAACGTCCTGCAGAAACTCCTGGAGGAATATGGGAGTGATGACACAAGGAATGT GAAAGAAACCACAGAGTACTTAAAAACATCATGGATCAATCTCAAACAAAGTATTGCTGACAGACAGAACGCCTTGG AGGCTGAGTGGAGGACGGTGCAGGCCTCTCGCAGAGATCTGGAAAACTTCCTGAAGTGGATCCAAGAAGCAGAGACC ACAGTGAATGTGCTTGTGGATGCCTCTCATCGGGAGAATGCTCTTCAGGATAGTATCTTGGCCAGGGAACTCAAACA GCAGATGCAGGACATCCAGGCAGAAATTGATGCCCACAATGACATATTTAAAAGCATTGACGGAAACAGGCAGAAGA TGGTAAAAGCTTTGGGAAATTCTGAAGAGGCTACTATGCTTCAACATCGACTGGATGATATGAACCAAAGATGGAAT GACTTAAAAGCAAAATCTGCTAGCATCAGGGCCCATTTGGAGGCCAGCGCTGAGAAGTGGAACAGGTTGCTGATGTC CTTAGAAGAACTGATCAAATGGCTGAATATGAAAGATGAAGAGCTTAAGAAACAAATGCCTATTGGAGGAGATGTTC CAGCCTTACAGCTCCAGTATGACCATTGTAAGGCCCTGAGACGGGAGTTAAAGGAGAAAGAATATTCTGTCCTGAAT GCTGTCGACCAGGCCCGAGTTTTCTTGGCTGATCAGCCAATTGAGGCCCCTGAAGAGCCAAGAAGAAACCTACAATC AAAAACAGAATTAACTCCTGAGGAGAGAGCCCAAAAGATTGCCAAAGCCATGCGCAAACAGTCTTCTGAAGTCAAAG AAAAATGGGAAAGTCTAAATGCTGTAACTAGCAATTGGCAAAAGCAAGTGGACAAGGCATTGGAGAAACTCAGAGAC CTGCAGGGAGCTATGGATGACCTGGACGCTGACATGAAGGAGGCAGAGTCCGTGCGGAATGGCTGGAAGCCCGTGGG AGACTTACTCATTGACTCGCTGCAGGATCACATTGAAAAAATCATGGCATTTAGAGAAGAAATTGCACCAATCAACT TTAAAGTTAAAACGGTGAATGATTTATCCAGTCAGCTGTCTCCACTTGACCTGCATCCCTCTCTAAAGATGTCTCGC CAGCTAGATGACCTTAATATGCGATGGAAACTTTTACAGGTTTCTGTGGATGATCGCCTTAAACAGCTTCAGGAAGC CCACAGAGATTTTGGACCATCCTCTCAGCATTTTCTCTCTACGTCAGTCCAGCTGCCGTGGCAAAGATCCATTTCAC ATAATAAAGTGCCCTATTACATCAACCATCAAACACAGACCACCTGTTGGGACCATCCTAAAATGACCGAACTCTTT CAATCCCTTGCTGACCTGAATAATGTACGTTTTTCTGCCTACCGTACAGCAATCAAAATCCGAAGACTACAAAAAGC ACTATGTTTGGATCTCTTAGAGTTGAGTACAACAAATGAAATTTTCAAACAGCACAAGTTGAACCAAAATGACCAGC TCCTCAGTGTTCCAGATGTCATCAACTGTCTGACAACAACTTATGATGGACTTGAGCAAATGCATAAGGACCTGGTC AACGTTCCACTCTGTGTTGATATGTGTCTCAATTGGTTGCTCAATGTCTATGACACGGGTCGAACTGGAAAAATTAG AGTGCAGAGTCTGAAGATTGGATTAATGTCTCTCTCCAAAGGTCTCTTGGAAGAAAAATACAGATATCTCTTTAAGG AAGTTGCAGGGCCAACAGAAATGTGTGACCAGAGGCAGCTGGGCCTGTTACTTCATGATGCCATCCAGATCCCCCGG CAGCTAGGTGAAGTAGCAGCTTTTGGAGGCAGTAATATTGAGCCTAGTGTTCGCAGCTGCTTCCAACAGAATAACAA TAAACCAGAAATAAGTGTGAAAGAGTTTATAGATTGGATGCATTTGGAACCACAGTCCATGGTTTGGCTCCCAGTTT TACATCGAGTGGCAGCAGCGGAGACTGCAAAACATCAGGCCAAATGCAACATCTGTAAAGAATGTCCAATTGTCGGG TTCAGGTATAGAAGCCTTAAGCATTTTAACTATGATGTCTGCCAGAGTTGTTTCTTTTCGGGTCGAACAGCAAAAGG TCACAAATTACATTACCCAATGGTGGAATATTGTATACCTACAACATCTGGGGAAGATGTACGAGACTTCACAAAGG TACTTAAGAACAAGTTCAGGTCGAAGAAGTACTTTGCCAAACACCCTCGACTTGGTTACCTGCCTGTCCAGACAGTT CTTGAAGGTGACAACTTAGAGACTCCTATCACACTCATCAGTATGTGGCCAGAGCACTATGACCCCTCACAATCTCC TCAACTGTTTCATGATGACACCCATTCAAGAATAGAACAATATGCCACACGACTGGCCCAGATGGAAAGGACTAATG GGTCTTTTCTCACTGATAGCAGCTCCACCACAGGAAGTGTGGAAGACGAGCACGCCCTCATCCAGCAGTATTGCCAA ACACTCGGAGGAGAGTCCCCAGTGAGCCAGCCGCAGAGCCCAGCTCAGATCCTGAAGTCAGTAGAGAGGGAAGAACG TGGAGAACTGGAGAGGATCATTGCTGACCTGGAGGAAGAACAAAGAAATCTACAGGTGGAGTATGAGCAGCTGAAGG ACCAGCACCTCCGAAGGGGGCTCCCTGTCGGTTCACCGCCAGAGTCGATTATATCTCCCCATCACACGTCTGAGGAT TCAGAACTTATAGCAGAAGCAAAACTCCTCAGGCAGCACAAAGGTCGGCTGGAGGCTAGGATGCAGATTTTAGAAGA TCACAATAAACAGCTGGAGTCTCAGCTCCACCGCCTCCGACAGCTGCTGGAGCAGCCTGAATCTGATTCCCGAATCA ATGGTGTTTCCCCATGGGCTTCTCCTCAGCATTCTGCACTGAGCTACTCGCTTGATCCAGATGCCTCCGGCCCACAG TTCCACCAGGCAGCGGGAGAGGACCTGCTGGCCCCACCGCACGACACCAGCACGGATCTCACGGAGGTCATGGAGCA GATTCACAGCACGTTTCCATCTTGCTGCCCAAATGTTCCCAGCAGGCCACAGGCAATGTGA 28 24028 / / SLW 875.245WO1 SEQ ID NO: 16 (UTRN aa, human) MAKYGEHEASPDNGQNEFSDIIKSRSDEHNDVQKKTFTKWINARFSKSGKPPINDMFTDLKDGRKLLDLLEGLTGTS LPKERGSTRVHALNNVNRVLQVLHQNNVELVNIGGTDIVDGNHKLTLGLLWSIILHWQVKDVMKDVMSDLQQTNSEK ILLSWVRQTTRPYSQVNVLNFTTSWTDGLAFNAVLHRHKPDLFSWDKVVKMSPIERLEHAFSKAQTYLGIEKLLDPE DVAVQLPDKKSIIMYLTSLFEVLPQQVTIDAIREVETLPRKYKKECEEEAINIQSTAPEEEHESPRAETPSTVTEVD MDLDSYQIALEEVLTWLLSAEDTFQEQDDISDDVEEVKDQFATHEAFMMELTAHQSSVGSVLQAGNQLITQGTLSDE EEFEIQEQMTLLNARWEALRVESMDRQSRLHDVLMELQKKQLQQLSAWLTLTEERIQKMETCPLDDDVKSLQKLLEE HKSLQSDLEAEQVKVNSLTHMVVIVDENSGESATAILEDQLQKLGERWTAVCRWTEERWNRLQEINILWQELLEEQC LLKAWLTEKEEALNKVQTSNFKDQKELSVSVRRLAILKEDMEMKRQTLDQLSEIGQDVGQLLDNSKASKKINSDSEE LTQRWDSLVQRLEDSSNQVTQAVAKLGMSQIPQKDLLETVRVREQAITKKSKQELPPPPPPKKRQIHVDIEAKKKFD AISAELLNWILKWKTAIQTTEIKEYMKMQDTSEMKKKLKALEKEQRERIPRADELNQTGQILVEQMGKEGLPTEEIK NVLEKVSSEWKNVSQHLEDLERKIQLQEDINAYFKQLDELEKVIKTKEEWVKHTSISESSRQSLPSLKDSCQRELTN LLGLHPKIEMARASCSALMSQPSAPDFVQRGFDSFLGRYQAVQEAVEDRQQHLENELKGQPGHAYLETLKTLKDVLN DSENKAQVSLNVLNDLAKVEKALQEKKTLDEILENQKPALHKLAEETKALEKNVHPDVEKLYKQEFDDVQGKWNKLK VLVSKDLHLLEEIALTLRAFEADSTVIEKWMDGVKDFLMKQQAAQGDDAGLQRQLDQCSAFVNEIETIESSLKNMKE IETNLRSGPVAGIKTWVQTRLGDYQTQLEKLSKEIATQKSRLSESQEKAANLKKDLAEMQEWMTQAEEEYLERDFEY KSPEELESAVEEMKRAKEDVLQKEVRVKILKDNIKLLAAKVPSGGQELTSELNVVLENYQLLCNRIRGKCHTLEEVW SCWIELLHYLDLETTWLNTLEERMKSTEVLPEKTDAVNEALESLESVLRHPADNRTQIRELGQTLIDGGILDDIISE KLEAFNSRYEDLSHLAESKQISLEKQLQVLRETDQMLQVLQESLGELDKQLTTYLTDRIDAFQVPQEAQKIQAEISA HELTLEELRRNMRSQPLTSPESRTARGGSQMDVLQRKLREVSTKFQLFQKPANFEQRMLDCKRVLDGVKAELHVLDV KDVDPDVIQTHLDKCMKLYKTLSEVKLEVETVIKTGRHIVQKQQTDNPKGMDEQLTSLKVLYNDLGAQVTEGKQDLE RASQLARKMKKEAASLSEWLSATETELVQKSTSEGLLGDLDTEISWAKNVLKDLEKRKADLNTITESSAALQNLIEG SEPILEERLCVLNAGWSRVRTWTEDWCNTLMNHQNQLEIFDGNVAHISTWLYQAEALLDEIEKKPTSKQEEIVKRLV SELDDANLQVENVRDQALILMNARGSSSRELVEPKLAELNRNFEKVSQHIKSAKLLIAQEPLYQCLVTTETFETGVP FSDLEKLENDIENMLKFVEKHLESSDEDEKMDEESAQIEEVLQRGEEMLHQPMEDNKKEKIRLQLLLLHTRYNKIKA IPIQQRKMGQLASGIRSSLLPTDYLVEINKILLCMDDVELSLNVPELNTAIYEDFSFQEDSLKNIKDQLDKLGEQIA VIHEKQPDVILEASGPEAIQIRDTLTQLNAKWDRINRMYSDRKGCFDRAMEEWRQFHCDLNDLTQWITEAEELLVDT CAPGGSLDLEKARIHQQELEVGISSHQPSFAALNRTGDGIVQKLSQADGSFLKEKLAGLNQRWDAIVAEVKDRQPRL KGESKQVMKYRHQLDEIICWLTKAEHAMQKRSTTELGENLQELRDLTQEMEVHAEKLKWLNRTELEMLSDKSLSLPE RDKISESLRTVNMTWNKICREVPTTLKECIQEPSSVSQTRIAAHPNVQKVVLVSSASDIPVQSHRTSEISIPADLDK TITELADWLVLIDQMLKSNIVTVGDVEEINKTVSRMKITKADLEQRHPQLDYVFTLAQNLKNKASSSDMRTAITEKL ERVKNQWDGTQHGVELRQQQLEDMIIDSLQWDDHREETEELMRKYEARLYILQQARRDPLTKQISDNQILLQELGPG DGIVMAFDNVLQKLLEEYGSDDTRNVKETTEYLKTSWINLKQSIADRQNALEAEWRTVQASRRDLENFLKWIQEAET TVNVLVDASHRENALQDSILARELKQQMQDIQAEIDAHNDIFKSIDGNRQKMVKALGNSEEATMLQHRLDDMNQRWN DLKAKSASIRAHLEASAEKWNRLLMSLEELIKWLNMKDEELKKQMPIGGDVPALQLQYDHCKALRRELKEKEYSVLN AVDQARVFLADQPIEAPEEPRRNLQSKTELTPEERAQKIAKAMRKQSSEVKEKWESLNAVTSNWQKQVDKALEKLRD LQGAMDDLDADMKEAESVRNGWKPVGDLLIDSLQDHIEKIMAFREEIAPINFKVKTVNDLSSQLSPLDLHPSLKMSR QLDDLNMRWKLLQVSVDDRLKQLQEAHRDFGPSSQHFLSTSVQLPWQRSISHNKVPYYINHQTQTTCWDHPKMTELF QSLADLNNVRFSAYRTAIKIRRLQKALCLDLLELSTTNEIFKQHKLNQNDQLLSVPDVINCLTTTYDGLEQMHKDLV NVPLCVDMCLNWLLNVYDTGRTGKIRVQSLKIGLMSLSKGLLEEKYRYLFKEVAGPTEMCDQRQLGLLLHDAIQIPR QLGEVAAFGGSNIEPSVRSCFQQNNNKPEISVKEFIDWMHLEPQSMVWLPVLHRVAAAETAKHQAKCNICKECPIVG FRYRSLKHFNYDVCQSCFFSGRTAKGHKLHYPMVEYCIPTTSGEDVRDFTKVLKNKFRSKKYFAKHPRLGYLPVQTV LEGDNLETPITLISMWPEHYDPSQSPQLFHDDTHSRIEQYATRLAQMERTNGSFLTDSSSTTGSVEDEHALIQQYCQ TLGGESPVSQPQSPAQILKSVEREERGELERIIADLEEEQRNLQVEYEQLKDQHLRRGLPVGSPPESIISPHHTSED SELIAEAKLLRQHKGRLEARMQILEDHNKQLESQLHRLRQLLEQPESDSRINGVSPWASPQHSALSYSLDPDASGPQ FHQAAGEDLLAPPHDTSTDLTEVMEQIHSTFPSCCPNVPSRPQAM* SEQ ID NO: 17 (ITGB3 nt, human) ATGCGAGCGCGGCCGCGGCCCCGGCCGCTCTGGGCGACTGTGCTGGCGCTGGGGGCGCTGGCGGGCGTTGGCGTAGG AGGGCCCAACATCTGTACCACGCGAGGTGTGAGCTCCTGCCAGCAGTGCCTGGCTGTGAGCCCCATGTGTGCCTGGT GCTCTGATGAGGCCCTGCCTCTGGGCTCACCTCGCTGTGACCTGAAGGAGAATCTGCTGAAGGATAACTGTGCCCCA GAATCCATCGAGTTCCCAGTGAGTGAGGCCCGAGTACTAGAGGACAGGCCCCTCAGCGACAAGGGCTCTGGAGACAG CTCCCAGGTCACTCAAGTCAGTCCCCAGAGGATTGCACTCCGGCTCCGGCCAGATGATTCGAAGAATTTCTCCATCC AAGTGCGGCAGGTGGAGGATTACCCTGTGGACATCTACTACTTGATGGACCTGTCTTACTCCATGAAGGATGATCTG TGGAGCATCCAGAACCTGGGTACCAAGCTGGCCACCCAGATGCGAAAGCTCACCAGTAACCTGCGGATTGGCTTCGG GGCATTTGTGGACAAGCCTGTGTCACCATACATGTATATCTCCCCACCAGAGGCCCTCGAAAACCCCTGCTATGATA 29 24028 / / SLW 875.245WO1 TGAAGACCACCTGCTTGCCCATGTTTGGCTACAAACACGTGCTGACGCTAACTGACCAGGTGACCCGCTTCAATGAG GAAGTGAAGAAGCAGAGTGTGTCACGGAACCGAGATGCCCCAGAGGGTGGCTTTGATGCCATCATGCAGGCTACAGT CTGTGATGAAAAGATTGGCTGGAGGAATGATGCATCCCACTTGCTGGTGTTTACCACTGATGCCAAGACTCATATAG CATTGGACGGAAGGCTGGCAGGCATTGTCCAGCCTAATGACGGGCAGTGTCATGTTGGTAGTGACAATCATTACTCT GCCTCCACTACCATGGATTATCCCTCTTTGGGGCTGATGACTGAGAAGCTATCCCAGAAAAACATCAATTTGATCTT TGCAGTGACTGAAAATGTAGTCAATCTCTATCAGAACTATAGTGAGCTCATCCCAGGGACCACAGTTGGGGTTCTGT CCATGGATTCCAGCAATGTCCTCCAGCTCATTGTTGATGCTTATGGGAAAATCCGTTCTAAAGTAGAGCTGGAAGTG CGTGACCTCCCTGAAGAGTTGTCTCTATCCTTCAATGCCACCTGCCTCAACAATGAGGTCATCCCTGGCCTCAAGTC TTGTATGGGACTCAAGATTGGAGACACGGTGAGCTTCAGCATTGAGGCCAAGGTGCGAGGCTGTCCCCAGGAGAAGG AGAAGTCCTTTACCATAAAGCCCGTGGGCTTCAAGGACAGCCTGATCGTCCAGGTCACCTTTGATTGTGACTGTGCC TGCCAGGCCCAAGCTGAACCTAATAGCCATCGCTGCAACAATGGCAATGGGACCTTTGAGTGTGGGGTATGCCGTTG TGGGCCTGGCTGGCTGGGATCCCAGTGTGAGTGCTCAGAGGAGGACTATCGCCCTTCCCAGCAGGACGAATGCAGCC CCCGGGAGGGTCAGCCCGTCTGCAGCCAGCGGGGCGAGTGCCTCTGTGGTCAATGTGTCTGCCACAGCAGTGACTTT GGCAAGATCACGGGCAAGTACTGCGAGTGTGACGACTTCTCCTGTGTCCGCTACAAGGGGGAGATGTGCTCAGGCCA TGGCCAGTGCAGCTGTGGGGACTGCCTGTGTGACTCCGACTGGACCGGCTACTACTGCAACTGTACCACGCGTACTG ACACCTGCATGTCCAGCAATGGGCTGCTGTGCAGCGGCCGCGGCAAGTGTGAATGTGGCAGCTGTGTCTGTATCCAG CCGGGCTCCTATGGGGACACCTGTGAGAAGTGCCCCACCTGCCCAGATGCCTGCACCTTTAAGAAAGAATGTGTGGA GTGTAAGAAGTTTGACCGGGGAGCCCTACATGACGAAAATACCTGCAACCGTTACTGCCGTGACGAGATTGAGTCAG TGAAAGAGCTTAAGGACACTGGCAAGGATGCAGTGAATTGTACCTATAAGAATGAGGATGACTGTGTCGTCAGATTC CAGTACTATGAAGATTCTAGTGGAAAGTCCATCCTGTATGTGGTAGAAGAGCCAGAGTGTCCCAAGGGCCCTGACAT CCTGGTGGTCCTGCTCTCAGTGATGGGGGCCATTCTGCTCATTGGCCTTGCCGCCCTGCTCATCTGGAAACTCCTCA TCACCATCCACGACCGAAAAGAATTCGCTAAATTTGAGGAAGAACGCGCCAGAGCAAAATGGGACACAGCCAACAAC CCACTGTATAAAGAGGCCACGTCTACCTTCACCAATATCACGTACCGGGGCACTTAA SEQ ID NO: 18 (ITGB3 aa, human) MRARPRPRPLWATVLALGALAGVGVGGPNICTTRGVSSCQQCLAVSPMCAWCSDEALPLGSPRCDLKENLLKDNCAP ESIEFPVSEARVLEDRPLSDKGSGDSSQVTQVSPQRIALRLRPDDSKNFSIQVRQVEDYPVDIYYLMDLSYSMKDDL WSIQNLGTKLATQMRKLTSNLRIGFGAFVDKPVSPYMYISPPEALENPCYDMKTTCLPMFGYKHVLTLTDQVTRFNE EVKKQSVSRNRDAPEGGFDAIMQATVCDEKIGWRNDASHLLVFTTDAKTHIALDGRLAGIVQPNDGQCHVGSDNHYS ASTTMDYPSLGLMTEKLSQKNINLIFAVTENVVNLYQNYSELIPGTTVGVLSMDSSNVLQLIVDAYGKIRSKVELEV RDLPEELSLSFNATCLNNEVIPGLKSCMGLKIGDTVSFSIEAKVRGCPQEKEKSFTIKPVGFKDSLIVQVTFDCDCA CQAQAEPNSHRCNNGNGTFECGVCRCGPGWLGSQCECSEEDYRPSQQDECSPREGQPVCSQRGECLCGQCVCHSSDF GKITGKYCECDDFSCVRYKGEMCSGHGQCSCGDCLCDSDWTGYYCNCTTRTDTCMSSNGLLCSGRGKCECGSCVCIQ PGSYGDTCEKCPTCPDACTFKKECVECKKFDRGALHDENTCNRYCRDEIESVKELKDTGKDAVNCTYKNEDDCVVRF QYYEDSSGKSILYVVEEPECPKGPDILVVLLSVMGAILLIGLAALLIWKLLITIHDRKEFAKFEEERARAKWDTANN PLYKEATSTFTNITYRGT* SEQ ID NO: 19 (ANK2 nt, human) ATGATGAACGAAGATGCAGCTCAGAAAAGCGACAGTGGAGAGAAGTTCAACGGCAGTAGTCAGAGGAGAAAAAGACC CAAGAAGTCTGACAGCAATGCAAGCTTCCTCCGTGCTGCCAGAGCAGGCAACCTGGACAAAGTTGTGGAATATCTGA AGGGGGGCATAGACATCAATACCTGCAATCAGAATGGACTCAACGCTCTCCATCTGGCTGCCAAGGAAGGCCACGTG GGGCTGGTGCAGGAGCTGCTGGGAAGAGGGTCCTCTGTGGATTCTGCCACTAAGAAGGGAAATACCGCTCTTCACAT TGCATCTTTGGCTGGACAAGCAGAAGTTGTCAAAGTTCTTGTTAAGGAAGGAGCCAATATTAATGCACAGTCTCAGA ATGGCTTTACTCCTTTATACATGGCTGCCCAAGAGAATCACATTGATGTTGTAAAATATTTGCTGGAAAATGGAGCT AATCAGAGCACTGCTACAGAGGATGGCTTTACTCCTCTAGCTGTGGCACTCCAGCAAGGACACAACCAGGCGGTGGC CATCCTCTTGGAGAATGACACCAAAGGGAAAGTGAGGCTGCCAGCTCTGCATATTGCCGCTAGGAAAGACGACACCA AATCTGCCGCACTTCTGCTTCAGAATGACCACAATGCTGACGTACAATCCAAGATGATGGTGAATAGGACAACTGAG AGTGGTTTTACCCCTTTGCACATAGCTGCACATTACGGAAATGTCAACGTGGCAACTCTTCTTCTAAACCGGGGAGC TGCTGTGGACTTCACAGCCAGGAATGGAATCACTCCTCTGCATGTGGCTTCCAAAAGAGGAAATACAAACATGGTGA AGCTCTTACTGGATCGAGGCGGTCAGATCGATGCCAAAACTAGGGATGGGTTGACACCACTTCACTGTGCTGCACGA AGTGGGCATGACCAAGTGGTGGAACTTCTGTTGGAACGGGGTGCCCCCTTGCTGGCAAGGACTAAGAATGGGCTGTC TCCACTACACATGGCTGCCCAGGGAGACCACGTGGAATGTGTGAAGCACCTGTTACAGCACAAGGCACCTGTTGATG ATGTCACCCTAGACTACCTGACAGCCCTCCACGTTGCTGCGCACTGTGGCCACTACCGTGTAACCAAACTCCTTTTA GACAAGAGAGCCAATCCGAACGCCAGAGCCCTGAATGGTTTTACTCCACTGCACATTGCCTGCAAGAAAAACCGCAT CAAAGTCATGGAACTGCTGGTGAAATATGGGGCTTCAATCCAAGCTATAACAGAGTCTGGCCTCACACCAATACATG TGGCTGCCTTCATGGGCCACTTGAACATTGTCCTCCTTCTGCTGCAGAACGGAGCCTCTCCAGATGTCACTAACATT CGTGGTGAGACGGCACTACACATGGCAGCCCGAGCCGGGCAGGTGGAAGTGGTCCGATGCCTCCTGAGAAATGGTGC 30 24028 / / SLW 875.245WO1 CCTTGTTGATGCCAGAGCCAGGGAGGAACAGACACCTTTACATATTGCCTCCCGCCTGGGTAAGACAGAAATTGTCC AGCTGCTTCTACAACATATGGCTCATCCAGATGCGGCCACTACAAATGGGTACACACCACTGCACATCTCTGCCCGG GAGGGCCAGGTGGATGTGGCATCAGTCCTATTGGAAGCAGGAGCAGCCCACTCCTTAGCTACCAAGAAGGGTTTTAC TCCCCTGCATGTAGCAGCCAAGTATGGAAGCCTGGATGTGGCAAAACTTCTCTTGCAACGCCGTGCTGCCGCAGATT CTGCAGGGAAGAACGGCCTTACCCCGCTCCATGTTGCTGCTCATTATGACAACCAGAAGGTGGCGCTGCTGTTACTG GAGAAGGGTGCTTCCCCTCATGCCACTGCCAAGAATGGCTATACTCCGTTACATATTGCTGCCAAGAAGAATCAAAT GCAGATAGCTTCCACACTCCTGAACTATGGAGCAGAGACAAACATTGTGACAAAGCAAGGAGTAACTCCACTCCATC TGGCCTCGCAGGAGGGGCACACAGATATGGTTACCTTGCTTCTGGATAAGGGAGCCAATATCCACATGTCAACTAAG AGTGGACTCACATCCTTACACCTTGCAGCCCAGGAAGATAAAGTGAATGTTGCTGATATTCTCACCAAGCATGGAGC TGATCAGGATGCTCATACAAAGCTTGGTTACACACCTTTAATTGTGGCCTGTCACTATGGAAATGTGAAAATGGTCA ACTTTCTTCTGAAGCAGGGAGCAAATGTTAACGCAAAAACCAAGAACGGCTACACGCCTTTGCACCAGGCCGCTCAG CAGGGTCACACGCACATCATCAACGTCCTGCTCCAGCATGGGGCCAAGCCCAACGCCACCACTGCGAATGGCAACAC TGCCTTGGCGATTGCTAAGCGTCTGGGCTACATCTCCGTGGTCGACACCCTGAAGGTTGTGACTGAGGAGGTCACCA CCACCACCACAACTATTACAGAAAAACACAAACTAAATGTACCTGAGACGATGACTGAGGTTCTTGATGTTTCTGAT GAAGAGGGTGATGACACAATGACTGGTGATGGGGGAGAATACCTTAGGCCTGAGGACCTAAAAGAACTGGGTGATGA CTCACTACCCAGCAGTCAGTTCCTGGATGGTATGAATTACCTGCGATACAGCTTGGAGGGAGGACGATCTGACAGCC TTCGATCCTTCAGTTCCGACAGGTCTCACACTCTGAGCCATGCCTCCTACCTGAGGGACAGTGCCGTGATGGATGAC TCAGTTGTGATTCCCAGTCACCAGGTGTCAACTCTAGCCAAGGAGGCAGAAAGGAATTCTTATCGCCTAAGCTGGGG CACTGAGAACTTAGACAACGTGGCTCTTTCTTCTAGTCCTATTCATTCAGGTTTCCTGGTTAGTTTTATGGTGGATG CCCGAGGTGGTGCTATGCGAGGATGCAGACACAATGGGCTCCGAATCATTATTCCACCTCGGAAATGTACTGCTCCA ACGCGAGTCACCTGCCGACTGGTCAAGCGCCACAGACTGGCAACAATGCCTCCAATGGTGGAAGGAGAAGGCCTGGC CAGTCGCCTGATCGAAGTTGGACCTTCTGGTGCTCAGTTCCTTGGTAAACTTCACCTGCCAACGGCTCCTCCCCCAC TTAATGAGGGAGAAAGTTTGGTCAGCCGCATTCTTCAGCTGGGGCCTCCTGGAACCAAATTCCTTGGGCCTGTGATC GTGGAGATCCCTCACTTTGCGGCCCTTCGAGGAAAGGAAAGGGAACTGGTGGTCCTGCGCAGTGAGAATGGGGACAG CTGGAAAGAGCATTTCTGTGACTACACTGAAGATGAATTGAATGAAATTCTTAACGGCATGGATGAAGTACTGGATA GCCCAGAAGACCTAGAAAAGAAACGAATCTGCCGCATCATCACCCGAGACTTCCCACAGTACTTTGCAGTGGTGTCT CGTATCAAACAGGACAGCAATCTGATTGGCCCAGAAGGAGGTGTACTGAGCAGCACAGTGGTGCCCCAGGTGCAGGC CGTCTTCCCAGAGGGGGCACTCACCAAGCGGATCCGCGTAGGCCTGCAGGCTCAACCTATGCACAGTGAGCTGGTTA AGAAGATCCTAGGCAACAAAGCTACCTTCAGCCCTATAGTCACTTTGGAACCTAGAAGAAGAAAATTCCACAAACCA ATTACCATGACCATTCCTGTCCCCAAAGCTTCAAGTGATGTCATGTTGAATGGTTTTGGGGGAGATGCACCAACCTT AAGATTACTATGCAGCATAACAGGTGGAACCACCCCTGCCCAGTGGGAAGATATTACAGGAACTACGCCATTAACAT TTGTCAATGAATGTGTTTCCTTTACAACAAACGTGTCTGCCAGGTTCTGGCTGATAGATTGTCGACAGATCCAGGAA TCCGTTACTTTTGCATCACAAGTATACAGAGAAATTATCTGCGTACCTTATATGGCCAAATTTGTAGTGTTTGCCAA ATCACATGACCCCATTGAAGCCAGGTTGAGGTGTTTCTGCATGACTGATGATAAAGTGGATAAGACCCTTGAACAAC AAGAAAATTTTGCTGAGGTGGCCAGAAGCAGGGATGTGGAGGTGTTAGAAGGAAAACCCATCTACGTTGATTGTTTC GGCAACTTGGTACCATTAACTAAAAGTGGCCAGCATCATATATTCAGTTTTTTTGCCTTCAAAGAAAATAGACTTCC TCTATTTGTCAAGGTACGCGATACGACTCAGGAACCTTGCGGACGACTATCATTTATGAAGGAGCCAAAATCCACGA GAGGCCTGGTGCATCAAGCTATTTGCAACTTAAACATCACTTTGCCGATTTATACAAAGGAATCAGAGTCAGATCAA GAACAGGAGGAAGAGATCGATATGACATCAGAAAAAAATGATGAGACAGAATCTACAGAAACATCTGTCCTGAAAAG TCACCTGGTTAATGAAGTTCCTGTCCTAGCAAGTCCGGACTTGCTCTCTGAAGTTTCTGAGATGAAACAAGATTTGA TCAAAATGACCGCCATCTTGACCACAGATGTGTCTGATAAGGCAGGTTCTATTAAAGTGAAGGAGCTGGTGAAGGCT GCTGAGGAAGAGCCAGGAGAGCCTTTTGAAATCGTTGAAAGAGTTAAAGAGGACTTAGAGAAAGTGAATGAAATCCT GAGAAGTGGAACCTGCACAAGAGATGAAAGCAGTGTGCAGAGCTCTCGGTCTGAGAGAGGATTAGTTGAAGAGGAAT GGGTTATTGTCAGTGATGAGGAAATAGAAGAGGCTAGGCAAAAAGCACCTTTAGAAATCACTGAATATCCATGTGTA GAAGTTAGAATAGATAAAGAGATCAAAGGAAAAGTAGAGAAAGACTCAACTGGGCTAGTGAACTACCTTACTGATGA TCTGAATACCTGTGTGCCTCTTCCCAAAGAGCAGCTGCAGACAGTTCAAGATAAGGCAGGGAAGAAATGTGAGGCTC TGGCTGTTGGCAGGAGCTCTGAAAAGGAAGGGAAAGACATACCCCCAGATGAGACACAGAGTACACAGAAACAGCAC AAACCAAGCTTGGGAATAAAGAAGCCAGTAAGAAGGAAATTAAAAGAAAAGCAGAAACAAAAAGAGGAAGGTTTACA AGCTAGTGCAGAGAAAGCTGAACTTAAAAAAGGTAGTTCAGAAGAGTCATTAGGTGAAGACCCAGGTTTAGCCCCTG AACCCCTTCCCACTGTCAAGGCCACATCTCCTTTGATAGAAGAAACTCCCATTGGTTCCATAAAGGACAAAGTAAAG GCCCTTCAGAAGCGAGTGGAAGATGAACAGAAAGGTCGAAGCAAGTTGCCCATCAGAGTCAAAGGCAAGGAGGACGT GCCAAAAAAGACCACCCACAGGCCACATCCAGCTGCGTCACCCTCTCTGAAGTCAGAGAGACATGCGCCAGGGTCTC CCTCCCCTAAAACAGAAAGACACTCTACTCTTTCCTCTTCCGCAAAAACTGAAAGGCACCCTCCAGTATCACCATCA AGTAAAACTGAGAAACACTCACCTGTGTCACCCTCTGCAAAAACGGAAAGACATTCACCTGCGTCATCATCGAGTAA AACTGAGAAACACTCACCTGTATCACCCTCGACAAAAACTGAAAGGCACTCTCCTGTGTCATCTACAAAAACAGAAA GACACCCACCTGTTTCGCCTTCAGGCAAAACAGACAAACGTCCACCTGTATCGCCCTCCGGGAGGACAGAAAAACAC CCGCCAGTATCGCCTGGGAGAACAGAAAAACGCTTGCCTGTTTCACCCTCCGGAAGAACGGACAAGCACCAACCTGT ATCAACAGCTGGGAAAACTGAGAAGCACCTGCCTGTGTCACCTTCTGGCAAAACAGAAAAGCAACCACCTGTATCCC 31 24028 / / SLW 875.245WO1 CCACTTCAAAAACAGAGAGGATTGAGGAAACCATGTCTGTTCGGGAGCTGATGAAGGCTTTCCAGTCAGGTCAGGAC CCTTCTAAACATAAAACTGGACTCTTTGAGCACAAATCAGCAAAACAAAAGCAGCCACAAGAGAAAGGTAAAGTTCG GGTAGAAAAAGAAAAGGGGCCGATACTAACCCAGAGAGAAGCTCAGAAAACAGAGAATCAGACAATCAAACGAGGCC AGAGACTCCCGGTAACGGGCACAGCAGAATCCAAAAGAGGAGTTCGTGTTTCCTCCATAGGAGTTAAGAAAGAAGAT GCAGCTGGAGGAAAGGAGAAAGTTCTCAGCCACAAAATACCTGAACCTGTTCAGTCAGTGCCTGAAGAAGAAAGCCA CAGAGAGAGCGAAGTGCCCAAAGAAAAGATGGCTGATGAGCAGGGAGACATGGATCTACAGATCAGCCCAGATAGGA AAACCTCCACTGACTTCTCTGAGGTCATTAAGCAAGAGTTGGAAGACAATGACAAATACCAACAATTCCGCCTGAGT GAGGAGACAGAAAAGGCACAGCTTCACTTAGACCAAGTACTCACTAGTCCTTTCAACACAACATTTCCACTCGACTA CATGAAAGATGAGTTCCTTCCAGCTCTGTCTTTACAAAGCGGTGCTTTAGATGGCAGTTCTGAAAGCCTAAAGAATG AGGGGGTAGCCGGCTCTCCGTGTGGCAGCCTGATGGAGGGGACCCCTCAGATTAGTTCAGAAGAAAGCTATAAGCAT GAAGGCCTAGCAGAGACCCCTGAGACGAGCCCAGAAAGCCTTTCTTTCTCACCAAAGAAAAGTGAGGAGCAAACTGG GGAAACAAAGGAAAGCACCAAGACAGAAACCACCACAGAAATTCGTTCAGAAAAAGAGCATCCCACGACCAAAGACA TTACTGGTGGCTCTGAAGAGCGAGGTGCCACAGTCACTGAGGACTCAGAGACCTCTACTGAGAGTTTTCAGAAAGAG GCCACTCTAGGCTCTCCCAAAGACACAAGCCCTAAAAGACAAGATGATTGCACAGGCAGCTGTAGTGTAGCATTAGC TAAAGAGACACCTACAGGACTGACTGAGGAGGCAGCCTGTGATGAAGGTCAACGTACCTTTGGTAGTTCAGCCCACA AGACACAAACTGATAGTGAGGTTCAAGAATCCACAGCCACCTCAGACGAGACAAAGGCCTTGCCGCTGCCTGAGGCT TCTGTAAAGACAGATACAGGAACTGAATCAAAACCTCAGGGAGTCATTAGAAGTCCCCAAGGGTTAGAACTTGCACT CCCTAGCCGAGATAGCGAAGTCCTCAGCGCTGTGGCTGATGACTCATTAGCAGTGAGCCACAAAGACTCTCTGGAAG CCAGCCCTGTGCTAGAAGATAACTCTTCACACAAAACCCCTGATTCTCTGGAGCCAAGTCCTCTGAAAGAATCCCCT TGCCGTGACTCTCTGGAAAGCAGCCCTGTTGAACCAAAGATGAAGGCTGGAATTTTTCCAAGTCACTTTCCTCTTCC TGCAGCTGTTGCCAAAACAGAACTCTTGACGGAAGTGGCCTCTGTGCGGTCCCGGCTACTCCGAGACCCTGATGGCA GTGCTGAGGATGACAGTCTTGAGCAGACATCGCTCATGGAGAGCTCAGGGAAGAGCCCCCTTTCTCCTGACACCCCC AGCTCTGAAGAAGTCAGCTATGAGGTTACACCCAAAACCACAGATGTAAGTACACCAAAACCAGCTGTGATTCATGA ATGTGCAGAGGAGGATGATTCAGAAAACGGGGAGAAAAAGAGGTTCACACCTGAAGAGGAGATGTTTAAAATGGTAA CCAAAATCAAAATGTTTGATGAACTTGAACAAGAAGCAAAGCAGAAAAGGGACTACAAAAAAGAACCCAAACAAGAA GAATCTTCTTCATCTTCTGACCCAGATGCTGACTGTTCAGTAGATGTGGATGAACCAAAACATACAGGCAGTGGGGA GGATGAAAGTGGTGTCCCTGTGTTAGTAACTTCGGAGAGCAGGAAGGTGTCTTCCTCCTCAGAAAGTGAACCTGAGT TGGCACAGCTTAAAAAAGGTGCTGACTCAGGCCTTTTACCAGAACCAGTGATTCGAGTACAACCTCCTTCTCCACTT CCATCAAGCATGGACTCCAATTCCAGTCCAGAAGAAGTACAATTCCAGCCTGTCGTTTCCAAACAATATACTTTCAA GATGAATGAAGATACTCAGGAAGAGCCAGGCAAATCAGAAGAAGAAAAAGATTCTGAATCCCATTTAGCTGAAGACC GTCATGCTGTTTCCACTGAGGCTGAAGACAGGTCTTATGATAAGCTAAACAGAGACACTGATCAGCCAAAAATCTGT GATGGCCATGGATGTGAGGCCATGAGTCCTAGCAGCTCAGCTGCTCCTGTCTCTTCAGGTCTACAGAGTCCGACTGG TGATGATGTTGATGAACAGCCAGTCATCTATAAAGAATCATTAGCTCTCCAAGGCACTCATGAAAAAGACACAGAGG GAGAAGAGCTTGATGTTTCTAGAGCAGAATCTCCACAAGCAGATTGCCCCAGTGAAAGCTTTTCATCTTCATCCTCT TTGCCTCATTGTTTGGTATCTGAAGGAAAAGAATTAGATGAAGACATATCTGCCACATCTTCTATTCAAAAAACAGA GGTCACAAAAACTGATGAAACATTTGAGAACTTACCAAAGGACTGCCCCTCTCAAGACTCATCCATTACTACTCAAA CAGATAGATTTTCCATGGATGTTCCCGTGTCTGACCTAGCTGAGAATGATGAAATCTATGATCCACAAATCACTAGC CCTTATGAAAATGTCCCTTCCCAATCTTTTTTCTCTAGTGAAGAAAGCAAAACCCAAACAGATGCAAATCACACCAC AAGTTTTCACTCTTCTGAAGTGTATTCTGTTACCATCACATCCCCTGTTGAAGACGTTGTAGTGGCAAGCTCCTCTA GTGGAACTGTTTTAAGCAAAGAATCTAATTTTGAGGGCCAGGACATAAAAATGGAATCCCAACAGGAAAGTACCTTG TGGGAAATGCAATCAGACAGTGTCTCTTCATCTTTCGAGCCTACTATGTCCGCTACAACAACAGTTGTTGGTGAACA AATAAGCAAAGTCATCATCACAAAAACTGATGTGGATTCTGATTCTTGGAGTGAAATTCGGGAAGACGATGAAGCCT TTGAGGCTCGTGTGAAAGAGGAAGAACAAAAGATATTTGGTTTGATGGTAGACAGACAATCACAGGGTACCACCCCT GACACCACTCCTGCTAGGACCCCAACTGAAGAGGGGACCCCAACAAGTGAGCAAAACCCATTTCTGTTTCAGGAAGG AAAATTGTTTGAAATGACCCGAAGTGGTGCCATTGATATGACCAAAAGGTCCTATGCAGATGAAAGTTTTCACTTTT TCCAAATTGGTCAAGAATCCAGGGAAGAGACTCTCTCTGAAGATGTGAAAGAAGGGGCTACTGGGGCTGATCCCCTA CCGCTGGAGACATCAGCTGAATCACTAGCACTTTCAGAATCAAAAGAAACAGTGGATGATGAGGCAGACTTACTTCC AGATGACGTGAGTGAGGAAGTAGAGGAAATACCTGCTTCGGATGCTCAACTTAACTCCCAAATGGGGATTTCAGCCT CCACTGAAACACCTACAAAAGAAGCTGTTAGTGTAGGGACCAAGGACCTCCCCACCGTGCAAACGGGTGATATACCT CCTCTCTCTGGTGTAAAGCAGATATCCTGCCCCGACTCTTCTGAACCAGCTGTACAAGTCCAGTTAGATTTTTCCAC ACTCACCAGGTCTGTTTATTCAGATAGGGGTGATGATTCTCCCGATTCTTCCCCAGAAGAACAGAAATCAGTAATCG AGATTCCTACTGCACCCATGGAGAATGTGCCTTTTACTGAAAGCAAATCCAAAATTCCTGTAAGGACTATGCCCACT TCCACCCCAGCACCTCCATCTGCAGAGTATGAGAGTTCAGTTTCTGAAGATTTTCTATCCAGTGTAGATGAGGAAAA TAAGGCGGATGAAGCAAAACCAAAGTCCAAACTCCCTGTCAAAGTACCCCTCCAAAGAGTTGAACAGCAGCTCTCAG ATCTAGACACCTCTGTCCAGAAGACAGTGGCTCCTCAGGGACAGGACATGGCAAGCATCGCACCAGATAATAGAAGC AAATCTGAATCTGATGCTAGTTCTTTGGATTCAAAGACCAAATGCCCAGTAAAAACCCGAAGTTACACTGAGACAGA AACAGAGAGCAGAGAGAGGGCCGAGGAACTTGAGTTAGAATCAGAAGAAGGGGCCACAAGACCAAAGATACTTACAT CCCGATTGCCAGTTAAGAGCAGAAGCACTACATCTTCCTGCAGGGGGGGCACGAGCCCCACAAAAGAAAGTAAGGAG 32 24028 / / SLW 875.245WO1 CATTTCTTTGACCTTTACAGAAATTCCATAGAATTCTTTGAGGAGATTAGTGATGAGGCTTCCAAATTAGTGGATAG GCTGACACAGTCAGAGAGGGAGCAGGAAATAGTTTCAGACGATGAAAGTAGTAGTGCCCTGGAAGTATCAGTAATTG AAAATCTGCCACCTGTTGAGACCGAGCACTCAGTTCCTGAGGACATCTTTGACACAAGGCCCATTTGGGATGAGTCT ATTGAGACTCTGATTGAACGCATCCCTGATGAAAATGGCCATGACCATGCTGAAGATCCACAGGATGAGCAGGAACG GATCGAGGAAAGGCTGGCTTATATTGCTGATCACCTTGGCTTCAGCTGGACAGAATTAGCAAGAGAACTGGATTTCA CTGAGGAGCAAATTCATCAAATTCGAATTGAAAATCCCAACTCTCTTCAAGACCAGAGTCATGCACTGTTGAAGTAC TGGCTAGAGAGGGATGGGAAACATGCTACAGATACCAACCTCGTTGAATGTCTCACCAAGATCAACCGAATGGATAT TGTTCATCTCATGGAGACCAACACAGAACCTCTCCAGGAGCGCATCAGTCATAGTTATGCAGAAATTGAACAGACCA TTACACTGGATCATAGTGAAGGGTTCTCGGTACTTCAAGAGGAGTTATGCACTGCACAGCACAAGCAGAAAGAGGAG CAAGCTGTTTCTAAAGAAAGTGAGACCTGCGATCACCCTCCTATCGTCTCAGAGGAAGACATTTCTGTTGGTTATTC CACTTTTCAGGATGGCGTCCCCAAAACTGAGGGGGACAGCTCAGCAACAGCACTCTTTCCCCAAACTCACAAGGAGC AAGTTCAACAGGATTTCTCAGGGAAAATGCAAGACCTGCCTGAAGAGTCATCTCTGGAATATCAGCAGGAATATTTT GTGACAACTCCAGGAACAGAAACATCAGAGACTCAGAAGGCTATGATAGTACCCAGCTCTCCCAGCAAGACACCTGA GGAAGTTAGCACCCCTGCAGAGGAGGAGAAGCTGTACCTCCAGACCCCAACATCCAGCGAGCGGGGAGGCTCTCCCA TCATACAAGAACCCGAAGAGCCCTCAGAGCACAGAGAGGAGAGCTCTCCGCGGAAAACCAGCCTCGTAATAGTGGAG TCTGCCGATAACCAGCCTGAGACCTGTGAAAGACTCGATGAAGATGCAGCTTTTGAAAAGGGAGACGATATGCCTGA AATACCCCCAGAAACAGTCACAGAAGAAGAATACATTGATGAGCATGGACACACCGTGGTAAAGAAGGTTACTAGGA AAATCATTAGGCGGTATGTATCCTCTGAAGGCACAGAGAAAGAAGAGATTATGGTGCAGGGAATGCCACAGGAACCT GTCAACATCGAGGAAGGGGATGGCTATTCCAAAGTTATAAAGCGTGTTGTATTGAAGAGTGACACCGAGCAGTCAGA GGACAACAATGAGTAA SEQ ID NO: 20 (ANK2 aa, human) MMNEDAAQKSDSGEKFNGSSQRRKRPKKSDSNASFLRAARAGNLDKVVEYLKGGIDINTCNQNGLNALHLAAKEGHV GLVQELLGRGSSVDSATKKGNTALHIASLAGQAEVVKVLVKEGANINAQSQNGFTPLYMAAQENHIDVVKYLLENGA NQSTATEDGFTPLAVALQQGHNQAVAILLENDTKGKVRLPALHIAARKDDTKSAALLLQNDHNADVQSKMMVNRTTE SGFTPLHIAAHYGNVNVATLLLNRGAAVDFTARNGITPLHVASKRGNTNMVKLLLDRGGQIDAKTRDGLTPLHCAAR SGHDQVVELLLERGAPLLARTKNGLSPLHMAAQGDHVECVKHLLQHKAPVDDVTLDYLTALHVAAHCGHYRVTKLLL DKRANPNARALNGFTPLHIACKKNRIKVMELLVKYGASIQAITESGLTPIHVAAFMGHLNIVLLLLQNGASPDVTNI RGETALHMAARAGQVEVVRCLLRNGALVDARAREEQTPLHIASRLGKTEIVQLLLQHMAHPDAATTNGYTPLHISAR EGQVDVASVLLEAGAAHSLATKKGFTPLHVAAKYGSLDVAKLLLQRRAAADSAGKNGLTPLHVAAHYDNQKVALLLL EKGASPHATAKNGYTPLHIAAKKNQMQIASTLLNYGAETNIVTKQGVTPLHLASQEGHTDMVTLLLDKGANIHMSTK SGLTSLHLAAQEDKVNVADILTKHGADQDAHTKLGYTPLIVACHYGNVKMVNFLLKQGANVNAKTKNGYTPLHQAAQ QGHTHIINVLLQHGAKPNATTANGNTALAIAKRLGYISVVDTLKVVTEEVTTTTTTITEKHKLNVPETMTEVLDVSD EEGDDTMTGDGGEYLRPEDLKELGDDSLPSSQFLDGMNYLRYSLEGGRSDSLRSFSSDRSHTLSHASYLRDSAVMDD SVVIPSHQVSTLAKEAERNSYRLSWGTENLDNVALSSSPIHSGFLVSFMVDARGGAMRGCRHNGLRIIIPPRKCTAP TRVTCRLVKRHRLATMPPMVEGEGLASRLIEVGPSGAQFLGKLHLPTAPPPLNEGESLVSRILQLGPPGTKFLGPVI VEIPHFAALRGKERELVVLRSENGDSWKEHFCDYTEDELNEILNGMDEVLDSPEDLEKKRICRIITRDFPQYFAVVS RIKQDSNLIGPEGGVLSSTVVPQVQAVFPEGALTKRIRVGLQAQPMHSELVKKILGNKATFSPIVTLEPRRRKFHKP ITMTIPVPKASSDVMLNGFGGDAPTLRLLCSITGGTTPAQWEDITGTTPLTFVNECVSFTTNVSARFWLIDCRQIQE SVTFASQVYREIICVPYMAKFVVFAKSHDPIEARLRCFCMTDDKVDKTLEQQENFAEVARSRDVEVLEGKPIYVDCF GNLVPLTKSGQHHIFSFFAFKENRLPLFVKVRDTTQEPCGRLSFMKEPKSTRGLVHQAICNLNITLPIYTKESESDQ EQEEEIDMTSEKNDETESTETSVLKSHLVNEVPVLASPDLLSEVSEMKQDLIKMTAILTTDVSDKAGSIKVKELVKA AEEEPGEPFEIVERVKEDLEKVNEILRSGTCTRDESSVQSSRSERGLVEEEWVIVSDEEIEEARQKAPLEITEYPCV EVRIDKEIKGKVEKDSTGLVNYLTDDLNTCVPLPKEQLQTVQDKAGKKCEALAVGRSSEKEGKDIPPDETQSTQKQH KPSLGIKKPVRRKLKEKQKQKEEGLQASAEKAELKKGSSEESLGEDPGLAPEPLPTVKATSPLIEETPIGSIKDKVK ALQKRVEDEQKGRSKLPIRVKGKEDVPKKTTHRPHPAASPSLKSERHAPGSPSPKTERHSTLSSSAKTERHPPVSPS SKTEKHSPVSPSAKTERHSPASSSSKTEKHSPVSPSTKTERHSPVSSTKTERHPPVSPSGKTDKRPPVSPSGRTEKH PPVSPGRTEKRLPVSPSGRTDKHQPVSTAGKTEKHLPVSPSGKTEKQPPVSPTSKTERIEETMSVRELMKAFQSGQD PSKHKTGLFEHKSAKQKQPQEKGKVRVEKEKGPILTQREAQKTENQTIKRGQRLPVTGTAESKRGVRVSSIGVKKED AAGGKEKVLSHKIPEPVQSVPEEESHRESEVPKEKMADEQGDMDLQISPDRKTSTDFSEVIKQELEDNDKYQQFRLS EETEKAQLHLDQVLTSPFNTTFPLDYMKDEFLPALSLQSGALDGSSESLKNEGVAGSPCGSLMEGTPQISSEESYKH EGLAETPETSPESLSFSPKKSEEQTGETKESTKTETTTEIRSEKEHPTTKDITGGSEERGATVTEDSETSTESFQKE ATLGSPKDTSPKRQDDCTGSCSVALAKETPTGLTEEAACDEGQRTFGSSAHKTQTDSEVQESTATSDETKALPLPEA SVKTDTGTESKPQGVIRSPQGLELALPSRDSEVLSAVADDSLAVSHKDSLEASPVLEDNSSHKTPDSLEPSPLKESP CRDSLESSPVEPKMKAGIFPSHFPLPAAVAKTELLTEVASVRSRLLRDPDGSAEDDSLEQTSLMESSGKSPLSPDTP SSEEVSYEVTPKTTDVSTPKPAVIHECAEEDDSENGEKKRFTPEEEMFKMVTKIKMFDELEQEAKQKRDYKKEPKQE ESSSSSDPDADCSVDVDEPKHTGSGEDESGVPVLVTSESRKVSSSSESEPELAQLKKGADSGLLPEPVIRVQPPSPL 33 24028 / / SLW 875.245WO1 PSSMDSNSSPEEVQFQPVVSKQYTFKMNEDTQEEPGKSEEEKDSESHLAEDRHAVSTEAEDRSYDKLNRDTDQPKIC DGHGCEAMSPSSSAAPVSSGLQSPTGDDVDEQPVIYKESLALQGTHEKDTEGEELDVSRAESPQADCPSESFSSSSS LPHCLVSEGKELDEDISATSSIQKTEVTKTDETFENLPKDCPSQDSSITTQTDRFSMDVPVSDLAENDEIYDPQITS PYENVPSQSFFSSEESKTQTDANHTTSFHSSEVYSVTITSPVEDVVVASSSSGTVLSKESNFEGQDIKMESQQESTL WEMQSDSVSSSFEPTMSATTTVVGEQISKVIITKTDVDSDSWSEIREDDEAFEARVKEEEQKIFGLMVDRQSQGTTP DTTPARTPTEEGTPTSEQNPFLFQEGKLFEMTRSGAIDMTKRSYADESFHFFQIGQESREETLSEDVKEGATGADPL PLETSAESLALSESKETVDDEADLLPDDVSEEVEEIPASDAQLNSQMGISASTETPTKEAVSVGTKDLPTVQTGDIP PLSGVKQISCPDSSEPAVQVQLDFSTLTRSVYSDRGDDSPDSSPEEQKSVIEIPTAPMENVPFTESKSKIPVRTMPT STPAPPSAEYESSVSEDFLSSVDEENKADEAKPKSKLPVKVPLQRVEQQLSDLDTSVQKTVAPQGQDMASIAPDNRS KSESDASSLDSKTKCPVKTRSYTETETESRERAEELELESEEGATRPKILTSRLPVKSRSTTSSCRGGTSPTKESKE HFFDLYRNSIEFFEEISDEASKLVDRLTQSEREQEIVSDDESSSALEVSVIENLPPVETEHSVPEDIFDTRPIWDES IETLIERIPDENGHDHAEDPQDEQERIEERLAYIADHLGFSWTELARELDFTEEQIHQIRIENPNSLQDQSHALLKY WLERDGKHATDTNLVECLTKINRMDIVHLMETNTEPLQERISHSYAEIEQTITLDHSEGFSVLQEELCTAQHKQKEE QAVSKESETCDHPPIVSEEDISVGYSTFQDGVPKTEGDSSATALFPQTHKEQVQQDFSGKMQDLPEESSLEYQQEYF VTTPGTETSETQKAMIVPSSPSKTPEEVSTPAEEEKLYLQTPTSSERGGSPIIQEPEEPSEHREESSPRKTSLVIVE SADNQPETCERLDEDAAFEKGDDMPEIPPETVTEEEYIDEHGHTVVKKVTRKIIRRYVSSEGTEKEEIMVQGMPQEP VNIEEGDGYSKVIKRVVLKSDTEQSEDNNE* SEQ ID NO: 21 (ACTN2 nt, human) ATGAACCAGATAGAGCCCGGCGTGCAGTACAACTACGTGTACGACGAGGATGAGTACATGATCCAGGAGGAGGAGTG GGACCGCGACCTGCTCCTGGACCCAGCCTGGGAGAAGCAGCAGAGGAAGACCTTCACTGCCTGGTGTAACTCCCACC TAAGGAAAGCCGGCACCCAGATTGAGAACATCGAGGAAGACTTCAGGAATGGCCTTAAGCTCATGCTGCTTTTGGAA GTCATCTCAGGGGAAAGGCTGCCCAAACCTGACCGGGGAAAAATGCGGTTCCACAAAATTGCTAATGTCAACAAAGC TTTGGATTACATAGCCAGCAAAGGGGTGAAACTGGTGTCCATTGGCGCTGAAGAAATTGTTGATGGCAACGTGAAAA TGACCCTGGGTATGATCTGGACCATCATCCTTCGCTTTGCTATTCAGGATATTTCGGTTGAAGAAACATCTGCCAAA GAAGGTCTGCTGCTTTGGTGTCAGAGGAAAACTGCTCCTTATAGAAATGTGAACATTCAGAACTTCCATACTAGCTG GAAAGATGGCCTTGGACTCTGTGCCCTCATCCACCGACACCGGCCTGACCTCATTGACTACTCAAAGCTTAACAAGG ATGACCCCATAGGAAATATTAACCTGGCCATGGAAATCGCTGAGAAGCACCTGGATATTCCTAAAATGTTGGATGCT GAAGACATCGTGAACACCCCTAAACCCGATGAAAGAGCCATCATGACGTACGTCTCTTGCTTCTACCACGCTTTTGC GGGCGCGGAGCAGGCCGAGACAGCGGCTAACAGGATATGTAAGGTTCTTGCTGTGAATCAAGAGAATGAGAGGCTGA TGGAAGAATATGAGAGGCTAGCGAGTGAGCTTTTGGAATGGATTCGTCGCACGATCCCCTGGCTGGAGAACCGGACT CCCGAGAAGACCATGCAAGCCATGCAGAAGAAGCTGGAGGACTTCCGGGATTACCGCCGGAAGCACAAGCCACCCAA GGTGCAGGAGAAATGCCAGCTGGAGATCAACTTCAACACGCTGCAGACCAAGCTGCGGATCAGCAACCGTCCTGCCT TCATGCCCTCCGAGGGCAAGATGGTGTCGGATATTGCTGGTGCCTGGCAGAGGCTGGAGCAGGCTGAGAAGGGTTAC GAGGAGTGGTTGCTCAATGAGATTCGGAGACTGGAGCGCTTGGAACACCTGGCTGAGAAGTTCAGGCAGAAGGCCTC AACGCACGAGACTTGGGCTTATGGCAAAGAGCAGATCTTGCTGCAGAAGGATTACGAGTCGGCGTCGCTGACAGAGG TGCGGGCTCTGCTGCGGAAGCACGAGGCGTTCGAGAGCGACCTGGCAGCGCACCAGGACCGCGTGGAGCAGATCGCA GCCATCGCGCAGGAGCTCAATGAACTGGACTATCACGACGCTGTGAATGTCAATGATCGGTGCCAGAAAATTTGTGA CCAGTGGGACCGACTGGGAACGCTTACTCAGAAGAGGAGAGAAGCCCTAGAGAGAATGGAGAAATTGCTAGAAACCA TTGATCAGCTTCACCTGGAGTTTGCCAAGAGGGCTGCTCCTTTCAACAATTGGATGGAGGGCGCTATGGAGGATCTG CAAGATATGTTCATTGTCCACAGCATTGAGGAGATCCAGAGTCTGATCACTGCGCATGAGCAGTTCAAGGCCACGCT GCCCGAGGCGGACGGAGAGCGGCAGTCCATCATGGCCATCCAGAACGAGGTGGAGAAGGTGATTCAGAGCTACAACA TCAGAATCAGCTCAAGCAACCCGTACAGCACTGTCACCATGGATGAGCTCCGGACCAAGTGGGACAAGGTGAAGCAA CTCGTGCCCATCCGCGATCAATCCCTGCAGGAGGAGCTGGCTCGCCAGCATGCTAACGAGCGTCTGAGGCGCCAGTT TGCTGCCCAAGCCAATGCCATTGGGCCCTGGATCCAGAACAAGATGGAGGAGATTGCCCGGAGCTCCATCCAGATCA CAGGAGCCCTGGAAGACCAGATGAACCAGCTGAAGCAGTATGAGCACAACATCATCAACTATAAGAACAACATCGAC AAGCTGGAGGGAGACCATCAGCTCATCCAGGAGGCCCTTGTCTTTGACAACAAGCACACGAACTACACGATGGAGCA CATTCGTGTTGGATGGGAGCTGCTGCTGACAACCATCGCCAGAACCATCAATGAGGTGGAGACTCAGATCCTGACGA GAGATGCGAAGGGCATCACCCAGGAGCAGATGAATGAGTTCAGAGCCTCCTTCAACCACTTTGACAGGAGGAAGAAT GGCCTGATGGATCATGAGGATTTCAGAGCCTGCCTGATTTCCATGGGTTATGACCTGGGTGAAGCCGAATTTGCCCG CATTATGACCCTGGTAGATCCCAACGGGCAAGGCACCGTCACCTTCCAATCCTTCATCGACTTCATGACTAGAGAGA CGGCTGACACCGACACTGCCGAGCAGGTCATCGCCTCCTTCCGGATCCTGGCTTCTGATAAGCCATACATCCTGGCG GAGGAGCTGCGTCGGGAGCTGCCCCCGGATCAGGCCCAGTACTGCATCAAGAGGATGCCCGCCTACTCGGGCCCAGG CAGTGTGCCTGGTGCACTGGATTACGCTGCGTTCTCTTCCGCACTCTACGGGGAGAGCGATCTGTGA SEQ ID NO: 22 (ACTN2 aa, human) 34 24028 / / SLW 875.245WO1 MNQIEPGVQYNYVYDEDEYMIQEEEWDRDLLLDPAWEKQQRKTFTAWCNSHLRKAGTQIENIEEDFRNGLKLMLLLE VISGERLPKPDRGKMRFHKIANVNKALDYIASKGVKLVSIGAEEIVDGNVKMTLGMIWTIILRFAIQDISVEETSAK EGLLLWCQRKTAPYRNVNIQNFHTSWKDGLGLCALIHRHRPDLIDYSKLNKDDPIGNINLAMEIAEKHLDIPKMLDA EDIVNTPKPDERAIMTYVSCFYHAFAGAEQAETAANRICKVLAVNQENERLMEEYERLASELLEWIRRTIPWLENRT PEKTMQAMQKKLEDFRDYRRKHKPPKVQEKCQLEINFNTLQTKLRISNRPAFMPSEGKMVSDIAGAWQRLEQAEKGY EEWLLNEIRRLERLEHLAEKFRQKASTHETWAYGKEQILLQKDYESASLTEVRALLRKHEAFESDLAAHQDRVEQIA AIAQELNELDYHDAVNVNDRCQKICDQWDRLGTLTQKRREALERMEKLLETIDQLHLEFAKRAAPFNNWMEGAMEDL QDMFIVHSIEEIQSLITAHEQFKATLPEADGERQSIMAIQNEVEKVIQSYNIRISSSNPYSTVTMDELRTKWDKVKQ LVPIRDQSLQEELARQHANERLRRQFAAQANAIGPWIQNKMEEIARSSIQITGALEDQMNQLKQYEHNIINYKNNID KLEGDHQLIQEALVFDNKHTNYTMEHIRVGWELLLTTIARTINEVETQILTRDAKGITQEQMNEFRASFNHFDRRKN GLMDHEDFRACLISMGYDLGEAEFARIMTLVDPNGQGTVTFQSFIDFMTRETADTDTAEQVIASFRILASDKPYILA EELRRELPPDQAQYCIKRMPAYSGPGSVPGALDYAAFSSALYGESDL* SEQ ID NO: 23 (PPP3CA nt, human) ATGTCCGAGCCCAAGGCAATTGATCCCAAGTTGTCGACGACCGACAGGGTGGTGAAAGCTGTTCCATTTCCTCCAAG TCACCGGCTTACAGCAAAAGAAGTGTTTGATAATGATGGAAAACCTCGTGTGGATATCTTAAAGGCGCATCTTATGA AGGAGGGAAGGCTGGAAGAGAGTGTTGCATTGAGAATAATAACAGAGGGTGCATCAATTCTTCGACAGGAAAAAAAT TTGCTGGATATTGATGCGCCAGTCACTGTTTGTGGGGACATTCATGGACAATTCTTTGATTTGATGAAGCTCTTTGA AGTCGGGGGATCTCCTGCCAACACTCGCTACCTCTTCTTAGGGGACTATGTTGACAGAGGGTACTTCAGTATTGAAT GTGTGCTGTATTTGTGGGCCTTGAAAATTCTCTACCCCAAAACACTGTTTTTACTTCGTGGAAATCATGAATGTAGA CATCTAACAGAGTATTTCACATTTAAACAAGAATGTAAAATAAAGTATTCAGAACGCGTATATGATGCCTGTATGGA TGCCTTTGACTGCCTTCCCCTGGCTGCCCTGATGAACCAACAGTTCCTGTGTGTGCATGGTGGTTTGTCTCCAGAGA TTAACACTTTAGATGATATCAGAAAATTAGACCGATTCAAAGAACCACCTGCATATGGACCTATGTGTGATATCCTG TGGTCAGACCCCCTGGAAGATTTTGGAAATGAGAAGACTCAGGAACATTTCACTCACAACACAGTCAGGGGGTGTTC ATACTTCTACAGTTACCCGGCTGTATGTGAATTCTTACAGCACAATAACTTGTTATCTATACTCCGAGCCCACGAAG CCCAAGATGCAGGGTACCGCATGTACAGGAAAAGCCAAACAACAGGCTTCCCTTCTCTAATTACAATTTTTTCAGCA CCAAATTACTTAGATGTATACAATAACAAAGCTGCAGTATTGAAGTATGAGAACAATGTTATGAATATCAGGCAATT CAACTGTTCTCCTCATCCATACTGGCTTCCAAATTTCATGGATGTTTTTACTTGGTCCCTTCCATTTGTTGGGGAAA AAGTGACTGAGATGCTGGTAAATGTCCTCAACATCTGCTCAGATGATGAACTAGGGTCAGAAGAAGATGGATTTGAT GGTGCAACAGCTGCAGCCCGGAAAGAGGTGATAAGGAACAAGATCCGAGCAATAGGCAAAATGGCCAGAGTGTTCTC AGTGCTCAGAGAAGAGAGTGAGAGTGTGCTGACGCTGAAAGGCTTGACCCCAACTGGCATGCTCCCCAGCGGAGTAC TTTCTGGAGGGAAGCAAACCCTGCAAAGCGCTACTGTTGAGGCTATTGAGGCTGATGAAGCTATCAAAGGATTTTCA CCACAACATAAGATCACTAGCTTCGAGGAAGCCAAGGGCTTAGACCGAATTAATGAGAGGATGCCGCCTCGCAGAGA TGCCATGCCCTCTGACGCCAACCTTAACTCCATCAACAAGGCTCTCACCTCAGAGACTAACGGCACGGACAGCAATG GCAGTAATAGCAGCAATATTCAGTGA SEQ ID NO: 24 (PPP3CA aa, human) MSEPKAIDPKLSTTDRVVKAVPFPPSHRLTAKEVFDNDGKPRVDILKAHLMKEGRLEESVALRIITEGASILRQEKN LLDIDAPVTVCGDIHGQFFDLMKLFEVGGSPANTRYLFLGDYVDRGYFSIECVLYLWALKILYPKTLFLLRGNHECR HLTEYFTFKQECKIKYSERVYDACMDAFDCLPLAALMNQQFLCVHGGLSPEINTLDDIRKLDRFKEPPAYGPMCDIL WSDPLEDFGNEKTQEHFTHNTVRGCSYFYSYPAVCEFLQHNNLLSILRAHEAQDAGYRMYRKSQTTGFPSLITIFSA PNYLDVYNNKAAVLKYENNVMNIRQFNCSPHPYWLPNFMDVFTWSLPFVGEKVTEMLVNVLNICSDDELGSEEDGFD GATAAARKEVIRNKIRAIGKMARVFSVLREESESVLTLKGLTPTGMLPSGVLSGGKQTLQSATVEAIEADEAIKGFS PQHKITSFEEAKGLDRINERMPPRRDAMPSDANLNSINKALTSETNGTDSNGSNSSNIQ* SEQ ID NO: 25 (CAMK2D nt, human) ATGGCTTCGACCACAACCTGCACCAGGTTCACGGACGAGTATCAGCTTTTCGAGGAGCTTGGAAAGGGGGCATTCTC AGTGGTGAGAAGATGTATGAAAATTCCTACTGGACAAGAATATGCTGCCAAAATTATCAACACCAAAAAGCTTTCTG CTAGGGATCATCAGAAACTAGAAAGAGAAGCTAGAATCTGCCGTCTTTTGAAGCACCCTAATATTGTGCGACTTCAT GATAGCATATCAGAAGAGGGCTTTCACTACTTGGTGTTTGATTTAGTTACTGGAGGTGAACTGTTTGAAGACATAGT GGCAAGAGAATACTACAGTGAAGCTGATGCCAGTCATTGTATACAGCAGATTCTAGAAAGTGTTAATCATTGTCACC TAAATGGCATAGTTCACAGGGACCTGAAGCCTGAGAATTTGCTTTTAGCTAGCAAATCCAAGGGAGCAGCTGTGAAA TTGGCAGACTTTGGCTTAGCCATAGAAGTTCAAGGGGACCAGCAGGCGTGGTTTGGTTTTGCTGGCACACCTGGATA TCTTTCTCCAGAAGTTTTACGTAAAGATCCTTATGGAAAGCCAGTGGATATGTGGGCATGTGGTGTCATTCTCTATA TTCTACTTGTGGGGTATCCACCCTTCTGGGATGAAGACCAACACAGACTCTATCAGCAGATCAAGGCTGGAGCTTAT GATTTTCCATCACCAGAATGGGACACGGTGACTCCTGAAGCCAAAGACCTCATCAATAAAATGCTTACTATCAACCC 35 24028 / / SLW 875.245WO1 TGCCAAACGCATCACAGCCTCAGAGGCACTGAAGCACCCATGGATCTGTCAACGTTCTACTGTTGCTTCCATGATGC ACAGACAGGAGACTGTAGACTGCTTGAAGAAATTTAATGCTAGAAGAAAACTAAAGGGTGCCATCTTGACAACTATG CTGGCTACAAGGAATTTCTCAGCAGCCAAGAGTTTGTTGAAGAAACCAGATGGAGTAAAGGAGTCAACTGAGAGTTC AAATACAACAATTGAGGATGAAGATGTGAAAGCACGAAAGCAAGAGATTATCAAAGTCACTGAACAACTGATCGAAG CTATCAACAATGGGGACTTTGAAGCCTACACAAAAATCTGTGACCCAGGCCTTACTGCTTTTGAACCTGAAGCTTTG GGTAATTTAGTGGAAGGGATGGATTTTCACCGATTCTACTTTGAAAATGCTTTGTCCAAAAGCAATAAACCAATCCA CACTATTATTCTAAACCCTCATGTACATCTGGTAGGGGATGATGCCGCCTGCATAGCATATATTAGGCTCACACAGT ACATGGATGGCAGTGGAATGCCAAAGACAATGCAGTCAGAAGAGACTCGTGTGTGGCACCGCCGGGATGGAAAGTGG CAGAATGTTCATTTTCATCGCTCGGGGTCACCAACAGTACCCATCAAGTAA SEQ ID NO: 26 (CAMK2D aa, human) MASTTTCTRFTDEYQLFEELGKGAFSVVRRCMKIPTGQEYAAKIINTKKLSARDHQKLEREARICRLLKHPNIVRLH DSISEEGFHYLVFDLVTGGELFEDIVAREYYSEADASHCIQQILESVNHCHLNGIVHRDLKPENLLLASKSKGAAVK LADFGLAIEVQGDQQAWFGFAGTPGYLSPEVLRKDPYGKPVDMWACGVILYILLVGYPPFWDEDQHRLYQQIKAGAY DFPSPEWDTVTPEAKDLINKMLTINPAKRITASEALKHPWICQRSTVASMMHRQETVDCLKKFNARRKLKGAILTTM LATRNFSAAKSLLKKPDGVKESTESSNTTIEDEDVKARKQEIIKVTEQLIEAINNGDFEAYTKICDPGLTAFEPEAL GNLVEGMDFHRFYFENALSKSNKPIHTIILNPHVHLVGDDAACIAYIRLTQYMDGSGMPKTMQSEETRVWHRRDGKW QNVHFHRSGSPTVPIK* SEQ ID NO: 27 (PRKCA nt, human) ATGGCTGACGTTTTCCCGGGCAACGACTCCACGGCGTCTCAGGACGTGGCCAACCGCTTCGCCCGCAAAGGGGCGCT GAGGCAGAAGAACGTGCACGAGGTGAAGGACCACAAATTCATCGCGCGCTTCTTCAAGCAGCCCACCTTCTGCAGCC ACTGCACCGACTTCATCTGGGGGTTTGGGAAACAAGGCTTCCAGTGCCAAGTTTGCTGTTTTGTGGTCCACAAGAGG TGCCATGAATTTGTTACTTTTTCTTGTCCGGGTGCGGATAAGGGACCCGACACTGATGACCCCAGGAGCAAGCACAA GTTCAAAATCCACACTTACGGAAGCCCCACCTTCTGCGATCACTGTGGGTCACTGCTCTATGGACTTATCCATCAAG GGATGAAATGTGACACCTGCGATATGAACGTTCACAAGCAATGCGTCATCAATGTCCCCAGCCTCTGCGGAATGGAT CACACTGAGAAGAGGGGGCGGATTTACCTAAAGGCTGAGGTTGCTGATGAAAAGCTCCATGTCACAGTACGAGATGC AAAAAATCTAATCCCTATGGATCCAAACGGGCTTTCAGATCCTTATGTGAAGCTGAAACTTATTCCTGATCCCAAGA ATGAAAGCAAGCAAAAAACCAAAACCATCCGCTCCACACTAAATCCGCAGTGGAATGAGTCCTTTACATTCAAATTG AAACCTTCAGACAAAGACCGACGACTGTCTGTAGAAATCTGGGACTGGGATCGAACAACAAGGAATGACTTCATGGG ATCCCTTTCCTTTGGAGTTTCGGAGCTGATGAAGATGCCGGCCAGTGGATGGTACAAGTTGCTTAACCAAGAAGAAG GTGAGTACTACAACGTACCCATTCCGGAAGGGGACGAGGAAGGAAACATGGAACTCAGGCAGAAATTCGAGAAAGCC AAACTTGGCCCTGCTGGCAACAAAGTCATCAGTCCCTCTGAAGACAGGAAACAACCTTCCAACAACCTTGACCGAGT GAAACTCACGGACTTCAATTTCCTCATGGTGTTGGGAAAGGGGAGTTTTGGAAAGGTGATGCTTGCCGACAGGAAGG GCACAGAAGAACTGTATGCAATCAAAATCCTGAAGAAGGATGTGGTGATTCAGGATGATGACGTGGAGTGCACCATG GTAGAAAAGCGAGTCTTGGCCCTGCTTGACAAACCCCCGTTCTTGACGCAGCTGCACTCCTGCTTCCAGACAGTGGA TCGGCTGTACTTCGTCATGGAATATGTCAACGGTGGGGACCTCATGTACCACATTCAGCAAGTAGGAAAATTTAAGG AACCACAAGCAGTATTCTATGCGGCAGAGATTTCCATCGGATTGTTCTTTCTTCATAAAAGAGGAATCATTTATAGG GATCTGAAGTTAGATAACGTCATGTTGGATTCAGAAGGACATATCAAAATTGCTGACTTTGGGATGTGCAAGGAACA CATGATGGATGGAGTCACGACCAGGACCTTCTGTGGGACTCCAGATTATATCGCCCCAGAGATAATCGCTTATCAGC CGTATGGAAAATCTGTGGACTGGTGGGCCTATGGCGTCCTGTTGTATGAAATGCTTGCCGGGCAGCCTCCATTTGAT GGTGAAGATGAAGACGAGCTATTTCAGTCTATCATGGAGCACAACGTTTCCTATCCAAAATCCTTGTCCAAGGAGGC TGTTTCTGTCTGCAAAGGACTGATGACCAAACACCCAGCCAAGCGGCTGGGCTGTGGGCCTGAGGGGGAGAGGGACG TGAGAGAGCATGCCTTCTTCCGGAGGATCGACTGGGAAAAACTGGAGAACAGGGAGATCCAGCCACCATTCAAGCCC AAAGTGTGTGGCAAAGGAGCAGAGAACTTTGACAAGTTCTTCACACGAGGACAGCCCGTCTTAACACCACCTGATCA GCTGGTTATTGCTAACATAGACCAGTCTGATTTTGAAGGGTTCTCGTATGTCAACCCCCAGTTTGTGCACCCCATCT TACAGAGTGCAGTATGA SEQ ID NO: 28 (PRKCA aa, human) MADVFPGNDSTASQDVANRFARKGALRQKNVHEVKDHKFIARFFKQPTFCSHCTDFIWGFGKQGFQCQVCCFVVHKR CHEFVTFSCPGADKGPDTDDPRSKHKFKIHTYGSPTFCDHCGSLLYGLIHQGMKCDTCDMNVHKQCVINVPSLCGMD HTEKRGRIYLKAEVADEKLHVTVRDAKNLIPMDPNGLSDPYVKLKLIPDPKNESKQKTKTIRSTLNPQWNESFTFKL KPSDKDRRLSVEIWDWDRTTRNDFMGSLSFGVSELMKMPASGWYKLLNQEEGEYYNVPIPEGDEEGNMELRQKFEKA KLGPAGNKVISPSEDRKQPSNNLDRVKLTDFNFLMVLGKGSFGKVMLADRKGTEELYAIKILKKDVVIQDDDVECTM VEKRVLALLDKPPFLTQLHSCFQTVDRLYFVMEYVNGGDLMYHIQQVGKFKEPQAVFYAAEISIGLFFLHKRGIIYR DLKLDNVMLDSEGHIKIADFGMCKEHMMDGVTTRTFCGTPDYIAPEIIAYQPYGKSVDWWAYGVLLYEMLAGQPPFD 36 24028 / / SLW 875.245WO1 GEDEDELFQSIMEHNVSYPKSLSKEAVSVCKGLMTKHPAKRLGCGPEGERDVREHAFFRRIDWEKLENREIQPPFKP KVCGKGAENFDKFFTRGQPVLTPPDQLVIANIDQSDFEGFSYVNPQFVHPILQSAV* SEQ ID NO: 29 (PTK2 nt, human) ATGGCAGCTGCTTACCTTGACCCCAACTTGAATCACACACCAAATTCGAGTACTAAGACTCACCTGGGTACTGGTAT GGAACGTTCTCCTGGTGCAATGGAGCGAGTATTAAAGGTCTTTCATTATTTTGAAAGCAATAGTGAGCCAACCACCT GGGCCAGTATTATCAGGCATGGAGATGCTACTGATGTCAGGGGCATCATTCAGAAGATAGTGGACAGTCACAAAGTA AAGCATGTGGCCTGCTATGGATTCCGCCTCAGTCACCTGCGGTCAGAGGAGGTTCACTGGCTTCACGTGGATATGGG CGTCTCCAGTGTGAGGGAGAAGTATGAGCTTGCTCACCCACCAGAGGAGTGGAAATATGAATTGAGAATTCGTTATT TGCCAAAAGGATTTCTAAACCAGTTTACTGAAGATAAGCCAACTTTGAATTTCTTCTATCAACAGGTGAAGAGCGAT TATATGTTAGAGATAGCTGATCAAGTGGACCAGGAAATTGCTTTGAAGTTGGGTTGTCTAGAAATACGGCGATCATA CTGGGAGATGCGGGGCAATGCACTAGAAAAGAAGTCTAACTATGAAGTATTAGAAAAAGATGTTGGTTTAAAGCGAT TTTTTCCTAAGAGTTTACTGGATTCTGTCAAGGCCAAAACACTAAGAAAACTGATCCAACAAACATTTAGACAATTT GCCAACCTTAATAGAGAAGAAAGTATTCTGAAATTCTTTGAGATCCTGTCTCCAGTCTACAGATTTGATAAGGAATG CTTCAAGTGTGCTCTTGGTTCAAGCTGGATTATTTCAGTGGAACTGGCAATCGGCCCAGAAGAAGGAATCAGTTACC TAACGGACAAGGGCTGCAATCCCACACATCTTGCTGACTTCACTCAAGTGCAAACCATTCAGTATTCAAACAGTGAA GACAAGGACAGAAAAGGAATGCTACAACTAAAAATAGCAGGTGCACCCGAGCCTCTGACAGTGACGGCACCATCCCT AACCATTGCGGAGAATATGGCTGACCTAATAGATGGGTACTGCCGGCTGGTGAATGGAACCTCGCAGTCATTTATCA TCAGACCTCAGAAAGAAGGTGAACGGGCTTTGCCATCAATACCAAAGTTGGCCAACAGCGAAAAGCAAGGCATGCGG ACACACGCCGTCTCTGTGTCAGAAACAGATGATTATGCTGAGATTATAGATGAAGAAGATACTTACACCATGCCCTC AACCAGGGATTATGAGATTCAAAGAGAAAGAATAGAACTTGGACGATGTATTGGAGAAGGCCAATTTGGAGATGTAC ATCAAGGCATTTATATGAGTCCAGAGAATCCAGCTTTGGCGGTTGCAATTAAAACATGTAAAAACTGTACTTCGGAC AGCGTGAGAGAGAAATTTCTTCAAGAAGCCTTAACAATGCGTCAGTTTGACCATCCTCATATTGTGAAGCTGATTGG AGTCATCACAGAGAATCCTGTCTGGATAATCATGGAGCTGTGCACACTTGGAGAGCTGAGGTCATTTTTGCAAGTAA GGAAATACAGTTTGGATCTAGCATCTTTGATCCTGTATGCCTATCAGCTTAGTACAGCTCTTGCATATCTAGAGAGC AAAAGATTTGTACACAGGGACATTGCTGCTCGGAATGTTCTGGTGTCCTCAAATGATTGTGTAAAATTAGGAGACTT TGGATTATCCCGATATATGGAAGATAGTACTTACTACAAAGCTTCCAAAGGAAAATTGCCTATTAAATGGATGGCTC CAGAGTCAATCAATTTTCGACGTTTTACCTCAGCTAGTGACGTATGGATGTTTGGTGTGTGTATGTGGGAGATACTG ATGCATGGTGTGAAGCCTTTTCAAGGAGTGAAGAACAATGATGTAATCGGTCGAATTGAAAATGGGGAAAGATTACC AATGCCTCCAAATTGTCCTCCTACCCTCTACAGCCTTATGACGAAATGCTGGGCCTATGACCCCAGCAGGCGGCCCA GGTTTACTGAACTTAAAGCTCAGCTCAGCACAATCCTGGAGGAAGAGAAGGCTCAGCAAGAAGAGCGCATGAGGATG GAGTCCAGAAGACAGGCCACAGTGTCCTGGGACTCCGGAGGGTCTGATGAAGCACCGCCCAAGCCCAGCAGACCGGG TTATCCCAGTCCGAGGTCCAGCGAAGGATTTTATCCCAGCCCACAGCACATGGTACAAACCAATCATTACCAGGTTT CTGGCTACCCTGGTTCACATGGAATCACAGCCATGGCTGGCAGCATCTATCCAGGTCAGGCATCTCTTTTGGACCAA ACAGATTCATGGAATCATAGACCTCAGGAGATAGCAATGTGGCAGCCCAATGTGGAGGACTCTACAGTATTGGACCT GCGAGGGATTGGGCAAGTGTTGCCAACCCATCTGATGGAAGAGCGTCTAATCCGACAGCAACAGGAAATGGAAGAAG ATCAGCGCTGGCTGGAAAAAGAGGAAAGATTTCTGAAACCTGATGTGAGACTCTCTCGAGGCAGTATTGACAGGGAG GATGGAAGTCTTCAGGGTCCGATTGGAAACCAACATATATATCAGCCTGTGGGTAAACCAGATCCTGCAGCTCCACC AAAGAAACCGCCTCGCCCTGGAGCTCCCGGTCATCTGGGAAGCCTTGCCAGCCTCAGCAGCCCTGCTGACAGCTACA ACGAGGGTGTCAAGCTTCAGCCCCAGGAAATCAGCCCCCCTCCTACTGCCAACCTGGACCGGTCGAATGATAAGGTG TACGAGAATGTGACGGGCCTGGTGAAAGCTGTCATCGAGATGTCCAGTAAAATCCAGCCAGCCCCACCAGAGGAGTA TGTCCCTATGGTGAAGGAAGTCGGCTTGGCCCTGAGGACATTATTGGCCACTGTGGATGAGACCATTCCCCTCCTAC CAGCCAGCACCCACCGAGAGATTGAGATGGCACAGAAGCTATTGAACTCTGACCTGGGTGAGCTCATCAACAAGATG AAACTGGCCCAGCAGTATGTCATGACCAGCCTCCAGCAAGAGTACAAAAAGCAAATGCTGACTGCTGCTCACGCCCT GGCTGTGGATGCCAAAAACTTACTCGATGTCATTGACCAAGCAAGACTGAAAATGCTTGGGCAGACGAGACCACACT GA SEQ ID NO: 30 (PTK2 aa, human) MAAAYLDPNLNHTPNSSTKTHLGTGMERSPGAMERVLKVFHYFESNSEPTTWASIIRHGDATDVRGIIQKIVDSHKV KHVACYGFRLSHLRSEEVHWLHVDMGVSSVREKYELAHPPEEWKYELRIRYLPKGFLNQFTEDKPTLNFFYQQVKSD YMLEIADQVDQEIALKLGCLEIRRSYWEMRGNALEKKSNYEVLEKDVGLKRFFPKSLLDSVKAKTLRKLIQQTFRQF ANLNREESILKFFEILSPVYRFDKECFKCALGSSWIISVELAIGPEEGISYLTDKGCNPTHLADFTQVQTIQYSNSE DKDRKGMLQLKIAGAPEPLTVTAPSLTIAENMADLIDGYCRLVNGTSQSFIIRPQKEGERALPSIPKLANSEKQGMR THAVSVSETDDYAEIIDEEDTYTMPSTRDYEIQRERIELGRCIGEGQFGDVHQGIYMSPENPALAVAIKTCKNCTSD SVREKFLQEALTMRQFDHPHIVKLIGVITENPVWIIMELCTLGELRSFLQVRKYSLDLASLILYAYQLSTALAYLES KRFVHRDIAARNVLVSSNDCVKLGDFGLSRYMEDSTYYKASKGKLPIKWMAPESINFRRFTSASDVWMFGVCMWEIL MHGVKPFQGVKNNDVIGRIENGERLPMPPNCPPTLYSLMTKCWAYDPSRRPRFTELKAQLSTILEEEKAQQEERMRM 37 24028 / / SLW 875.245WO1 ESRRQATVSWDSGGSDEAPPKPSRPGYPSPRSSEGFYPSPQHMVQTNHYQVSGYPGSHGITAMAGSIYPGQASLLDQ TDSWNHRPQEIAMWQPNVEDSTVLDLRGIGQVLPTHLMEERLIRQQQEMEEDQRWLEKEERFLKPDVRLSRGSIDRE DGSLQGPIGNQHIYQPVGKPDPAAPPKKPPRPGAPGHLGSLASLSSPADSYNEGVKLQPQEISPPPTANLDRSNDKV YENVTGLVKAVIEMSSKIQPAPPEEYVPMVKEVGLALRTLLATVDETIPLLPASTHREIEMAQKLLNSDLGELINKM KLAQQYVMTSLQQEYKKQMLTAAHALAVDAKNLLDVIDQARLKMLGQTRPH* SEQ ID NO: 31 (TNNI3 nt, human) ATGGCGGATGGGAGCAGCGATGCGGCTAGGGAACCTCGCCCTGCACCAGCCCCAATCAGACGCCGCTCCTCCAACTA CCGCGCTTATGCCACGGAGCCGCACGCCAAGAAAAAATCTAAGATCTCCGCCTCGAGAAAATTGCAGCTGAAGACTC TGCTGCTGCAGATTGCAAAGCAAGAGCTGGAGCGAGAGGCGGAGGAGCGGCGCGGAGAGAAGGGGCGCGCTCTGAGC ACCCGCTGCCAGCCGCTGGAGTTGGCCGGGCTGGGCTTCGCGGAGCTGCAGGACTTGTGCCGACAGCTCCACGCCCG TGTGGACAAGGTGGATGAAGAGAGATACGACATAGAGGCAAAAGTCACCAAGAACATCACGGAGATTGCAGATCTGA CTCAGAAGATCTTTGACCTTCGAGGCAAGTTTAAGCGGCCCACCCTGCGGAGAGTGAGGATCTCTGCAGATGCCATG ATGCAGGCGCTGCTGGGGGCCCGGGCTAAGGAGTCCCTGGACCTGCGGGCCCACCTCAAGCAGGTGAAGAAGGAGGA CACCGAGAAGGAAAACCGGGAGGTGGGAGACTGGCGCAAGAACATCGATGCACTGAGTGGAATGGAGGGCCGCAAGA AAAAGTTTGAGAGCTGA SEQ ID NO: 32 (TNNI3 aa, human) MADGSSDAAREPRPAPAPIRRRSSNYRAYATEPHAKKKSKISASRKLQLKTLLLQIAKQELEREAEERRGEKGRALS TRCQPLELAGLGFAELQDLCRQLHARVDKVDEERYDIEAKVTKNITEIADLTQKIFDLRGKFKRPTLRRVRISADAM MQALLGARAKESLDLRAHLKQVKKEDTEKENREVGDWRKNIDALSGMEGRKKKFES* SEQ ID NO: 33 (TNNT2 nt, human) ATGTCTGACATAGAAGAGGTGGTGGAAGAGTACGAGGAGGAGGAGCAGGAAGAAGCAGCTGTTGAAGAAGAGGAGGA CTGGAGAGAGGACGAAGACGAGCAGGAGGAGGCAGCGGAAGAGGATGCTGAAGCAGAGGCTGAGACCGAGGAGACCA GGGCAGAAGAAGATGAAGAAGAAGAGGAAGCAAAGGAGGCTGAAGATGGCCCAATGGAGGAGTCCAAACCAAAGCCC AGGTCGTTCATGCCCAACTTGGTGCCTCCCAAGATCCCCGATGGAGAGAGAGTGGACTTTGATGACATCCACCGGAA GCGCATGGAGAAGGACCTGAATGAGTTGCAGGCGCTGATCGAGGCTCACTTTGAGAACAGGAAGAAAGAGGAGGAGG AGCTCGTTTCTCTCAAAGACAGGATCGAGAGACGTCGGGCAGAGCGGGCCGAGCAGCAGCGCATCCGGAATGAGCGG GAGAAGGAGCGGCAGAACCGCCTGGCTGAAGAGAGGGCTCGACGAGAGGAGGAGGAGAACAGGAGGAAGGCTGAGGA TGAGGCCCGGAAGAAGAAGGCTTTGTCCAACATGATGCATTTTGGGGGTTACATCCAGAAGACAGAGCGGAAAAGTG GGAAGAGGCAGACTGAGCGGGAAAAGAAGAAGAAGATTCTGGCTGAGAGGAGGAAGGTGCTGGCCATTGACCACCTG AATGAAGATCAGCTGAGGGAGAAGGCCAAGGAGCTGTGGCAGAGCATCTATAACTTGGAGGCAGAGAAGTTCGACCT GCAGGAGAAGTTCAAGCAGCAGAAATATGAGATCAATGTTCTCCGAAACAGGATCAACGATAACCAGAAAGTCTCCA AGACCCGCGGGAAGGCTAAAGTCACCGGGCGCTGGAAATAG SEQ ID NO: 34 (TNNT2 aa, human) MSDIEEVVEEYEEEEQEEAAVEEEEDWREDEDEQEEAAEEDAEAEAETEETRAEEDEEEEEAKEAEDGPMEESKPKP RSFMPNLVPPKIPDGERVDFDDIHRKRMEKDLNELQALIEAHFENRKKEEEELVSLKDRIERRRAERAEQQRIRNER EKERQNRLAEERARREEEENRRKAEDEARKKKALSNMMHFGGYIQKTERKSGKRQTEREKKKKILAERRKVLAIDHL NEDQLREKAKELWQSIYNLEAEKFDLQEKFKQQKYEINVLRNRINDNQKVSKTRGKAKVTGRWK* SEQ ID NO: 35 (MYBPC3 nt, human) ATGCCTGAGCCGGGGAAGAAGCCAGTCTCAGCTTTTAGCAAGAAGCCACGGTCAGTGGAAGTGGCCGCAGGCAGCCC TGCCGTGTTCGAGGCCGAGACAGAGCGGGCAGGAGTGAAGGTGCGCTGGCAGCGCGGAGGCAGTGACATCAGCGCCA GCAACAAGTACGGCCTGGCCACAGAGGGCACACGGCATACGCTGACAGTGCGGGAAGTGGGCCCTGCCGACCAGGGA TCTTACGCAGTCATTGCTGGCTCCTCCAAGGTCAAGTTCGACCTCAAGGTCATAGAGGCAGAGAAGGCAGAGCCCAT GCTGGCCCCTGCCCCTGCCCCTGCTGAGGCCACTGGAGCCCCTGGAGAAGCCCCGGCCCCAGCCGCTGAGCTGGGAG AAAGTGCCCCAAGTCCCAAAGGGTCAAGCTCAGCAGCTCTCAATGGTCCTACCCCTGGAGCCCCCGATGACCCCATT GGCCTCTTCGTGATGCGGCCACAGGATGGCGAGGTGACCGTGGGTGGCAGCATCACCTTCTCAGCCCGCGTGGCCGG CGCCAGCCTCCTGAAGCCGCCTGTGGTCAAGTGGTTCAAGGGCAAATGGGTGGACCTGAGCAGCAAGGTGGGCCAGC ACCTGCAGCTGCACGACAGCTACGACCGCGCCAGCAAGGTCTATCTGTTCGAGCTGCACATCACCGATGCCCAGCCT GCCTTCACTGGCAGCTACCGCTGTGAGGTGTCCACCAAGGACAAATTTGACTGCTCCAACTTCAATCTCACTGTCCA CGAGGCCATGGGCACCGGAGACCTGGACCTCCTATCAGCCTTCCGCCGCACGAGCCTGGCTGGAGGTGGTCGGCGGA TCAGTGATAGCCATGAGGACACTGGGATTCTGGACTTCAGCTCACTGCTGAAAAAGAGAGACAGTTTCCGGACCCCG 38 24028 / / SLW 875.245WO1 AGGGACTCGAAGCTGGAGGCACCAGCAGAGGAGGACGTGTGGGAGATCCTACGGCAGGCACCCCCATCTGAGTACGA GCGCATCGCCTTCCAGTACGGCGTCACTGACCTGCGCGGCATGCTAAAGAGGCTCAAGGGCATGAGGCGCGATGAGA AGAAGAGCACAGCCTTTCAGAAGAAGCTGGAGCCGGCCTACCAGGTGAGCAAAGGCCACAAGATCCGGCTGACCGTG GAACTGGCTGACCATGACGCTGAGGTCAAATGGCTCAAGAATGGCCAGGAGATCCAGATGAGCGGCAGCAAGTACAT CTTTGAGTCCATCGGTGCCAAGCGTACCCTGACCATCAGCCAGTGCTCATTGGCGGACGACGCAGCCTACCAGTGCG TGGTGGGTGGCGAGAAGTGTAGCACGGAGCTCTTTGTGAAAGAGCCCCCTGTGCTCATCACGCGCCCCTTGGAGGAC CAGCTGGTGATGGTGGGGCAGCGGGTGGAGTTTGAGTGTGAAGTATCGGAGGAGGGGGCGCAAGTCAAATGGCTGAA GGACGGGGTGGAGCTGACCCGGGAGGAGACCTTCAAATACCGGTTCAAGAAGGACGGGCAGAGACACCACCTGATCA TCAACGAGGCCATGCTGGAGGACGCGGGGCACTATGCACTGTGCACTAGCGGGGGCCAGGCGCTGGCTGAGCTCATT GTGCAGGAAAAGAAGCTGGAGGTGTACCAGAGCATCGCAGACCTGATGGTGGGCGCAAAGGACCAGGCGGTGTTCAA ATGTGAGGTCTCAGATGAGAATGTTCGGGGTGTGTGGCTGAAGAATGGGAAGGAGCTGGTGCCCGACAGCCGCATAA AGGTGTCCCACATCGGGCGGGTCCACAAACTGACCATTGACGACGTCACACCTGCCGACGAGGCTGACTACAGCTTT GTGCCCGAGGGCTTCGCCTGCAACCTGTCAGCCAAGCTCCACTTCATGGAGGTCAAGATTGACTTCGTACCCAGGCA GGAACCTCCCAAGATCCACCTGGACTGCCCAGGCCGCATACCAGACACCATTGTGGTTGTAGCTGGAAATAAGCTAC GTCTGGACGTCCCTATCTCTGGGGACCCTGCTCCCACTGTGATCTGGCAGAAGGCTATCACGCAGGGGAATAAGGCC CCAGCCAGGCCAGCCCCAGATGCCCCAGAGGACACAGGTGACAGCGATGAGTGGGTGTTTGACAAGAAGCTGCTGTG TGAGACCGAGGGCCGGGTCCGCGTGGAGACCACCAAGGACCGCAGCATCTTCACGGTCGAGGGGGCAGAGAAGGAAG ATGAGGGCGTCTACACGGTCACAGTGAAGAACCCTGTGGGCGAGGACCAGGTCAACCTCACAGTCAAGGTCATCGAC GTGCCAGACGCACCTGCGGCCCCCAAGATCAGCAACGTGGGAGAGGACTCCTGCACAGTACAGTGGGAGCCGCCTGC CTACGATGGCGGGCAGCCCATCCTGGGCTACATCCTGGAGCGCAAGAAGAAGAAGAGCTACCGGTGGATGCGGCTGA ACTTCGACCTGATTCAGGAGCTGAGTCATGAAGCGCGGCGCATGATCGAGGGCGTGGTGTACGAGATGCGCGTCTAC GCGGTCAACGCCATCGGCATGTCCAGGCCCAGCCCTGCCTCCCAGCCCTTCATGCCTATCGGTCCCCCCAGCGAACC CACCCACCTGGCAGTAGAGGACGTCTCTGACACCACGGTCTCCCTCAAGTGGCGGCCCCCAGAGCGCGTGGGAGCAG GAGGCCTGGATGGCTACAGCGTGGAGTACTGCCCAGAGGGCTGCTCAGAGTGGGTGGCTGCCCTGCAGGGGCTGACA GAGCACACATCGATACTGGTGAAGGACCTGCCCACGGGGGCCCGGCTGCTTTTCCGAGTGCGGGCACACAATATGGC AGGGCCTGGAGCCCCTGTTACCACCACGGAGCCGGTGACAGTGCAGGAGATCCTGCAACGGCCACGGCTTCAGCTGC CCAGGCACCTGCGCCAGACCATTCAGAAGAAGGTCGGGGAGCCTGTGAACCTTCTCATCCCTTTCCAGGGCAAGCCC CGGCCTCAGGTGACCTGGACCAAAGAGGGGCAGCCCCTGGCAGGCGAGGAGGTGAGCATCCGCAACAGCCCCACAGA CACCATCCTGTTCATCCGGGCCGCTCGCCGCGTGCATTCAGGCACTTACCAGGTGACGGTGCGCATTGAGAACATGG AGGACAAGGCCACGCTGGTGCTGCAGGTTGTTGACAAGCCAAGTCCTCCCCAGGATCTCCGGGTGACTGACGCCTGG GGTCTTAATGTGGCTCTGGAGTGGAAGCCACCCCAGGATGTCGGCAACACGGAGCTCTGGGGGTACACAGTGCAGAA AGCCGACAAGAAGACCATGGAGTGGTTCACCGTCTTGGAGCATTACCGCCGCACCCACTGCGTGGTGCCAGAGCTCA TCATTGGCAATGGCTACTACTTCCGCGTCTTCAGCCAGAATATGGTTGGCTTTAGTGACAGAGCGGCCACCACCAAG GAGCCCGTCTTTATCCCCAGACCAGGCATCACCTATGAGCCACCCAACTATAAGGCCCTGGACTTCTCCGAGGCCCC AAGCTTCACCCAGCCCCTGGTGAACCGCTCGGTCATCGCGGGCTACACTGCTATGCTCTGCTGTGCTGTCCGGGGTA GCCCCAAGCCCAAGATTTCCTGGTTCAAGAATGGCCTGGACCTGGGAGAAGACGCCCGCTTCCGCATGTTCAGCAAG CAGGGAGTGTTGACTCTGGAGATTAGAAAGCCCTGCCCCTTTGACGGGGGCATCTATGTCTGCAGGGCCACCAACTT ACAGGGCGAGGCACGGTGTGAGTGCCGCCTGGAGGTGCGAGTGCCTCAGTGA SEQ ID NO: 36 (MYBPC3 aa, human) MPEPGKKPVSAFSKKPRSVEVAAGSPAVFEAETERAGVKVRWQRGGSDISASNKYGLATEGTRHTLTVREVGPADQG SYAVIAGSSKVKFDLKVIEAEKAEPMLAPAPAPAEATGAPGEAPAPAAELGESAPSPKGSSSAALNGPTPGAPDDPI GLFVMRPQDGEVTVGGSITFSARVAGASLLKPPVVKWFKGKWVDLSSKVGQHLQLHDSYDRASKVYLFELHITDAQP AFTGSYRCEVSTKDKFDCSNFNLTVHEAMGTGDLDLLSAFRRTSLAGGGRRISDSHEDTGILDFSSLLKKRDSFRTP RDSKLEAPAEEDVWEILRQAPPSEYERIAFQYGVTDLRGMLKRLKGMRRDEKKSTAFQKKLEPAYQVSKGHKIRLTV ELADHDAEVKWLKNGQEIQMSGSKYIFESIGAKRTLTISQCSLADDAAYQCVVGGEKCSTELFVKEPPVLITRPLED QLVMVGQRVEFECEVSEEGAQVKWLKDGVELTREETFKYRFKKDGQRHHLIINEAMLEDAGHYALCTSGGQALAELI VQEKKLEVYQSIADLMVGAKDQAVFKCEVSDENVRGVWLKNGKELVPDSRIKVSHIGRVHKLTIDDVTPADEADYSF VPEGFACNLSAKLHFMEVKIDFVPRQEPPKIHLDCPGRIPDTIVVVAGNKLRLDVPISGDPAPTVIWQKAITQGNKA PARPAPDAPEDTGDSDEWVFDKKLLCETEGRVRVETTKDRSIFTVEGAEKEDEGVYTVTVKNPVGEDQVNLTVKVID VPDAPAAPKISNVGEDSCTVQWEPPAYDGGQPILGYILERKKKKSYRWMRLNFDLIQELSHEARRMIEGVVYEMRVY AVNAIGMSRPSPASQPFMPIGPPSEPTHLAVEDVSDTTVSLKWRPPERVGAGGLDGYSVEYCPEGCSEWVAALQGLT EHTSILVKDLPTGARLLFRVRAHNMAGPGAPVTTTEPVTVQEILQRPRLQLPRHLRQTIQKKVGEPVNLLIPFQGKP RPQVTWTKEGQPLAGEEVSIRNSPTDTILFIRAARRVHSGTYQVTVRIENMEDKATLVLQVVDKPSPPQDLRVTDAW GLNVALEWKPPQDVGNTELWGYTVQKADKKTMEWFTVLEHYRRTHCVVPELIIGNGYYFRVFSQNMVGFSDRAATTK EPVFIPRPGITYEPPNYKALDFSEAPSFTQPLVNRSVIAGYTAMLCCAVRGSPKPKISWFKNGLDLGEDARFRMFSK QGVLTLEIRKPCPFDGGIYVCRATNLQGEARCECRLEVRVPQ* 39 24028 / / SLW 875.245WO1 SEQ ID NO: 37 (LAMP2 nt, human) ATGGTGTGCTTCCGCCTCTTCCCGGTTCCGGGCTCAGGGCTCGTTCTGGTCTGCCTAGTCCTGGGAGCTGTGCGGTC TTATGCATTGGAACTTAATTTGACAGATTCAGAAAATGCCACTTGCCTTTATGCAAAATGGCAGATGAATTTCACAG TACGCTATGAAACTACAAATAAAACTTATAAAACTGTAACCATTTCAGACCATGGCACTGTGACATATAATGGAAGC ATTTGTGGGGATGATCAGAATGGTCCCAAAATAGCAGTGCAGTTCGGACCTGGCTTTTCCTGGATTGCGAATTTTAC CAAGGCAGCATCTACTTATTCAATTGACAGCGTCTCATTTTCCTACAACACTGGTGATAACACAACATTTCCTGATG CTGAAGATAAAGGAATTCTTACTGTTGATGAACTTTTGGCCATCAGAATTCCATTGAATGACCTTTTTAGATGCAAT AGTTTATCAACTTTGGAAAAGAATGATGTTGTCCAACACTACTGGGATGTTCTTGTACAAGCTTTTGTCCAAAATGG CACAGTGAGCACAAATGAGTTCCTGTGTGATAAAGACAAAACTTCAACAGTGGCACCCACCATACACACCACTGTGC CATCTCCTACTACAACACCTACTCCAAAGGAAAAACCAGAAGCTGGAACCTATTCAGTTAATAATGGCAATGATACT TGTCTGCTGGCTACCATGGGGCTGCAGCTGAACATCACTCAGGATAAGGTTGCTTCAGTTATTAACATCAACCCCAA TACAACTCACTCCACAGGCAGCTGCCGTTCTCACACTGCTCTACTTAGACTCAATAGCAGCACCATTAAGTATCTAG ACTTTGTCTTTGCTGTGAAAAATGAAAACCGATTTTATCTGAAGGAAGTGAACATCAGCATGTATTTGGTTAATGGC TCCGTTTTCAGCATTGCAAATAACAATCTCAGCTACTGGGATGCCCCCCTGGGAAGTTCTTATATGTGCAACAAAGA GCAGACTGTTTCAGTGTCTGGAGCATTTCAGATAAATACCTTTGATCTAAGGGTTCAGCCTTTCAATGTGACACAAG GAAAGTATTCTACAGCTCAAGACTGCAGTGCAGATGACGACAACTTCCTTGTGCCCATAGCGGTGGGAGCTGCCTTG GCAGGAGTACTTATTCTAGTGTTGCTGGCTTATTTTATTGGTCTCAAGCACCATCATGCTGGATATGAGCAATTTTA G SEQ ID NO: 38 (LAPM2 aa, human) MVCFRLFPVPGSGLVLVCLVLGAVRSYALELNLTDSENATCLYAKWQMNFTVRYETTNKTYKTVTISDHGTVTYNGS ICGDDQNGPKIAVQFGPGFSWIANFTKAASTYSIDSVSFSYNTGDNTTFPDAEDKGILTVDELLAIRIPLNDLFRCN SLSTLEKNDVVQHYWDVLVQAFVQNGTVSTNEFLCDKDKTSTVAPTIHTTVPSPTTTPTPKEKPEAGTYSVNNGNDT CLLATMGLQLNITQDKVASVININPNTTHSTGSCRSHTALLRLNSSTIKYLDFVFAVKNENRFYLKEVNISMYLVNG SVFSIANNNLSYWDAPLGSSYMCNKEQTVSVSGAFQINTFDLRVQPFNVTQGKYSTAQDCSADDDNFLVPIAVGAAL AGVLILVLLAYFIGLKHHHAGYEQF* SEQ ID NO: 39 (AIFM1 nt, human) ATGTTCCGGTGTGGAGGCCTGGCGGCGGGTGCTTTGAAGCAGAAGCTGGTGCCCTTGGTGCGGACCGTGTGCGTCCG AAGCCCGAGGCAGAGGAACCGGCTCCCAGGCAACTTGTTCCAGCGATGGCATGTTCCTCTAGAACTCCAGATGACAA GACAAATGGCTAGCTCTGGTGCATCAGGGGGCAAAATCGATAATTCTGTGTTAGTCCTTATTGTGGGCTTATCAACA GTAGGAGCTGGTGCCTATGCCTACAAGACTATGAAAGAGGATGAAAAAAGATACAATGAAAGAATTTCAGGGTTAGG GCTGACACCAGAACAGAAACAGAAAAAGGCCGCGTTATCTGCTTCAGAAGGAGAGGAAGTTCCTCAAGACAAGGCGC CAAGTCATGTTCCTTTCCTGCTAATTGGTGGAGGCACAGCTGCTTTTGCTGCAGCCAGATCCATCCGGGCTCGGGAT CCTGGGGCCAGGGTACTGATTGTATCTGAAGATCCTGAGCTGCCGTACATGCGACCTCCTCTTTCAAAAGAACTGTG GTTTTCAGATGACCCAAATGTCACAAAGACACTGCGATTCAAACAGTGGAATGGAAAAGAGAGAAGCATATATTTCC AGCCACCTTCTTTCTATGTCTCTGCTCAGGACCTGCCTCATATTGAGAATGGTGGTGTGGCTGTCCTCACTGGGAAG AAGGTAGTACAGCTGGATGTGAGAGACAACATGGTGAAACTTAATGATGGCTCTCAAATAACCTATGAAAAGTGCTT GATTGCAACAGGAGGTACTCCAAGAAGTCTGTCTGCCATTGATAGGGCTGGAGCAGAGGTGAAGAGTAGAACAACGC TTTTCAGAAAGATTGGAGACTTTAGAAGCTTGGAGAAGATTTCACGGGAAGTCAAATCAATTACGATTATCGGTGGG GGCTTCCTTGGTAGCGAACTGGCCTGTGCTCTTGGCAGAAAGGCTCGAGCCTTGGGCACAGAAGTGATTCAACTCTT CCCCGAGAAAGGAAATATGGGAAAGATCCTCCCCGAATACCTCAGCAACTGGACCATGGAAAAAGTCAGACGAGAGG GGGTTAAGGTGATGCCCAATGCTATTGTGCAATCCGTTGGAGTCAGCAGTGGCAAGTTACTTATCAAGCTGAAAGAC GGCAGGAAGGTAGAAACTGACCACATAGTGGCAGCTGTGGGCCTGGAGCCCAATGTTGAGTTGGCCAAGACTGGTGG CCTGGAAATAGACTCAGATTTTGGTGGCTTCCGGGTAAATGCAGAGCTACAAGCACGCTCTAACATCTGGGTGGCAG GAGATGCTGCATGCTTCTACGATATAAAGTTGGGAAGGAGGCGGGTAGAGCACCATGATCACGCTGTTGTGAGTGGA AGATTGGCTGGAGAAAATATGACTGGAGCTGCTAAGCCGTACTGGCATCAGTCAATGTTCTGGAGTGATTTGGGCCC CGATGTTGGCTATGAAGCTATTGGTCTTGTGGACAGTAGTTTGCCCACAGTTGGTGTTTTTGCAAAAGCAACTGCAC AAGACAACCCCAAATCTGCCACAGAGCAGTCAGGAACTGGTATCCGATCAGAGAGTGAGACAGAGTCCGAGGCCTCA GAAATTACTATTCCTCCCAGCACCCCGGCAGTTCCACAGGCTCCCGTCCAGGGGGAGGACTACGGCAAAGGTGTCAT CTTCTACCTCAGGGACAAAGTGGTCGTGGGGATTGTGCTATGGAACATCTTTAACCGAATGCCAATAGCAAGGAAGA TCATTAAGGACGGTGAGCAGCATGAAGATCTCAATGAAGTAGCCAAACTATTCAACATTCATGAAGACTGA SEQ ID NO: 40 (AIFM1 aa, human) 40 24028 / / SLW 875.245WO1 MFRCGGLAAGALKQKLVPLVRTVCVRSPRQRNRLPGNLFQRWHVPLELQMTRQMASSGASGGKIDNSVLVLIVGLST VGAGAYAYKTMKEDEKRYNERISGLGLTPEQKQKKAALSASEGEEVPQDKAPSHVPFLLIGGGTAAFAAARSIRARD PGARVLIVSEDPELPYMRPPLSKELWFSDDPNVTKTLRFKQWNGKERSIYFQPPSFYVSAQDLPHIENGGVAVLTGK KVVQLDVRDNMVKLNDGSQITYEKCLIATGGTPRSLSAIDRAGAEVKSRTTLFRKIGDFRSLEKISREVKSITIIGG GFLGSELACALGRKARALGTEVIQLFPEKGNMGKILPEYLSNWTMEKVRREGVKVMPNAIVQSVGVSSGKLLIKLKD GRKVETDHIVAAVGLEPNVELAKTGGLEIDSDFGGFRVNAELQARSNIWVAGDAACFYDIKLGRRRVEHHDHAVVSG RLAGENMTGAAKPYWHQSMFWSDLGPDVGYEAIGLVDSSLPTVGVFAKATAQDNPKSATEQSGTGIRSESETESEAS EITIPPSTPAVPQAPVQGEDYGKGVIFYLRDKVVVGIVLWNIFNRMPIARKIIKDGEQHEDLNEVAKLFNIHED* SEQ ID NO: 41 (SPTBN2 nt, human) ATGAGCAGCACGCTGTCACCCACAGACTTTGACAGCTTGGAAATCCAGGGCCAGTACAGTGACATCAACAACCGCTG GGACCTTCCTGACTCGGACTGGGACAATGACAGCAGCTCGGCCCGCCTCTTTGAGAGGTCTCGCATTAAGGCTCTGG CAGATGAACGAGAAGCTGTGCAGAAGAAAACCTTCACCAAGTGGGTAAACTCGCACCTGGCCCGGGTCACGTGCCGG GTGGGGGACCTGTACAGCGACCTCCGGGACGGACGCAACCTGCTGAGGCTCCTCGAGGTGCTCTCGGGAGAGATACT GCCAAAGCCTACAAAGGGCCGCATGCGGATCCACTGCCTGGAGAACGTGGACAAGGCACTGCAGTTCCTCAAGGAGC AGAAAGTGCACTTGGAAAACATGGGCTCCCATGACATTGTGGACGGAAACCACCGACTGACCCTTGGGCTGGTCTGG ACCATCATCCTTCGATTCCAGATCCAAGACATCAGTGTGGAGACAGAAGACAACAAGGAGAAGAAGTCAGCCAAGGA TGCCCTGCTTCTGTGGTGCCAGATGAAGACTGCAGGTTATCCCAACGTCAATGTACACAACTTCACCACCAGCTGGA GAGATGGACTAGCTTTCAACGCCATCGTGCATAAACACCGGCCAGACCTGCTGGATTTTGAGTCTCTGAAGAAGTGT AATGCACACTATAATCTGCAGAATGCATTCAATCTGGCTGAAAAGGAACTGGGACTTACCAAGCTGCTGGATCCCGA AGACGTGAATGTGGACCAGCCAGATGAGAAGTCAATCATTACCTATGTGGCTACTTACTACCATTACTTCTCCAAGA TGAAGGCCCTGGCCGTGGAAGGCAAGAGAATTGGCAAGGTGCTGGACCATGCCATGGAGGCAGAGCGCCTGGTGGAG AAATACGAGTCCCTGGCCTCGGAGCTGCTGCAGTGGATCGAGCAAACGATCGTGACCCTCAATGACCGGCAGTTGGC CAACTCCCTTAGCGGGGTCCAGAACCAGCTGCAGTCCTTCAACTCCTACCGCACCGTGGAGAAGCCGCCCAAGTTTA CCGAGAAAGGGAACTTGGAAGTGCTGCTCTTCACCATCCAGAGCAAGCTTCGGGCCAACAACCAGAAGGTCTACACG CCCCGCGAGGGCCGGCTCATCTCGGACATCAACAAGGCTTGGGAGCGGCTGGAGAAGGCGGAGCACGAGCGTGAGCT GGCCCTGCGCACCGAGCTCATCCGCCAGGAGAAGCTGGAGCAGCTGGCCGCCCGCTTCGACCGCAAGGCTGCCATGC GGGAGACCTGGCTCAGCGAGAACCAGCGCCTCGTGTCCCAGGACAACTTTGGGCTGGAGCTGGCAGCTGTCGAGGCA GCAGTACGGAAGCACGAAGCCATTGAGACGGACATCGTGGCCTACAGCGGCCGGGTGCAGGCAGTGGACGCCGTGGC TGCAGAGCTGGCCGCCGAGCGCTACCACGACATCAAGCGCATCGCCGCTCGGCAGCACAACGTGGCACGGCTCTGGG ACTTCTTGCGGCAGATGGTGGCCGCCCGGCGGGAGCGGCTCCTCCTCAACCTGGAGCTGCAGAAGGTGTTCCAGGAC CTGCTCTACCTCATGGACTGGATGGAAGAGATGAAGGGCCGGCTGCAGTCTCAGGACCTGGGCAGGCACCTAGCAGG AGTGGAGGACCTGCTGCAGCTGCACGAGCTGGTGGAGGCAGACATCGCCGTGCAGGCCGAGAGGGTGCGGGCCGTCA GCGCCTCTGCCCTGCGCTTCTGCAACCCAGGGAAAGAGTATAGACCTTGCGACCCGCAGCTGGTGTCGGAGCGGGTG GCCAAGCTAGAGCAGAGCTATGAGGCACTGTGCGAGTTGGCAGCGGCGCGGCGGGCCCGGCTGGAGGAATCACGGCG GCTCTGGCGTTTCCTCTGGGAGGTGGGTGAAGCTGAGGCCTGGGTGCGGGAGCAGCAGCACCTCCTGGCCTCAGCCG ACACGGGCCGAGACCTGACCGGTGCCCTCCGCCTGCTCAACAAGCACACAGCCCTGCGGGGCGAGATGAGCGGCCGG CTGGGGCCCCTGAAGCTCACCCTGGAGCAGGGCCAGCAGTTGGTGGCCGAGGGTCACCCTGGGGCAAGCCAGGCCTC TGCCCGTGCAGCTGAACTCCAAGCCCAGTGGGAGCGGCTAGAGGCCCTGGCCGAGGAGCGTGCCCAGCGGCTGGCCC AAGCCGCCAGCCTCTACCAGTTCCAGGCCGATGCAAACGACATGGAGGCCTGGTTGGTTGACGCACTGCGCCTGGTG TCCAGCCCCGAGCTGGGGCACGACGAGTTCTCCACGCAGGCTCTAGCCAGGCAGCATCGGGCCCTGGAGGAGGAGAT TCGAAGCCACCGGCCAACCCTGGACGCCTTGAGGGAACAGGCAGCAGCCCTGCCCCCCACACTGAGCCGCACGCCCG AGGTGCAGAGCCGGGTGCCCACCCTGGAGCGGCACTACGAGGAGCTGCAGGCCCGGGCAGGCGAGCGAGCGCGGGCC TTGGAGGCAGCCCTGGCGCTCTACACCATGCTCAGCGAGGCCGGGGCCTGTGGACTCTGGGTGGAGGAGAAGGAGCA GTGGCTCAACGGGCTGGCCCTGCCTGAACGCCTGGAGGACCTGGAGGTCGTGCAGCAGAGGTTCGAGACCCTGGAGC CTGAAATGAACACCCTTGCAGCACAAATCACCGCGGTGAATGACATTGCCGAGCAGTTACTGAAGGCCAACCCCCCA GGCAAAGACCGCATTGTCAACACCCAGGAGCAGCTCAACCACAGGTGGCAGCAGTTTCGGCGTCTGGCAGACGGCAA GAAGGCAGCTCTCACCTCAGCCCTGAGCATCCAGAACTACCACTTAGAGTGCACGGAGACCCAGGCCTGGATGAGAG AGAAGACCAAAGTCATCGAGTCCACCCAGGGCCTAGGCAACGATCTGGCTGGGGTGCTGGCCCTGCAGCGCAAGCTG GCCGGCACGGAGCGGGACCTGGAGGCCATCGCCGCCCGGGTGGGCGAACTGACTCGAGAGGCAAATGCCCTGGCTGC CGGCCATCCCGCTCAGGCAGTGGCCATCAACGCCCGGCTGAGAGAGGTGCAGACCGGCTGGGAGGACCTCAGGGCCA CCATGCGGCGTCGAGAAGAGTCGCTGGGGGAGGCGCGGCGGCTGCAGGACTTCTTGCGCAGCTTGGATGACTTCCAG GCCTGGCTAGGCCGCACTCAGACTGCTGTGGCCTCTGAAGAAGGGCCGGCCACCCTGCCTGAGGCAGAGGCCCTCCT GGCCCAACATGCAGCCCTGCGGGGAGAGGTGGAGCGGGCCCAGAGCGAGTATAGCCGGCTGCGAGCCCTGGGCGAGG AGGTGACCCGGGACCAGGCTGACCCCCAGTGCCTCTTCCTACGACAGCGACTGGAGGCCCTGGGAACTGGCTGGGAG GAGCTGGGCCGAATGTGGGAGAGCCGGCAAGGTCGCCTGGCCCAGGCCCACGGCTTCCAGGGATTCCTGCGGGATGC TCGTCAGGCTGAGGGCGTGCTCAGCAGCCAGGAATATGTTCTGTCTCACACGGAGATGCCAGGGACACTCCAGGCTG 41 24028 / / SLW 875.245WO1 CTGATGCTGCCATTAAAAAACTGGAGGACTTCATGAGCACCATGGACGCCAATGGGGAACGGATCCACGGGCTCCTG GAGGCTGGCCGCCAGCTGGTATCTGAAGGCAACATCCACGCCGACAAGATTCGGGAAAAGGCAGACTCCATTGAGAG GAGGCACAAGAAGAATCAAGACGCAGCGCAGCAATTTCTGGGCCGTCTTCGGGACAACCGGGAGCAGCAGCATTTCC TGCAAGATTGTCACGAGCTGAAGCTCTGGATCGACGAGAAGATGCTGACAGCCCAGGACGTGTCCTATGACGAGGCC CGCAACCTGCATACTAAGTGGCAGAAGCACCAGGCATTCATGGCCGAGCTGGCTGCCAACAAAGACTGGCTGGACAA GGTGGACAAGGAAGGGCGAGAGCTCACCCTTGAGAAGCCAGAGCTGAAAGCCCTGGTGTCGGAGAAGCTGAGAGACC TGCACAGGCGCTGGGACGAGCTGGAGACCACCACCCAAGCCAAGGCCCGCAGCCTCTTTGATGCCAACCGAGCTGAG CTGTTTGCCCAGAGCTGCTGTGCCCTGGAGAGCTGGCTGGAGAGCCTGCAGGCCCAGCTGCACTCGGATGACTACGG CAAGGACCTCACCAGCGTCAACATCCTGCTCAAGAAGCAGCAGATGCTGGAATGGGAGATGGCTGTGAGAGAGAAGG AGGTGGAGGCAATCCAGGCCCAGGCCAAAGCACTGGCCCAGGAGGACCAGGGTGCAGGGGAGGTGGAGAGAACCTCG AGGGCCGTGGAGGAGAAGTTCAGGGCCTTGTGCCAGCCCATGCGGGAACGCTGCCGGCGCCTGCAGGCTTCTCGCGA GCAGCACCAGTTCCACCGCGATGTGGAAGATGAGATTTTGTGGGTGACAGAGCGGCTGCCCATGGCCAGCTCCATGG AGCATGGCAAGGACCTGCCCAGCGTCCAGCTTCTCATGAAGAAAAACCAGACCCTGCAGAAAGAGATTCAGGGCCAT GAGCCCCGGATCGCGGACCTGAGGGAGCGGCAGCGTGCTCTAGGTGCAGCAGCAGCAGGTCCAGAGCTGGCTGAGCT GCAGGAAATGTGGAAACGCCTGGGCCACGAGCTGGAACTTCGAGGGAAGCGACTGGAGGATGCCCTGCGAGCCCAGC AGTTCTACCGCGATGCCGCCGAGGCGGAGGCCTGGATGGGCGAGCAGGAATTACACATGATGGGCCAGGAGAAGGCC AAGGATGAGCTGAGTGCCCAGGCAGAGGTGAAGAAGCACCAGGTGCTGGAGCAAGCCCTGGCCGACTACGCGCAGAC CATCCACCAGCTGGCGGCCAGCAGCCAGGACATGATTGACCACGAGCACCCAGAGAGCACTCGGATATCCATCCGCC AAGCCCAGGTGGACAAGCTGTATGCCGGCCTGAAGGAGCTGGCTGGAGAGCGGCGGGAGCGCCTGCAGGAGCACCTC CGGCTGTGCCAGCTCCGCCGCGAGCTGGATGACCTGGAACAGTGGATCCAGGAGCGCGAGGTGGTGGCGGCCTCCCA CGAGCTGGGCCAGGACTACGAGCATGTGACTATGCTCCGAGACAAATTCCGAGAGTTCTCCCGGGACACAAGCACCA TCGGTCAGGAGCGCGTAGATAGCGCCAATGCGCTGGCCAATGGGCTCATTGCTGGGGGCCATGCTGCACGGGCCACC GTGGCCGAGTGGAAGGACAGTCTCAACGAGGCCTGGGCTGACCTGCTTGAGCTGCTGGACACACGGGGTCAGGTGCT GGCCGCGGCGTACGAGCTGCAGCGCTTCCTGCACGGGGCACGCCAAGCCCTGGCGCGGGTGCAGCACAAGCAGCAGC AGCTTCCGGACGGGACTGGCCGCGACCTCAACGCTGCCGAGGCCCTGCAGCGCCGACACTGTGCCTACGAGCATGAC ATTCAGGCCCTCAGCCCCCAGGTCCAGCAGGTGCAGGACGACGGCCACCGGCTCCAGAAGGCCTACGCTGGAGACAA GGCTGAGGAGATCGGCCGCCACATGCAGGCCGTGGCCGAGGCCTGGGCCCAGCTTCAGGGAAGCTCTGCCGCCCGCC GGCAGCTGCTGCTGGACACCACAGACAAGTTCCGCTTCTTCAAGGCTGTCCGGGAACTGATGCTCTGGATGGATGAG GTCAACCTGCAGATGGATGCCCAGGAGCGTCCCCGGGATGTGTCCTCCGCGGATCTAGTCATCAAGAACCAGCAAGG CATCAAGGCAGAGATAGAGGCCCGGGCAGACCGCTTCTCCTCCTGCATCGACATGGGGAAGGAGCTGCTGGCCAGGA GCCACTATGCGGCCGAGGAGATCTCAGAGAAGCTGTCTCAGCTGCAGGCACGGCGCCAGGAGACAGCTGAGAAGTGG CAGGAGAAGATGGACTGGCTTCAGCTGGTTTTGGAGGTGCTTGTGTTTGGAAGAGATGCAGGGATGGCAGAGGCCTG GCTCTGCAGCCAGGAGCCACTGGTGCGCAGCGCTGAGCTGGGTTGCACGGTCGACGAAGTTGAGAGCCTCATCAAGC GGCACGAGGCCTTCCAGAAGTCAGCAGTGGCCTGGGAGGAGCGATTCTGTGCGCTGGAGAAGCTTACTGCGCTAGAG GAGCGGGAGAAGGAGCGAAAGAGAAAGAGGGAGGAGGAGGAGCGGCGGAAACAGCCGCCTGCTCCCGAACCCACAGC CAGTGTGCCTCCAGGGGACCTGGTGGGCGGCCAGACAGCTTCTGACACCACCTGGGACGGAACCCAGCCACGGCCAC CACCATCCACACAAGCACCCAGTGTTAATGGAGTCTGCACAGATGGAGAGCCCTCACAGCCCCTGCTGGGACAACAG AGACTTGAGCACAGCAGCTTCCCCGAAGGGCCGGGACCTGGCTCAGGGGACGAAGCCAATGGGCCCCGGGGAGAGAG GCAGACCCGGACTCGGGGCCCGGCCCCATCTGCAATGCCCCAGAGCAGGTCTACCGAGTCAGCCCATGCTGCCACCC TGCCGCCTCGAGGCCCAGAGCCATCTGCCCAGGAGCAGATGGAGGGGATGCTGTGCCGCAAGCAGGAGATGGAGGCC TTCGGGAAGAAGGCTGCCAACAGGTCCTGGCAGAACGTGTACTGTGTCCTGCGGCGTGGGAGCCTCGGCTTTTACAA GGATGCCAAGGCAGCCAGCGCGGGAGTGCCATACCACGGAGAAGTGCCTGTCAGCCTGGCCAGGGCCCAGGGCAGCG TCGCCTTTGATTACCGAAAGCGCAAACATGTCTTCAAGCTGGGCTTACAGGATGGAAAAGAATATTTATTCCAGGCC AAGGATGAGGCAGAGATGAGCTCGTGGCTACGGGTGGTGAATGCAGCCATTGCCACAGCGTCTTCTGCCTCTGGAGA GCCTGAAGAGCCGGTGGTGCCCAGCACCACCCGGGGCATGACCCGGGCCATGACCATGCCCCCAGTGTCACCCGTCG GGGCTGAGGGGCCTGTTGTGCTCCGCAGCAAAGACGGCAGAGAACGAGAGCGAGAAAAACGCTTCAGCTTCTTTAAG AAGAACAAGTAG SEQ ID NO: 42 (SPTBN2 aa, human) MSSTLSPTDFDSLEIQGQYSDINNRWDLPDSDWDNDSSSARLFERSRIKALADEREAVQKKTFTKWVNSHLARVTCR VGDLYSDLRDGRNLLRLLEVLSGEILPKPTKGRMRIHCLENVDKALQFLKEQKVHLENMGSHDIVDGNHRLTLGLVW TIILRFQIQDISVETEDNKEKKSAKDALLLWCQMKTAGYPNVNVHNFTTSWRDGLAFNAIVHKHRPDLLDFESLKKC NAHYNLQNAFNLAEKELGLTKLLDPEDVNVDQPDEKSIITYVATYYHYFSKMKALAVEGKRIGKVLDHAMEAERLVE KYESLASELLQWIEQTIVTLNDRQLANSLSGVQNQLQSFNSYRTVEKPPKFTEKGNLEVLLFTIQSKLRANNQKVYT PREGRLISDINKAWERLEKAEHERELALRTELIRQEKLEQLAARFDRKAAMRETWLSENQRLVSQDNFGLELAAVEA AVRKHEAIETDIVAYSGRVQAVDAVAAELAAERYHDIKRIAARQHNVARLWDFLRQMVAARRERLLLNLELQKVFQD LLYLMDWMEEMKGRLQSQDLGRHLAGVEDLLQLHELVEADIAVQAERVRAVSASALRFCNPGKEYRPCDPQLVSERV 42 24028 / / SLW 875.245WO1 AKLEQSYEALCELAAARRARLEESRRLWRFLWEVGEAEAWVREQQHLLASADTGRDLTGALRLLNKHTALRGEMSGR LGPLKLTLEQGQQLVAEGHPGASQASARAAELQAQWERLEALAEERAQRLAQAASLYQFQADANDMEAWLVDALRLV SSPELGHDEFSTQALARQHRALEEEIRSHRPTLDALREQAAALPPTLSRTPEVQSRVPTLERHYEELQARAGERARA LEAALALYTMLSEAGACGLWVEEKEQWLNGLALPERLEDLEVVQQRFETLEPEMNTLAAQITAVNDIAEQLLKANPP GKDRIVNTQEQLNHRWQQFRRLADGKKAALTSALSIQNYHLECTETQAWMREKTKVIESTQGLGNDLAGVLALQRKL AGTERDLEAIAARVGELTREANALAAGHPAQAVAINARLREVQTGWEDLRATMRRREESLGEARRLQDFLRSLDDFQ AWLGRTQTAVASEEGPATLPEAEALLAQHAALRGEVERAQSEYSRLRALGEEVTRDQADPQCLFLRQRLEALGTGWE ELGRMWESRQGRLAQAHGFQGFLRDARQAEGVLSSQEYVLSHTEMPGTLQAADAAIKKLEDFMSTMDANGERIHGLL EAGRQLVSEGNIHADKIREKADSIERRHKKNQDAAQQFLGRLRDNREQQHFLQDCHELKLWIDEKMLTAQDVSYDEA RNLHTKWQKHQAFMAELAANKDWLDKVDKEGRELTLEKPELKALVSEKLRDLHRRWDELETTTQAKARSLFDANRAE LFAQSCCALESWLESLQAQLHSDDYGKDLTSVNILLKKQQMLEWEMAVREKEVEAIQAQAKALAQEDQGAGEVERTS RAVEEKFRALCQPMRERCRRLQASREQHQFHRDVEDEILWVTERLPMASSMEHGKDLPSVQLLMKKNQTLQKEIQGH EPRIADLRERQRALGAAAAGPELAELQEMWKRLGHELELRGKRLEDALRAQQFYRDAAEAEAWMGEQELHMMGQEKA KDELSAQAEVKKHQVLEQALADYAQTIHQLAASSQDMIDHEHPESTRISIRQAQVDKLYAGLKELAGERRERLQEHL RLCQLRRELDDLEQWIQEREVVAASHELGQDYEHVTMLRDKFREFSRDTSTIGQERVDSANALANGLIAGGHAARAT VAEWKDSLNEAWADLLELLDTRGQVLAAAYELQRFLHGARQALARVQHKQQQLPDGTGRDLNAAEALQRRHCAYEHD IQALSPQVQQVQDDGHRLQKAYAGDKAEEIGRHMQAVAEAWAQLQGSSAARRQLLLDTTDKFRFFKAVRELMLWMDE VNLQMDAQERPRDVSSADLVIKNQQGIKAEIEARADRFSSCIDMGKELLARSHYAAEEISEKLSQLQARRQETAEKW QEKMDWLQLVLEVLVFGRDAGMAEAWLCSQEPLVRSAELGCTVDEVESLIKRHEAFQKSAVAWEERFCALEKLTALE EREKERKRKREEEERRKQPPAPEPTASVPPGDLVGGQTASDTTWDGTQPRPPPSTQAPSVNGVCTDGEPSQPLLGQQ RLEHSSFPEGPGPGSGDEANGPRGERQTRTRGPAPSAMPQSRSTESAHAATLPPRGPEPSAQEQMEGMLCRKQEMEA FGKKAANRSWQNVYCVLRRGSLGFYKDAKAASAGVPYHGEVPVSLARAQGSVAFDYRKRKHVFKLGLQDGKEYLFQA KDEAEMSSWLRVVNAAIATASSASGEPEEPVVPSTTRGMTRAMTMPPVSPVGAEGPVVLRSKDGREREREKRFSFFK KNK* SEQ ID NO: 43 (DES nt, human) ATGAGCCAGGCCTACTCGTCCAGCCAGCGCGTGTCCTCCTACCGCCGCACCTTCGGCGGGGCCCCGGGCTTCCCACT CGGCTCCCCGCTGAGTTCGCCCGTGTTCCCGCGGGCGGGTTTCGGCTCTAAGGGCTCCTCCAGCTCGGTGACGTCCC GCGTGTACCAGGTGTCGCGCACGTCGGGCGGGGCCGGGGGCCTGGGGTCGCTGCGGGCCAGCCGGCTGGGGACCACC CGCACGCCCTCCTCCTACGGCGCAGGCGAGCTGCTGGACTTCTCACTGGCCGACGCGGTGAACCAGGAGTTTCTGAC CACGCGCACCAACGAGAAGGTGGAGCTGCAGGAGCTCAATGACCGCTTCGCCAACTACATCGAGAAGGTGCGCTTCC TGGAGCAGCAGAACGCGGCGCTCGCCGCCGAAGTGAACCGGCTCAAGGGCCGCGAGCCGACGCGAGTGGCCGAGCTC TACGAGGAGGAGCTGCGGGAGCTGCGGCGCCAGGTGGAGGTGCTCACTAACCAGCGCGCGCGCGTCGACGTCGAGCG CGACAACCTGCTCGACGACCTGCAGCGGCTCAAGGCCAAGCTGCAGGAGGAGATTCAGTTGAAGGAAGAAGCAGAGA ACAATTTGGCTGCCTTCCGAGCGGACGTGGATGCAGCTACTCTAGCTCGCATTGACCTGGAGCGCAGAATTGAATCT CTCAACGAGGAGATCGCGTTCCTTAAGAAAGTGCATGAAGAGGAGATCCGTGAGTTGCAGGCTCAGCTTCAGGAACA GCAGGTCCAGGTGGAGATGGACATGTCTAAGCCAGACCTCACTGCCGCCCTCAGGGACATCCGGGCTCAGTATGAGA CCATCGCGGCTAAGAACATTTCTGAAGCTGAGGAGTGGTACAAGTCGAAGGTGTCAGACCTGACCCAGGCAGCCAAC AAGAACAACGACGCCCTGCGCCAGGCCAAGCAGGAGATGATGGAATACCGACACCAGATCCAGTCCTACACCTGCGA GATTGACGCCCTGAAGGGCACTAACGATTCCCTGATGAGGCAGATGCGGGAATTGGAGGACCGATTTGCCAGTGAGG CCAGTGGCTACCAGGACAACATTGCGCGCCTGGAGGAGGAAATCCGGCACCTCAAGGATGAGATGGCCCGCCATCTG CGCGAGTACCAGGACCTGCTCAACGTGAAGATGGCCCTGGATGTGGAGATTGCCACCTACCGGAAGCTGCTGGAGGG AGAGGAGAGCCGGATCAATCTCCCCATCCAGACCTACTCTGCCCTCAACTTCCGAGAAACCAGCCCTGAGCAAAGGG GTTCTGAGGTCCATACCAAGAAGACGGTGATGATCAAGACCATCGAGACACGGGATGGGGAGGTCGTCAGTGAGGCC ACACAGCAGCAGCATGAAGTGCTCTAA SEQ ID NO: 44 (DES aa, human) MSQAYSSSQRVSSYRRTFGGAPGFPLGSPLSSPVFPRAGFGSKGSSSSVTSRVYQVSRTSGGAGGLGSLRASRLGTT RTPSSYGAGELLDFSLADAVNQEFLTTRTNEKVELQELNDRFANYIEKVRFLEQQNAALAAEVNRLKGREPTRVAEL YEEELRELRRQVEVLTNQRARVDVERDNLLDDLQRLKAKLQEEIQLKEEAENNLAAFRADVDAATLARIDLERRIES LNEEIAFLKKVHEEEIRELQAQLQEQQVQVEMDMSKPDLTAALRDIRAQYETIAAKNISEAEEWYKSKVSDLTQAAN KNNDALRQAKQEMMEYRHQIQSYTCEIDALKGTNDSLMRQMRELEDRFASEASGYQDNIARLEEEIRHLKDEMARHL REYQDLLNVKMALDVEIATYRKLLEGEESRINLPIQTYSALNFRETSPEQRGSEVHTKKTVMIKTIETRDGEVVSEA TQQQHEVL* 43 24028 / / SLW 875.245WO1 The contribution of calpain activation in the downregulation of RyR2, Serca2a and CaV1.2 was investigated in TAC-treated wildtype versus JP2CR ventricular lysates. It was found that TAC-induced calpain activation was significantly blunted in JP2CRhearts compared to WT suggesting that the improved Ca2+homeostasis observed in JP2CRhearts limits calpain activity under stress conditions and slows the development of cardiac dysfunction. Using heterologous expression in HEK cells, it was demonstrated that calpains directly cleave RyR2, Serca2a and CaV1.2. HEK293T cells were co-transfected with cDNAs for Calpain-1 (CAPN1) or Calpain-2 (CAPN2) and full-length tagged RyR2, Serca2a and CaV1.2 and in vitro cleavage assays were performed from cell lysates by supplying reactions with µM and mM Ca2+that activates Calpain- 1 and calpain-2, respectively. While calpain-1 and calpain-2 similarly cleave RyR2 and Serca2a, CaV1.2 is more sensitive to calpain-1 than calpain-2 as the full length is completely degraded by calpain-1 but only partially by calpain 2. Taken together, these data suggest that the JP2CRpreserves E-C coupling by sustaining E-C CICR and E-C coupling during stress that attenuates calpain activation and the subsequent cleavage of critical E-C coupling proteins such as RyR2, Serca2a and CaV1.2. Validation of these HF-sensitive calpain substrates suggest they, and other calpain substrates listed above, may also be possible cleavage resistant gene therapy agents similar to JP2CR. Provided herein is the use of site-specific calpain cleavage of JP2 to protect the heart against stress induced pathological cardiac remodeling in vivo. Further provided herein is the development of two viral-based gene therapy agents that improve HF when administered. These agents provide cardiomyocytes with two beneficial, but mutually exclusive, functions of Junctophilin-2 (JP2 or JPH2). The first mechanism is sustaining the normal function of JP2 as a structural protein that facilitates and maintains the integrity of plasma membrane - sarcoplasmic reticulum junctions (also called cardiac dyads). JP2 and cardiac dyads are needed for normal heart contraction by enabling efficient intracellular Ca2+homeostasis via processes known as Ca2+induced Ca2+release (CICR) and excitation-contraction (E-C) coupling. The structural integrity of JP2 and dyad junctions, however, is sensitive to cardiac stresses and its downregulation at cardiac dyads is recognized as a proximal event in HF. During HF, intracellular Ca2+levels rise triggering the proteolytic cleavage of JP2 by Ca2+activated calpain proteases. As a result, CICR and E-C coupling become impaired and unsynchronized leading to further Ca2+overload conditions and additional JP2 cleavage. Interestingly, calpain cleavage of JP2 is not entirely detrimental as it releases a previously masked function within the JP2 N-terminal proteolytic fragment (JP2NT). After cleavage, JP2NT readily translocates into the nucleus where it represses 44 24028 / / SLW 875.245WO1 the expression of HF-related genes. In the disease heart, however, JP2NT levels decline over time and loses its ability to slow HF progression (Guo 2018). Provided herein are compositions and methods for effective gene therapy in HF patients. Further provided herein are compositions and methods for effective gene therapy in HF patients by simultaneously targeting multiple relevant HF mechanisms. Also provided herein are the compositions and methods for supplying cardiomyocytes with intact cleavage resistant JP2, cleaved JP2NT, and / or other therapeutically relevant proteins as separate and / or synergistic gene therapy agents in treating HF. Demonstrated herein is the effective JP2 / JP2NT gene therapy, which is achievable through, for example, adeno-associated virus (AAV) mediated gene delivery into the heart. It is shown that HF can be improved by expressing either a calpain resistant mutation of JP2 (JP2CR) that sustains dyad integrity and E-C coupling despite elevated Ca2+levels or by expressing the JP2NT fragment that represses pathological gene expression. Also shown is a synergistic benefit that is achieved by co-expressing both JP2CRand JP2NT. These findings indicate effective gene therapy can be achieved by expressing proteins that antagonize different HF pathways. Examples of synergistic combinations include 1) different forms of the same protein (e.g., JP2 / JP2NT), 2) cardioprotective proteins of different types and activities (structural, transcriptional, signaling, regulators), and 3) stress-dependent cleaved proteins that are each modified to be resistant to calpain or other proteases (e.g., JP2, SERCA2a, Cav1.2, and other calpain substrates listed above). Definitions “JP2” refers to junctophilin-2 protein and “JPH2” refers to the gene encoding junctophilin- 2 protein. JP2 protein is a membrane structural protein that regulates Ca2+handling in cardiomyocytes. As described below. JP2 expression was demonstrated to be down-regulated in failing hearts from patients with ischemic heart disease and is regulated by proteolytic processing by the Ca2+-sensitive enzyme calpain. Calpain-1 can cleave JP2 at the sites found at amino acids R572 and T573 of human JP2, as set forth in SEQ ID NO: 1. In some embodiments of the instant disclosure, a polynucleotide encoding JP2 for use in generating a gene therapy vector may comprise a deletion of amino acids R572 and T573 of a JP2 reference sequence as set forth in SEQ ID NO: 1. WT JP2 aa Mouse JP2 aa (see also NCBI reference sequence NP_067541.1) MSGGRFDFDDGGAYCGGWEGGKAHGHGLCTGPKGQGEYSGSWNFGFEVAGVYTWPSGNTFEGYWSQGKRHGLGIETK GRWLYKGEWTHGFKGRYGIRQSTNSGAKYEGTWNNGLQDGYGTETYADGGTYQGQFTNGMRHGYGVRQSVPYGMAVV VRSPLRTSLSSLRSEHSNGTVAPDSPAADGPMLPSPPVPRGGFALTLLATAEAARPQGLFTRGTLLGRLRRSESRTS LGSQRSRLSFLKSELSSGASDAASTGSLAEGAEGPDDAAAPFDADIDATTTETYMGEWKNDKRSGFGVSERSSGLRY EGEWLDNLRHGYGRTTLPDGHREEGKYRHNVLVKGTKRRVLPLKSSKVRQKVEHGVEGAQRAAAIARQKAEIAASRT 45 24028 / / SLW 875.245WO1 SHAKAKAEAAEQAALAANQESNIARTLAKELAPDFYQPGPEYQKRRLLQEILENSESLLEPPERGLGTGLPERPRES PQLHERETPQPEGGPPSPAGTPPQPKRPRPGASKDGLLSPGSWNGEPGGEGSRPATPSDGAGRRSPARPASEHMAIE ALQPPPAPSQEPEVAMYRGYHSYAVRTGPPEPPPLEDEQEPEPEPEPEVRRSDSAPPSPVSATVPEEEPPAPRSPVP AKQATLEPKPIVPKAEPKAKARKTEARGLSKAGAKKKGRKEVAQAKEAEVEVEEVPNTVLICMVILLNIGLAILFVH LLT* (SEQ ID NO: 45) Human JP2 aa (NP_065166.2): MSGGRFDFDDGGAYCGGWEGGKAHGHGLCTGPKGQGEYSGSWNFGFEVAGVYTWPSGNTFEGYWSQGKRHGLGIETK GRWLYKGEWTHGFKGRYGIRQSSSSGAKYEGTWNNGLQDGYGTETYADGGTYQGQFTNGMRHGYGVRQSVPYGMAVV VRSPLRTSLSSLRSEHSNGTVAPDSPASPASDGPALPSPAIPRGGFALSLLANAEAAARAPKGGGLFQRGALLGKLR RAESRTSVGSQRSRVSFLKSDLSSGASDAASTASLGEAAEGADEAAPFEADIDATTTETYMGEWKNDKRSGFGVSER SSGLRYEGEWLDNLRHGYGCTTLPDGHREEGKYRHNVLVKDTKRRMLQLKSNKVRQKVEHSVEGAQRAAAIARQKAE IAASRTSHAKAKAEAAEQAALAANQESNIARTLARELAPDFYQPGPEYQKRRLLQEILENSESLLEPPDRGAGAAGL PQPPRESPQLHERETPRPEGGSPSPAGTPPQPKRPRPGVSKDGLLSPGAWNGEPSGEGSRSVTPSEGAGRRSPARPA TERMAIEALQAPPAPSREPEVALYQGYHSYAVRTTPPEPPPFEDQPEPEVSGSESAPSSPATAPLQAPTLRGPEPAR ETPAKLEPKPIIPKAEPRAKARKTEARGLTKAGAKKKARKEAALAAEAEVEVEEVPNTILICMVILLNIGLAILFVH LLT* (SEQ ID NO: 1) WT JP2 nt Mouse JP2 nt (derived from NCBI reference sequence NM_021566.2) ATGAGCGGGGGCCGCTTTGACTTTGATGATGGCGGGGCGTATTGTGGGGGCTGGGAAGGGGGAAAGGCACACGGGCA CGGACTGTGCACCGGCCCCAAGGGCCAGGGTGAATACTCGGGCTCCTGGAATTTTGGCTTTGAAGTGGCAGGCGTCT ATACCTGGCCCAGTGGGAATACCTTTGAGGGATATTGGAGCCAGGGCAAACGACATGGGCTTGGCATAGAGACCAAG GGGCGCTGGCTCTACAAGGGGGAGTGGACGCATGGCTTTAAGGGGCGCTACGGAATCCGGCAGAGCACAAACAGTGG TGCCAAGTACGAGGGCACTTGGAATAACGGCCTACAGGACGGCTATGGCACGGAGACCTACGCAGACGGAGGAACCT ATCAAGGCCAATTCACCAACGGCATGCGCCATGGCTACGGTGTGCGCCAAAGCGTGCCCTACGGGATGGCAGTGGTG GTGCGTTCTCCGCTGCGCACTTCTCTGTCCTCGCTGCGCAGCGAGCACAGCAATGGAACGGTGGCTCCGGACTCACC GGCGGCAGATGGGCCCATGCTGCCTTCGCCCCCAGTGCCGCGCGGTGGTTTCGCGCTCACTCTGCTGGCCACAGCAG AGGCCGCGCGACCCCAAGGGCTGTTCACGCGTGGCACACTGCTGGGTCGGCTGCGACGCTCAGAATCACGCACATCA CTGGGCAGCCAGCGGAGCCGCTTGAGCTTTCTCAAGAGCGAGCTGAGTTCCGGAGCCAGCGATGCCGCATCCACTGG CAGCCTGGCCGAGGGCGCTGAGGGCCCCGACGACGCGGCTGCGCCCTTCGATGCCGACATCGACGCCACCACCACGG AAACCTACATGGGCGAGTGGAAGAACGACAAGCGCTCGGGCTTCGGCGTGAGCGAGCGTTCCAGCGGCCTGCGCTAC GAGGGCGAGTGGCTGGACAACCTGCGCCACGGCTACGGCCGCACCACGCTGCCCGACGGCCACCGCGAGGAGGGCAA GTACCGCCACAATGTGCTGGTCAAGGGCACCAAGCGCCGCGTGCTGCCGCTCAAGAGCAGCAAGGTCCGCCAGAAGG TGGAGCACGGGGTGGAGGGCGCCCAGCGCGCAGCAGCCATCGCGCGCCAGAAGGCCGAGATTGCCGCCTCCAGGACA AGCCATGCCAAAGCCAAGGCAGAGGCAGCAGAACAGGCTGCCCTGGCTGCCAACCAGGAGTCCAACATCGCCCGTAC ATTGGCCAAGGAGCTGGCTCCAGACTTCTACCAGCCAGGTCCGGAGTATCAGAAGCGTCGGCTGCTCCAGGAGATCC TGGAGAACTCTGAGAGCTTGCTGGAGCCCCCAGAGCGGGGTCTGGGCACCGGCCTCCCGGAGCGGCCCCGGGAAAGC CCGCAGCTGCATGAGCGCGAGACCCCGCAGCCCGAGGGCGGACCCCCGTCTCCGGCCGGGACGCCCCCGCAACCCAA GAGGCCCCGGCCCGGAGCGTCAAAGGACGGCCTGCTGAGTCCAGGCTCCTGGAACGGGGAGCCCGGCGGAGAGGGCA GCCGGCCCGCCACGCCGTCGGATGGCGCCGGTCGTCGCAGCCCCGCGCGCCCCGCCTCGGAGCACATGGCCATCGAG GCGCTGCAGCCGCCGCCCGCGCCCTCGCAGGAGCCCGAGGTAGCAATGTACCGCGGCTACCATAGCTACGCCGTGCG CACCGGGCCACCCGAGCCTCCGCCCTTGGAGGATGAGCAGGAGCCCGAGCCGGAGCCCGAGCCCGAGGTCCGGCGAT CCGACTCGGCGCCCCCGTCCCCCGTCTCCGCCACCGTCCCGGAGGAGGAGCCCCCTGCGCCGCGAAGCCCGGTGCCT GCCAAGCAAGCCACTCTGGAGCCCAAGCCCATCGTCCCCAAAGCAGAGCCCAAGGCCAAGGCGCGCAAGACAGAGGC CCGAGGACTGAGCAAGGCCGGTGCCAAGAAGAAGGGCCGTAAGGAAGTGGCGCAGGCGAAGGAGGCCGAGGTGGAGG TGGAGGAGGTACCCAACACCGTCCTCATCTGTATGGTGATCTTGCTGAACATCGGCCTGGCTATCCTATTTGTTCAC CTCCTGACTTGA (SEQ ID NO: 46) Human JP2 nt (from NM_020433.5): ATGAGTGGGGGCCGCTTCGACTTTGATGATGGAGGGGCGTACTGCGGGGGCTGGGAGGGGGGAAAGGCCCATGGGCA TGGACTGTGCACAGGCCCCAAGGGCCAGGGCGAATACTCTGGCTCCTGGAACTTTGGCTTTGAGGTGGCAGGTGTCT ACACCTGGCCCAGCGGAAACACCTTTGAGGGATACTGGAGCCAGGGCAAACGGCATGGGCTGGGCATAGAGACCAAG GGGCGCTGGCTCTACAAGGGCGAGTGGACACATGGCTTCAAGGGACGCTACGGAATCCGGCAGAGCTCAAGCAGCGG TGCCAAGTATGAGGGCACCTGGAACAATGGCCTGCAAGACGGCTATGGCACCGAGACCTATGCTGATGGAGGGACGT 46 24028 / / SLW 875.245WO1 ACCAAGGCCAGTTCACCAACGGCATGCGCCATGGCTACGGAGTACGCCAGAGCGTGCCCTACGGGATGGCCGTGGTG GTGCGCTCGCCGCTGCGCACGTCGCTGTCGTCCCTGCGCAGCGAGCACAGCAACGGCACGGTGGCCCCGGACTCTCC CGCCTCGCCGGCCTCCGACGGCCCCGCGCTGCCCTCGCCCGCCATCCCGCGTGGCGGCTTCGCGCTCAGCCTCCTGG CCAATGCCGAGGCGGCCGCGCGGGCGCCCAAGGGCGGCGGCCTCTTCCAGCGGGGCGCGCTGCTGGGCAAGCTGCGG CGCGCAGAGTCGCGCACGTCCGTGGGTAGCCAGCGCAGCCGTGTCAGCTTCCTTAAGAGCGACCTCAGCTCGGGCGC CAGCGACGCCGCGTCCACCGCCAGCCTGGGAGAGGCCGCCGAGGGCGCCGACGAGGCCGCACCCTTCGAGGCCGATA TCGACGCCACCACCACCGAGACCTACATGGGCGAGTGGAAGAACGACAAACGCTCGGGCTTCGGCGTGAGCGAACGC TCCAGTGGCCTCCGCTACGAGGGCGAGTGGCTGGACAACCTGCGCCACGGCTATGGCTGCACCACGCTGCCCGACGG CCACCGCGAGGAGGGCAAGTACCGCCACAACGTGCTGGTCAAGGACACCAAGCGCCGCATGCTGCAGCTCAAGAGCA ACAAGGTCCGCCAGAAAGTGGAGCACAGTGTGGAGGGTGCCCAGCGCGCCGCTGCTATCGCGCGCCAGAAGGCCGAG ATTGCCGCCTCCAGGACAAGCCACGCCAAGGCCAAAGCTGAGGCAGCGGAACAGGCCGCCCTGGCTGCCAACCAGGA GTCCAACATTGCTCGCACTTTGGCCAGGGAGCTGGCTCCGGACTTCTACCAGCCAGGTCCGGAATATCAGAAGCGCC GGCTGCTGCAGGAGATCCTGGAGAACTCGGAGAGCCTGCTGGAGCCCCCCGACCGGGGCGCCGGCGCAGCGGGCCTC CCACAGCCGCCCCGCGAGAGCCCGCAGCTGCACGAGCGTGAGACCCCTCGGCCCGAGGGTGGCTCCCCGTCACCGGC CGGGACGCCCCCGCAGCCCAAGCGGCCCAGGCCCGGGGTGTCCAAGGACGGCCTGCTGAGCCCAGGCGCCTGGAACG GCGAGCCCAGCGGTGAGGGCAGCCGGTCAGTCACTCCGTCCGAGGGCGCGGGCCGCCGCAGCCCCGCGCGTCCAGCC ACCGAGCGCATGGCCATCGAGGCTCTGCAGGCACCGCCTGCGCCGTCGCGGGAGCCGGAGGTGGCGCTTTACCAGGG CTACCACAGCTATGCTGTGCGCACCACGCCGCCCGAGCCCCCACCCTTTGAGGACCAGCCCGAGCCCGAGGTCTCCG GGTCCGAGTCCGCGCCCTCGTCCCCGGCCACCGCCCCGCTGCAGGCCCCCACGCTCCGAGGCCCCGAGCCTGCACGC GAGACCCCCGCCAAGCTGGAGCCCAAGCCCATCATCCCCAAAGCCGAGCCCAGGGCCAAGGCCCGCAAGACTGAGGC TCGAGGGCTGACCAAGGCGGGGGCCAAGAAGAAGGCGCGGAAGGAGGCCGCACTGGCGGCAGAGGCGGAGGTGGAGG TGGAAGAGGTCCCCAACACCATCCTCATCTGCATGGTGATCCTGCTGAACATCGGCCTGGCCATCCTCTTTGTTCAC CTCCTGACCTGA (SEQ ID NO: 2) JP2CRnt Mouse JP2CRnt: ATGAGCGGGGGCCGCTTTGACTTTGATGATGGCGGGGCGTATTGTGGGGGCTGGGAAGGGGGAAAGGCACACGGGCA CGGACTGTGCACCGGCCCCAAGGGCCAGGGTGAATACTCGGGCTCCTGGAATTTTGGCTTTGAAGTGGCAGGCGTCT ATACCTGGCCCAGTGGGAATACCTTTGAGGGATATTGGAGCCAGGGCAAACGACATGGGCTTGGCATAGAGACCAAG GGGCGCTGGCTCTACAAGGGGGAGTGGACGCATGGCTTTAAGGGGCGCTACGGAATCCGGCAGAGCACAAACAGTGG TGCCAAGTACGAGGGCACTTGGAATAACGGCCTACAGGACGGCTATGGCACGGAGACCTACGCAGACGGAGGAACCT ATCAAGGCCAATTCACCAACGGCATGCGCCATGGCTACGGTGTGCGCCAAAGCGTGCCCTACGGGATGGCAGTGGTG GTGCGTTCTCCGCTGCGCACTTCTCTGTCCTCGCTGCGCAGCGAGCACAGCAATGGAACGGTGGCTCCGGACTCACC GGCGGCAGATGGGCCCATGCTGCCTTCGCCCCCAGTGCCGCGCGGTGGTTTCGCGCTCACTCTGCTGGCCACAGCAG AGGCCGCGCGACCCCAAGGGCTGTTCACGCGTGGCACACTGCTGGGTCGGCTGCGACGCTCAGAATCACGCACATCA CTGGGCAGCCAGCGGAGCCGCTTGAGCTTTCTCAAGAGCGAGCTGAGTTCCGGAGCCAGCGATGCCGCATCCACTGG CAGCCTGGCCGAGGGCGCTGAGGGCCCCGACGACGCGGCTGCGCCCTTCGATGCCGACATCGACGCCACCACCACGG AAACCTACATGGGCGAGTGGAAGAACGACAAGCGCTCGGGCTTCGGCGTGAGCGAGCGTTCCAGCGGCCTGCGCTAC GAGGGCGAGTGGCTGGACAACCTGCGCCACGGCTACGGCCGCACCACGCTGCCCGACGGCCACCGCGAGGAGGGCAA GTACCGCCACAATGTGCTGGTCAAGGGCACCAAGCGCCGCGTGCTGCCGCTCAAGAGCAGCAAGGTCCGCCAGAAGG TGGAGCACGGGGTGGAGGGCGCCCAGCGCGCAGCAGCCATCGCGCGCCAGAAGGCCGAGATTGCCGCCTCCAGGACA AGCCATGCCAAAGCCAAGGCAGAGGCAGCAGAACAGGCTGCCCTGGCTGCCAACCAGGAGTCCAACATCGCCCGTAC ATTGGCCAAGGAGCTGGCTCCAGACTTCTACCAGCCAGGTCCGGAGTATCAGAAGCGTCGGCTGCTCCAGGAGATCC TGGAGAACTCTGAGAGCTTGCTGGAGCCCCCAGAGCGGGGTCTGGGCACCGGCCTCCCGGAGCGGCCCCGGGAAAGC CCGCAGCTGCATGAGCGCGAGACCCCGCAGCCCGAGGGCGGACCCCCGTCTCCGGCCGGGACGCCCCCGCAACCCAA GAGGCCCCGGCCCGGAGCGTCAAAGGACGGCCTGCTGAGTCCAGGCTCCTGGAACGGGGAGCCCGGCGGAGAGGGCA GCCGGCCCGCCACGCCGTCGGATGGCGCCGGTCGTCGCAGCCCCGCGCGCCCCGCCTCGGAGCACATGGCCATCGAG GCGCTGCAGCCGCCGCCCGCGCCCTCGCAGGAGCCCGAGGTAGCAATGTACCGCGGCTACCATAGCTACCCCGAGCC TCCGCCCTTGGAGGATGAGCAGGAGCCCGAGCCGGAGCCCGAGCCCGAGGTCCGGCGATCCGACTCGGCGCCCCCGT CCCCCGTCTCCGCCACCGTCCCGGAGGAGGAGCCCCCTGCGCCGCGAAGCCCGGTGCCTGCCAAGCAAGCCACTCTG GAGCCCAAGCCCATCGTCCCCAAAGCAGAGCCCAAGGCCAAGGCGCGCAAGACAGAGGCCCGAGGACTGAGCAAGGC CGGTGCCAAGAAGAAGGGCCGTAAGGAAGTGGCGCAGGCGAAGGAGGCCGAGGTGGAGGTGGAGGAGGTACCCAACA CCGTCCTCATCTGTATGGTGATCTTGCTGAACATCGGCCTGGCTATCCTATTTGTTCACCTCCTGACTTGA (SEQ ID NO: 47) Human JP2CRnt: 47 24028 / / SLW 875.245WO1 ATGAGTGGGGGCCGCTTCGACTTTGATGATGGAGGGGCGTACTGCGGGGGCTGGGAGGGGGGAAAGGCCCATGGGCA TGGACTGTGCACAGGCCCCAAGGGCCAGGGCGAATACTCTGGCTCCTGGAACTTTGGCTTTGAGGTGGCAGGTGTCT ACACCTGGCCCAGCGGAAACACCTTTGAGGGATACTGGAGCCAGGGCAAACGGCATGGGCTGGGCATAGAGACCAAG GGGCGCTGGCTCTACAAGGGCGAGTGGACACATGGCTTCAAGGGACGCTACGGAATCCGGCAGAGCTCAAGCAGCGG TGCCAAGTATGAGGGCACCTGGAACAATGGCCTGCAAGACGGCTATGGCACCGAGACCTATGCTGATGGAGGGACGT ACCAAGGCCAGTTCACCAACGGCATGCGCCATGGCTACGGAGTACGCCAGAGCGTGCCCTACGGGATGGCCGTGGTG GTGCGCTCGCCGCTGCGCACGTCGCTGTCGTCCCTGCGCAGCGAGCACAGCAACGGCACGGTGGCCCCGGACTCTCC CGCCTCGCCGGCCTCCGACGGCCCCGCGCTGCCCTCGCCCGCCATCCCGCGTGGCGGCTTCGCGCTCAGCCTCCTGG CCAATGCCGAGGCGGCCGCGCGGGCGCCCAAGGGCGGCGGCCTCTTCCAGCGGGGCGCGCTGCTGGGCAAGCTGCGG CGCGCAGAGTCGCGCACGTCCGTGGGTAGCCAGCGCAGCCGTGTCAGCTTCCTTAAGAGCGACCTCAGCTCGGGCGC CAGCGACGCCGCGTCCACCGCCAGCCTGGGAGAGGCCGCCGAGGGCGCCGACGAGGCCGCACCCTTCGAGGCCGATA TCGACGCCACCACCACCGAGACCTACATGGGCGAGTGGAAGAACGACAAACGCTCGGGCTTCGGCGTGAGCGAACGC TCCAGTGGCCTCCGCTACGAGGGCGAGTGGCTGGACAACCTGCGCCACGGCTATGGCTGCACCACGCTGCCCGACGG CCACCGCGAGGAGGGCAAGTACCGCCACAACGTGCTGGTCAAGGACACCAAGCGCCGCATGCTGCAGCTCAAGAGCA ACAAGGTCCGCCAGAAAGTGGAGCACAGTGTGGAGGGTGCCCAGCGCGCCGCTGCTATCGCGCGCCAGAAGGCCGAG ATTGCCGCCTCCAGGACAAGCCACGCCAAGGCCAAAGCTGAGGCAGCGGAACAGGCCGCCCTGGCTGCCAACCAGGA GTCCAACATTGCTCGCACTTTGGCCAGGGAGCTGGCTCCGGACTTCTACCAGCCAGGTCCGGAATATCAGAAGCGCC GGCTGCTGCAGGAGATCCTGGAGAACTCGGAGAGCCTGCTGGAGCCCCCCGACCGGGGCGCCGGCGCAGCGGGCCTC CCACAGCCGCCCCGCGAGAGCCCGCAGCTGCACGAGCGTGAGACCCCTCGGCCCGAGGGTGGCTCCCCGTCACCGGC CGGGACGCCCCCGCAGCCCAAGCGGCCCAGGCCCGGGGTGTCCAAGGACGGCCTGCTGAGCCCAGGCGCCTGGAACG GCGAGCCCAGCGGTGAGGGCAGCCGGTCAGTCACTCCGTCCGAGGGCGCGGGCCGCCGCAGCCCCGCGCGTCCAGCC ACCGAGCGCATGGCCATCGAGGCTCTGCAGGCACCGCCTGCGCCGTCGCGGGAGCCGGAGGTGGCGCTTTACCAGGG CTACCACAGCTATCCCGAGCCCCCACCCTTTGAGGACCAGCCCGAGCCCGAGGTCTCCGGGTCCGAGTCCGCGCCCT CGTCCCCGGCCACCGCCCCGCTGCAGGCCCCCACGCTCCGAGGCCCCGAGCCTGCACGCGAGACCCCCGCCAAGCTG GAGCCCAAGCCCATCATCCCCAAAGCCGAGCCCAGGGCCAAGGCCCGCAAGACTGAGGCTCGAGGGCTGACCAAGGC GGGGGCCAAGAAGAAGGCGCGGAAGGAGGCCGCACTGGCGGCAGAGGCGGAGGTGGAGGTGGAAGAGGTCCCCAACA CCATCCTCATCTGCATGGTGATCCTGCTGAACATCGGCCTGGCCATCCTCTTTGTTCACCTCCTGACCTGA (SEQ ID NO: 3) JP2CRaa Mouse JP2 CR aa: MSGGRFDFDDGGAYCGGWEGGKAHGHGLCTGPKGQGEYSGSWNFGFEVAGVYTWPSGNTFEGYWSQGKRHGLGIETK GRWLYKGEWTHGFKGRYGIRQSTNSGAKYEGTWNNGLQDGYGTETYADGGTYQGQFTNGMRHGYGVRQSVPYGMAVV VRSPLRTSLSSLRSEHSNGTVAPDSPAADGPMLPSPPVPRGGFALTLLATAEAARPQGLFTRGTLLGRLRRSESRTS LGSQRSRLSFLKSELSSGASDAASTGSLAEGAEGPDDAAAPFDADIDATTTETYMGEWKNDKRSGFGVSERSSGLRY EGEWLDNLRHGYGRTTLPDGHREEGKYRHNVLVKGTKRRVLPLKSSKVRQKVEHGVEGAQRAAAIARQKAEIAASRT SHAKAKAEAAEQAALAANQESNIARTLAKELAPDFYQPGPEYQKRRLLQEILENSESLLEPPERGLGTGLPERPRES PQLHERETPQPEGGPPSPAGTPPQPKRPRPGASKDGLLSPGSWNGEPGGEGSRPATPSDGAGRRSPARPASEHMAIE ALQPPPAPSQEPEVAMYRGYHSYPEPPPLEDEQEPEPEPEPEVRRSDSAPPSPVSATVPEEEPPAPRSPVPAKQATL EPKPIVPKAEPKAKARKTEARGLSKAGAKKKGRKEVAQAKEAEVEVEEVPNTVLICMVILLNIGLAILFVHLLT* (SEQ ID NO: 48) Human JP2CRaa: MSGGRFDFDDGGAYCGGWEGGKAHGHGLCTGPKGQGEYSGSWNFGFEVAGVYTWPSGNTFEGYWSQGKRHGLGIETK GRWLYKGEWTHGFKGRYGIRQSSSSGAKYEGTWNNGLQDGYGTETYADGGTYQGQFTNGMRHGYGVRQSVPYGMAVV VRSPLRTSLSSLRSEHSNGTVAPDSPASPASDGPALPSPAIPRGGFALSLLANAEAAARAPKGGGLFQRGALLGKLR RAESRTSVGSQRSRVSFLKSDLSSGASDAASTASLGEAAEGADEAAPFEADIDATTTETYMGEWKNDKRSGFGVSER SSGLRYEGEWLDNLRHGYGCTTLPDGHREEGKYRHNVLVKDTKRRMLQLKSNKVRQKVEHSVEGAQRAAAIARQKAE IAASRTSHAKAKAEAAEQAALAANQESNIARTLARELAPDFYQPGPEYQKRRLLQEILENSESLLEPPDRGAGAAGL PQPPRESPQLHERETPRPEGGSPSPAGTPPQPKRPRPGVSKDGLLSPGAWNGEPSGEGSRSVTPSEGAGRRSPARPA TERMAIEALQAPPAPSREPEVALYQGYHSYPEPPPFEDQPEPEVSGSESAPSSPATAPLQAPTLRGPEPARETPAKL JP2NT nt 48 24028 / / SLW 875.245WO1 Mouse JP2NT nt: ATGAGCGGGGGCCGCTTTGACTTTGATGATGGCGGGGCGTATTGTGGGGGCTGGGAAGGGGGAAAGGCACACGGGCA CGGACTGTGCACCGGCCCCAAGGGCCAGGGTGAATACTCGGGCTCCTGGAATTTTGGCTTTGAAGTGGCAGGCGTCT ATACCTGGCCCAGTGGGAATACCTTTGAGGGATATTGGAGCCAGGGCAAACGACATGGGCTTGGCATAGAGACCAAG GGGCGCTGGCTCTACAAGGGGGAGTGGACGCATGGCTTTAAGGGGCGCTACGGAATCCGGCAGAGCACAAACAGTGG TGCCAAGTACGAGGGCACTTGGAATAACGGCCTACAGGACGGCTATGGCACGGAGACCTACGCAGACGGAGGAACCT ATCAAGGCCAATTCACCAACGGCATGCGCCATGGCTACGGTGTGCGCCAAAGCGTGCCCTACGGGATGGCAGTGGTG GTGCGTTCTCCGCTGCGCACTTCTCTGTCCTCGCTGCGCAGCGAGCACAGCAATGGAACGGTGGCTCCGGACTCACC GGCGGCAGATGGGCCCATGCTGCCTTCGCCCCCAGTGCCGCGCGGTGGTTTCGCGCTCACTCTGCTGGCCACAGCAG AGGCCGCGCGACCCCAAGGGCTGTTCACGCGTGGCACACTGCTGGGTCGGCTGCGACGCTCAGAATCACGCACATCA CTGGGCAGCCAGCGGAGCCGCTTGAGCTTTCTCAAGAGCGAGCTGAGTTCCGGAGCCAGCGATGCCGCATCCACTGG CAGCCTGGCCGAGGGCGCTGAGGGCCCCGACGACGCGGCTGCGCCCTTCGATGCCGACATCGACGCCACCACCACGG AAACCTACATGGGCGAGTGGAAGAACGACAAGCGCTCGGGCTTCGGCGTGAGCGAGCGTTCCAGCGGCCTGCGCTAC GAGGGCGAGTGGCTGGACAACCTGCGCCACGGCTACGGCCGCACCACGCTGCCCGACGGCCACCGCGAGGAGGGCAA GTACCGCCACAATGTGCTGGTCAAGGGCACCAAGCGCCGCGTGCTGCCGCTCAAGAGCAGCAAGGTCCGCCAGAAGG TGGAGCACGGGGTGGAGGGCGCCCAGCGCGCAGCAGCCATCGCGCGCCAGAAGGCCGAGATTGCCGCCTCCAGGACA AGCCATGCCAAAGCCAAGGCAGAGGCAGCAGAACAGGCTGCCCTGGCTGCCAACCAGGAGTCCAACATCGCCCGTAC ATTGGCCAAGGAGCTGGCTCCAGACTTCTACCAGCCAGGTCCGGAGTATCAGAAGCGTCGGCTGCTCCAGGAGATCC TGGAGAACTCTGAGAGCTTGCTGGAGCCCCCAGAGCGGGGTCTGGGCACCGGCCTCCCGGAGCGGCCCCGGGAAAGC CCGCAGCTGCATGAGCGCGAGACCCCGCAGCCCGAGGGCGGACCCCCGTCTCCGGCCGGGACGCCCCCGCAACCCAA GAGGCCCCGGCCCGGAGCGTCAAAGGACGGCCTGCTGAGTCCAGGCTCCTGGAACGGGGAGCCCGGCGGAGAGGGCA GCCGGCCCGCCACGCCGTCGGATGGCGCCGGTCGTCGCAGCCCCGCGCGCCCCGCCTCGGAGCACATGGCCATCGAG GCGCTGCAGCCGCCGCCCGCGCCCTCGCAGGAGCCCGAGGTAGCAATGTACCGCGGCTACCATAGCTACGCCGTGCG CTGA (SEQ ID NO: 49) Human JP2NT nt: ATGAGTGGGGGCCGCTTCGACTTTGATGATGGAGGGGCGTACTGCGGGGGCTGGGAGGGGGGAAAGGCCCATGGGCA TGGACTGTGCACAGGCCCCAAGGGCCAGGGCGAATACTCTGGCTCCTGGAACTTTGGCTTTGAGGTGGCAGGTGTCT ACACCTGGCCCAGCGGAAACACCTTTGAGGGATACTGGAGCCAGGGCAAACGGCATGGGCTGGGCATAGAGACCAAG GGGCGCTGGCTCTACAAGGGCGAGTGGACACATGGCTTCAAGGGACGCTACGGAATCCGGCAGAGCTCAAGCAGCGG TGCCAAGTATGAGGGCACCTGGAACAATGGCCTGCAAGACGGCTATGGCACCGAGACCTATGCTGATGGAGGGACGT ACCAAGGCCAGTTCACCAACGGCATGCGCCATGGCTACGGAGTACGCCAGAGCGTGCCCTACGGGATGGCCGTGGTG GTGCGCTCGCCGCTGCGCACGTCGCTGTCGTCCCTGCGCAGCGAGCACAGCAACGGCACGGTGGCCCCGGACTCTCC CGCCTCGCCGGCCTCCGACGGCCCCGCGCTGCCCTCGCCCGCCATCCCGCGTGGCGGCTTCGCGCTCAGCCTCCTGG CCAATGCCGAGGCGGCCGCGCGGGCGCCCAAGGGCGGCGGCCTCTTCCAGCGGGGCGCGCTGCTGGGCAAGCTGCGG CGCGCAGAGTCGCGCACGTCCGTGGGTAGCCAGCGCAGCCGTGTCAGCTTCCTTAAGAGCGACCTCAGCTCGGGCGC CAGCGACGCCGCGTCCACCGCCAGCCTGGGAGAGGCCGCCGAGGGCGCCGACGAGGCCGCACCCTTCGAGGCCGATA TCGACGCCACCACCACCGAGACCTACATGGGCGAGTGGAAGAACGACAAACGCTCGGGCTTCGGCGTGAGCGAACGC TCCAGTGGCCTCCGCTACGAGGGCGAGTGGCTGGACAACCTGCGCCACGGCTATGGCTGCACCACGCTGCCCGACGG CCACCGCGAGGAGGGCAAGTACCGCCACAACGTGCTGGTCAAGGACACCAAGCGCCGCATGCTGCAGCTCAAGAGCA ACAAGGTCCGCCAGAAAGTGGAGCACAGTGTGGAGGGTGCCCAGCGCGCCGCTGCTATCGCGCGCCAGAAGGCCGAG ATTGCCGCCTCCAGGACAAGCCACGCCAAGGCCAAAGCTGAGGCAGCGGAACAGGCCGCCCTGGCTGCCAACCAGGA GTCCAACATTGCTCGCACTTTGGCCAGGGAGCTGGCTCCGGACTTCTACCAGCCAGGTCCGGAATATCAGAAGCGCC GGCTGCTGCAGGAGATCCTGGAGAACTCGGAGAGCCTGCTGGAGCCCCCCGACCGGGGCGCCGGCGCAGCGGGCCTC CCACAGCCGCCCCGCGAGAGCCCGCAGCTGCACGAGCGTGAGACCCCTCGGCCCGAGGGTGGCTCCCCGTCACCGGC CGGGACGCCCCCGCAGCCCAAGCGGCCCAGGCCCGGGGTGTCCAAGGACGGCCTGCTGAGCCCAGGCGCCTGGAACG GCGAGCCCAGCGGTGAGGGCAGCCGGTCAGTCACTCCGTCCGAGGGCGCGGGCCGCCGCAGCCCCGCGCGTCCAGCC ACCGAGCGCATGGCCATCGAGGCTCTGCAGGCACCGCCTGCGCCGTCGCGGGAGCCGGAGGTGGCGCTTTACCAGGG CTACCACAGCTATGCTGTGCGCTGA (SEQ ID NO: 5) JP2NT aa Mouse JP2NT aa: MSGGRFDFDDGGAYCGGWEGGKAHGHGLCTGPKGQGEYSGSWNFGFEVAGVYTWPSGNTFEGYWSQGKRHGLGIETK GRWLYKGEWTHGFKGRYGIRQSTNSGAKYEGTWNNGLQDGYGTETYADGGTYQGQFTNGMRHGYGVRQSVPYGMAVV VRSPLRTSLSSLRSEHSNGTVAPDSPAADGPMLPSPPVPRGGFALTLLATAEAARPQGLFTRGTLLGRLRRSESRTS 49 24028 / / SLW 875.245WO1 LGSQRSRLSFLKSELSSGASDAASTGSLAEGAEGPDDAAAPFDADIDATTTETYMGEWKNDKRSGFGVSERSSGLRY EGEWLDNLRHGYGRTTLPDGHREEGKYRHNVLVKGTKRRVLPLKSSKVRQKVEHGVEGAQRAAAIARQKAEIAASRT SHAKAKAEAAEQAALAANQESNIARTLAKELAPDFYQPGPEYQKRRLLQEILENSESLLEPPERGLGTGLPERPRES PQLHERETPQPEGGPPSPAGTPPQPKRPRPGASKDGLLSPGSWNGEPGGEGSRPATPSDGAGRRSPARPASEHMAIE ALQPPPAPSQEPEVAMYRGYHSYAVR* (SEQ ID NO: 50) Human JP2NT aa: MSGGRFDFDDGGAYCGGWEGGKAHGHGLCTGPKGQGEYSGSWNFGFEVAGVYTWPSGNTFEGYWSQGKRHGLGIETK GRWLYKGEWTHGFKGRYGIRQSSSSGAKYEGTWNNGLQDGYGTETYADGGTYQGQFTNGMRHGYGVRQSVPYGMAVV VRSPLRTSLSSLRSEHSNGTVAPDSPASPASDGPALPSPAIPRGGFALSLLANAEAAARAPKGGGLFQRGALLGKLR RAESRTSVGSQRSRVSFLKSDLSSGASDAASTASLGEAAEGADEAAPFEADIDATTTETYMGEWKNDKRSGFGVSER SSGLRYEGEWLDNLRHGYGCTTLPDGHREEGKYRHNVLVKDTKRRMLQLKSNKVRQKVEHSVEGAQRAAAIARQKAE IAASRTSHAKAKAEAAEQAALAANQESNIARTLARELAPDFYQPGPEYQKRRLLQEILENSESLLEPPDRGAGAAGL PQPPRESPQLHERETPRPEGGSPSPAGTPPQPKRPRPGVSKDGLLSPGAWNGEPSGEGSRSVTPSEGAGRRSPARPA TERMAIEALQAPPAPSREPEVALYQGYHSYAVR* (SEQ ID NO: 6) A “vector” or “delivery” vehicle refers to a macromolecule or association of macromolecules that comprises or associates with a polynucleotide or polypeptide, and which can be used to mediate delivery of the polynucleotide or polypeptide to a cell or intercellular space, either in vitro or in vivo. Illustrative vectors include, for example, plasmids, viral vectors, liposomes, nanoparticles, or microparticles and other delivery vehicles. In one embodiment, a polynucleotide to be delivered, sometimes referred to as a “target polynucleotide” or “transgene,” may comprise a coding sequence of interest in gene therapy (such as a gene encoding a protein of therapeutic interest), a coding sequence of interest and / or a selectable or detectable marker. “Transduction,” “transfection,” “transformation” or “transducing” as used herein, are terms referring to a process for the introduction of an exogenous polynucleotide into a host cell leading to expression of the polynucleotide, e.g., the transgene in the cell, and includes the use of recombinant virus to introduce the exogenous polynucleotide to the host cell. Transduction, transfection or transformation of a polynucleotide in a cell may be determined by methods well known to the art including, but not limited to, protein expression (including steady state levels), e.g., by ELISA, flow cytometry and Western blot, measurement of DNA and RNA by hybridization assays, e.g., Northern blots, Southern blots and gel shift mobility assays. Methods used for the introduction of the exogenous polynucleotide include well-known techniques such as viral infection or transfection, lipofection, transformation and electroporation, as well as other non-viral gene delivery techniques. The introduced polynucleotide may be stably or transiently maintained in the host cell. “Gene delivery” refers to the introduction of an exogenous polynucleotide into a cell for gene transfer, and may encompass targeting, binding, uptake, transport, localization, replicon integration and expression. 50 24028 / / SLW 875.245WO1 “Gene transfer” refers to the introduction of an exogenous polynucleotide into a cell which may encompass targeting, binding, uptake, transport, localization and replicon integration, but is distinct from and does not imply subsequent expression of the gene. “Gene expression” or “expression” refers to the process of gene transcription, translation, and post-translational modification. An “Infectious” virus or viral particle is one that comprises a polynucleotide component which is capable of delivering into a cell for which the viral species is trophic. The term does not necessarily imply any replication capacity of the virus. The term “polynucleotide” refers to a polymeric form of nucleotides of any length, including deoxyribonucleotides or ribonucleotides, or analogs thereof. A polynucleotide may comprise modified nucleotides, such as methylated or capped nucleotides and nucleotide analogs, and may be interrupted by non-nucleotide components. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The term polynucleotide, as used herein, refers interchangeably to double- and single-stranded molecules. Unless otherwise specified or required, any embodiment of the invention described herein that is a polynucleotide encompasses both the double-stranded form and each of two complementary single-stranded forms known or predicted to make up the double-stranded form. A “transcriptional regulatory sequence” refers to a genomic region that controls the transcription of a gene or coding sequence to which it is operably linked. Transcriptional regulatory sequences of use in the present invention generally include at least one transcriptional promoter and may also include one or more enhancers and / or terminators of transcription. “Operably linked” refers to an arrangement of two or more components, wherein the components so described are in a relationship permitting them to function in a coordinated manner. By way of illustration, a transcriptional regulatory sequence (TRS) or a promoter is operably linked to a coding sequence if the TRS or promoter promotes transcription of the coding sequence. An operably linked TRS is generally joined in cis with the coding sequence, but it is not necessarily directly adjacent to it. “Heterologous” means derived from a genotypically distinct entity from the entity to which it is compared. For example, a polynucleotide introduced by genetic engineering techniques into a different cell type is a heterologous polynucleotide (and, when expressed, can encode a heterologous polypeptide). Similarly, a transcriptional regulatory element such as a promoter that is removed from its native coding sequence and operably linked to a different coding sequence is a heterologous transcriptional regulatory element. 51 24028 / / SLW 875.245WO1 A “terminator” refers to a polynucleotide sequence that tends to diminish or prevent read- through transcription (i.e., it diminishes or prevent transcription originating on one side of the terminator from continuing through to the other side of the terminator). The degree to which transcription is disrupted is typically a function of the base sequence and / or the length of the terminator sequence. In particular, as is well known in numerous molecular biological systems, particular DNA sequences, generally referred to as “transcriptional termination sequences” are specific sequences that tend to disrupt read-through transcription by RNA polymerase, presumably by causing the RNA polymerase molecule to stop and / or disengage from the DNA being transcribed. Typical example of such sequence-specific terminators include polyadenylation (“polyA”) sequences, e.g., SV40 polyA. In addition to or in place of such sequence-specific terminators, insertions of relatively long DNA sequences between a promoter and a coding region also tend to disrupt transcription of the coding region, generally in proportion to the length of the intervening sequence. This effect presumably arises because there is always some tendency for an RNA polymerase molecule to become disengaged from the DNA being transcribed, and increasing the length of the sequence to be traversed before reaching the coding region would generally increase the likelihood that disengagement would occur before transcription of the coding region was completed or possibly even initiated. Terminators may thus prevent transcription from only one direction (“uni-directional” terminators) or from both directions (“bi-directional” terminators) and may be comprised of sequence-specific termination sequences or sequence-non-specific terminators or both. A variety of such terminator sequences are known in the art. “Host cells,” “cell lines,” “cell cultures,” “packaging cell line” and other such terms denote higher eukaryotic cells, such as mammalian cells including human cells, useful in the present invention. e.g., to produce recombinant virus or recombinant polypeptide. These cells include the progeny of the original cell that was transduced. It is understood that the progeny of a single cell may not necessarily be completely identical (in morphology or in genomic complement) to the original parent cell. “Recombinant,” as applied to a polynucleotide means that the polynucleotide is the product of various combinations of cloning, restriction and / or ligation steps, and other procedures that result in a construct that is distinct from a polynucleotide found in nature. A recombinant virus is a viral particle comprising a recombinant polynucleotide. The terms respectively include replicates of the original polynucleotide construct and progeny of the original virus construct. A “control element” or “control sequence” is a nucleotide sequence involved in an interaction of molecules that contributes to the functional regulation of a polynucleotide, including replication, duplication, transcription, splicing, translation, or degradation of the polynucleotide. 52 24028 / / SLW 875.245WO1 The regulation may affect the frequency, speed, or specificity of the process, and may be enhancing or inhibitory in nature. Control elements known in the art include, for example, transcriptional regulatory sequences such as promoters and enhancers. A promoter is a DNA region capable under certain conditions of binding RNA polymerase and initiating transcription of a coding region usually located downstream (in the 3′ direction) from the promoter. Promoters include AAV promoters, e.g., P5, P19, P40 and AAV ITR promoters, as well as heterologous promoters. An “expression vector” is a vector comprising a region which encodes a gene product of interest and is used for effecting the expression of the gene product in an intended target cell. An expression vector also comprises control elements operatively linked to the encoding region to facilitate expression of the protein in the target. The combination of control elements and a gene or genes to which they are operably linked for expression is sometimes referred to as an “expression cassette,” a large number of which are known and available in the art or can be readily constructed from components that are available in the art. The terms “polypeptide” and “protein” are used interchangeably herein to refer to polymers of amino acids of any length. The terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, acetylation, phosphorylation, lipidation, or conjugation with a labeling component. An “Isolated” polynucleotide, e.g., plasmid, virus, polypeptide or other substance refers to a preparation of the substance devoid of at least some of the other components that may also be present where the substance or a similar substance naturally occurs or is initially prepared from. Thus, for example, an isolated substance may be prepared by using a purification technique to enrich it from a source mixture. Isolated nucleic acid, peptide or polypeptide is present in a form or setting that is different from that in which it is found in nature. For example, a given DNA sequence (e.g., a gene) is found on the host cell chromosome in proximity to neighboring genes; RNA sequences, such as a specific mRNA sequence encoding a specific protein, are found in the cell as a mixture with numerous other mRNAs that encode a multitude of proteins. The isolated nucleic acid molecule may be present in single-stranded or double-stranded form. When an isolated nucleic acid molecule is to be utilized to express a protein, the molecule will contain at a minimum the sense or coding strand (i.e., the molecule may single-stranded), but may contain both the sense and anti-sense strands (i.e., the molecule may be double-stranded). Enrichment can be measured on an absolute basis, such as weight per volume of solution, or it can be measured in relation to a second, potentially interfering substance present in the source mixture. For example, a 2-fold enrichment, 10-fold enrichment, 100-fold enrichment, or a 1000-fold enrichment. 53 24028 / / SLW 875.245WO1 The term “exogenous,” when used in relation to a protein, gene, nucleic acid, or polynucleotide in a cell or organism refers to a protein, gene, nucleic acid, or polynucleotide which has been introduced into the cell or organism by artificial or natural means. An exogenous nucleic acid may be from a different organism or cell, or it may be one or more additional copies of a nucleic acid which occurs naturally within the organism or cell. By way of a non-limiting example, an exogenous nucleic acid is in a chromosomal location different from that of natural cells or is otherwise flanked by a different nucleic acid sequence than that found in nature, e.g., an expression cassette which links a promoter from one gene to an open reading frame for a gene product from a different gene. “Transformed” or “transgenic” is used herein to include any host cell or cell line, which has been altered or augmented by the presence of at least one recombinant DNA sequence. The host cells of the present invention are typically produced by transfection with a DNA sequence in a plasmid expression vector, as an isolated linear DNA sequence, or infection with a recombinant viral vector. The term “sequence homology” means the proportion of base matches between two nucleic acid sequences or the proportion amino acid matches between two amino acid sequences. When sequence homology is expressed as a percentage, e.g., 50%, the percentage denotes the proportion of matches over the length of a selected sequence that is compared to some other sequence. Gaps (in either of the two sequences) are permitted to maximize matching; gap lengths of 15 bases or less are usually used, 6 bases or less are preferred with 2 bases or less more preferred. When using oligonucleotides as probes or treatments, the sequence homology between the target nucleic acid and the oligonucleotide sequence is generally not less than 17 target base matches out of 20 possible oligonucleotide base pair matches (85%); not less than 9 matches out of 10 possible base pair matches (90%), or not less than 19 matches out of 20 possible base pair matches (95%). Two amino acid sequences are homologous if there is a partial or complete identity between their sequences. For example, 85% homology means that 85% of the amino acids are identical when the two sequences are aligned for maximum matching. Gaps (in either of the two sequences being matched) are allowed in maximizing matching; gap lengths of 5 or less are preferred with 2 or less being more preferred. Alternatively, two protein sequences (or polypeptide sequences derived from them of at least 30 amino acids in length) are homologous, as this term is used herein, if they have an alignment score of at more than 5 (in standard deviation units) using the program ALIGN with the mutation data matrix and a gap penalty of 6 or greater. The two 54 24028 / / SLW 875.245WO1 sequences or parts thereof are more homologous if their amino acids are greater than or equal to 50% identical when optimally aligned using the ALIGN program. The term “corresponds to” is used herein to mean that a polynucleotide sequence is structurally related to all or a portion of a reference polynucleotide sequence, or that a polypeptide sequence is structurally related to all or a portion of a reference polypeptide sequence, e.g., they have at least 80%, 82%, 85%, 87%, 90%, 92%, 95%, 97% or more, e.g., 99% or 100%, sequence identity. In contradistinction, the term “complementary to” is used herein to mean that the complementary sequence is homologous to all or a portion of a reference polynucleotide sequence. For illustration, the nucleotide sequence “TATAC” corresponds to a reference sequence “TATAC” and is complementary to a reference sequence “GTATA”. The term “sequence identity” means that two polynucleotide sequences are identical (i.e., on a nucleotide-by-nucleotide basis) over the window of comparison. The term “percentage of sequence identity” means that two polynucleotide sequences are identical (i.e., on a nucleotide- by-nucleotide basis) over the window of comparison. The term “percentage of sequence identity” is calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity. The terms “substantial identity” as used herein denote a characteristic of a polynucleotide sequence, wherein the polynucleotide comprises a sequence that has at least 85 percent sequence identity, preferably at least 90 to 95 percent sequence identity, more usually at least 99 percent sequence identity as compared to a reference sequence over a comparison window of at least 20 nucleotide positions, frequently over a window of at least 20-50 nucleotides, wherein the percentage of sequence identity is calculated by comparing the reference sequence to the polynucleotide sequence which may include deletions or additions which total 20 percent or less of the reference sequence over the window of comparison. As used herein, the term “variant” refers to a protein that has one or more amino-acid substitution, insertion, or deletion as compared to a parental protein. As used herein, the term “functional variant” refers to a protein that has one or more amino-acid substitution, insertion, or deletion as compared to a parental protein, and which retains one or more desired activities of the parental protein. As used herein, “substantially pure” or “purified” means an object species is the predominant species present (i.e., on a molar basis it is more abundant than any other individual 55 24028 / / SLW 875.245WO1 species in the composition), for instance, a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all macromolecular species present. Generally, a substantially pure composition will comprise more than about 80 percent of all macromolecular species present in the composition, or more than about 85%, about 90%, about 95%, and about 99%. The object species may be purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single macromolecular species. In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. The term “about”, when immediately preceding a number or numeral, means that the number or numeral ranges plus or minus 10%. It should be understood that the terms “a” and “an” as used herein refer to “one or more” of the enumerated components unless otherwise indicated. The use of the alternative (e.g., “or”) should be understood to mean either one, both, or any combination thereof of the alternatives. The term “and / or” should be understood to mean either one, or both of the alternatives. As used herein, the terms “include” and “comprise” are used synonymously. Preparation of Expression Cassettes To prepare expression cassettes encoding JP2 or mutant or truncated forms thereof, a peptide thereof, or a fusion thereof, for transformation, the recombinant DNA sequence or segment may be circular or linear, double-stranded or single-stranded. A DNA sequence which encodes an RNA sequence that is substantially complementary to a mRNA sequence encoding a gene product of interest is typically a “sense” DNA sequence cloned into a cassette in the opposite orientation (i.e., 3′ to 5′ rather than 5′ to 3). Generally, the DNA sequence or segment is in the form of chimeric DNA, such as plasmid DNA, that can also contain coding regions flanked by control sequences which promote the expression of the DNA in a cell. As used herein, “chimeric” means that a vector comprises DNA from at least two different species, or comprises DNA from the same species, which is linked or associated in a manner which does not occur in the “native” or wild type of the species. Aside from DNA sequences that serve as transcription units, or portions thereof, a portion of the DNA may be untranscribed, serving a regulatory or a structural function. For example, the DNA may itself comprise a promoter that is active in eukaryotic cells, e.g., mammalian cells, or in certain cell types, or may utilize a promoter already present in the genome that is the transformation target of the lymphotropic virus. Such promoters include the CMV promoter, as 56 24028 / / SLW 875.245WO1 well as the SV40 late promoter and retroviral LTRs (long terminal repeat elements), although many other promoter elements well known to the art may be employed, e.g., the MMTV, RSV, MLV or HIV LTR in the practice of the invention. In one embodiment, expression is inducible. In one embodiment, a tissue-specific promoter (or enhancer) is employed, e.g., a cardiac-specific promoter or enhancer or a skeletal muscle-specific promoter or enhancer. Such control elements include, but are not limited to, those derived from the actin and myosin gene families, such as from the myoD gene family (Weintraub et al., Science, 251, 761 (1991)); the myocyte-specific enhancer binding factor MEF-2; control elements derived from the human skeletal actin gene, and the cardiac actin gene; muscle creatine kinase sequence elements and the murine creatine kinase enhancer (mCK) element; control elements derived from the skeletal fast-twitch troponin C gene, the slow-twitch cardiac troponin C gene and the slow-twitch troponin I genes. Cardiac cell restricted promoters include but are not limited to promoters from the following genes; a α-myosin heavy chain gene, e.g., a ventricular α-myosin heavy chain gene, β-myosin heavy chain gene, e.g., a ventricular β-myosin heavy chain gene, myosin light chain 2v gene, e.g., a ventricular myosin light chain 2 gene, myosin light chain 2a gene, e.g., a ventricular myosin light chain 2 gene, cardiomyocyte-restricted cardiac ankyrin repeat protein (CARP) gene, cardiac α-actin gene, cardiac m2 muscarinic acetylcholine gene, ANP gene, BNP gene, cardiac troponin C gene, cardiac troponin I gene, cardiac troponin T gene, cardiac sarcoplasmic reticulum Ca-ATPase gene, skeletal α-actin gene, as well as an artificial cardiac cell-specific promoter. Further, chamber-specific promoters or enhancers may also be employed, e.g., for atrial- specific expression, the quail slow myosin chain type 3 (MyHC3) or ANP promoter, or the cGATA-6 enhancer, may be employed. For ventricle-specific expression, the iroquois homeobox gene may be employed. Examples of ventricular myocyte-specific promoters include a ventricular myosin light chain 2 promoter and a ventricular myosin heavy chain promoter. Other elements functional in the host cells, such as introns, enhancers, polyadenylation sequences and the like, may also be a part of the recombinant DNA. Such elements may or may not be necessary for the function of the DNA but may provide improved expression of the DNA by affecting transcription, stability of the mRNA, or the like. Such elements may be included in the DNA as desired to obtain the optimal performance of the transforming DNA in the cell. The recombinant DNA to be introduced into the cells may contain either a selectable marker gene or a reporter gene or both to facilitate identification and selection of transformed cells from the population of cells sought to be transformed. Alternatively, the selectable marker may be carried on a separate piece of DNA and used in a co-transformation procedure. Both selectable markers and reporter genes may be flanked with appropriate regulatory sequences to enable expression in 57 24028 / / SLW 875.245WO1 the host cells. Useful selectable markers are well known in the art and include, for example, antibiotic and herbicide-resistance genes, such as neo, hpt, dhfr, bar, aroA, puro, hyg, dapA and the like. See also, the genes listed on Table 1 of Lundquist et al. (U.S. Pat. No.5,848,956). Reporter genes are used for identifying potentially transformed cells and for evaluating the functionality of regulatory sequences. Reporter genes which encode for easily assayable proteins are well known in the art. In general, a reporter gene is a gene which is not present in or expressed by the recipient organism or tissue and which encodes a protein whose expression is manifested by some easily detectable property, e.g., enzymatic activity. Exemplary reporter genes include the chloramphenicol acetyl transferase gene (cat) from Tn9 of E. coli, the beta-glucuronidase gene (gus) of the uidA locus of E. coli, the green, red, or blue fluorescent protein gene, and the luciferase gene. Expression of the reporter gene is assayed at a suitable time after the DNA has been introduced into the recipient cells. The general methods for constructing recombinant DNA which can transform target cells are well known to those skilled in the art, and the same compositions and methods of construction may be utilized to produce the DNA useful herein. The recombinant DNA can be readily introduced into the host cells, e.g., mammalian, bacterial, yeast or insect cells, or prokaryotic cells, by transfection with an expression vector comprising the recombinant DNA by any procedure useful for the introduction into a particular cell, e.g., physical or biological methods, to yield a transformed (transgenic) cell having the recombinant DNA so that the DNA sequence of interest is expressed by the host cell. In one embodiment, the recombinant DNA is stably integrated into the genome of the cell. Physical methods to introduce a recombinant DNA into a host cell include calcium- mediated methods, lipofection, particle bombardment, microinjection, electroporation, and the like. Biological methods to introduce the DNA of interest into a host cell include the use of DNA and RNA viral vectors. Viral vectors, e.g., retroviral or lentiviral vectors, have become a widely used method for inserting genes into eukaryotic cells, such as mammalian, e.g., human cells. Other viral vectors can be derived from poxviruses, e.g., vaccinia viruses, herpes viruses, adenoviruses, adeno-associated viruses, baculoviruses, and the like. To confirm the presence of the recombinant DNA sequence in the host cell, a variety of assays may be performed. Such assays include, for example, molecular biological assays well known to those of skill in the art, such as Southern and Northern blotting, RT-PCR and PCR; biochemical assays, such as detecting the presence or absence of a particular gene product, e.g., by immunological means (ELISAs and Western blots) or by other molecular assays. 58 24028 / / SLW 875.245WO1 To detect and quantitate RNA produced from introduced recombinant DNA segments, RT- PCR may be employed. In this application of PCR, it is first necessary to reverse transcribe RNA into DNA, using enzymes such as reverse transcriptase, and then through the use of conventional PCR techniques amplify the DNA. In most instances PCR techniques, while useful, will not demonstrate integrity of the RNA product. Further information about the nature of the RNA product may be obtained by Northern blotting. This technique demonstrates the presence of an RNA species and gives information about the integrity of that RNA. The presence or absence of an RNA species can also be determined using dot or slot blot Northern hybridizations. These techniques are modifications of Northern blotting and only demonstrate the presence or absence of an RNA species. While Southern blotting and PCR may be used to detect the recombinant DNA segment in question, they do not provide information as to whether the recombinant DNA segment is being expressed. Expression may be evaluated by specifically identifying the peptide products of the introduced DNA sequences or evaluating the phenotypic changes brought about by the expression of the introduced DNA segment in the host cell. Vectors for Delivery Delivery vectors include, for example, viral vectors, microparticles, nanoparticles, liposomes and other lipid-containing complexes, and other macromolecular complexes capable of mediating delivery of a gene to a host cell, e.g., to provide for recombinant expression of a polypeptide encoded by the gene. Vectors can also comprise other components or functionalities that further modulate gene delivery and / or gene expression, or that otherwise provide beneficial properties. Such other components include, for example, components that influence binding or targeting to cells (including components that mediate cell-type or tissue-specific binding); components that influence uptake of the vector by the cell; components that influence localization of the transferred gene within the cell after uptake (such as agents mediating nuclear localization); and components that influence expression of the gene. Such components also might include markers, such as detectable and / or selectable markers that can be used to detect or select for cells that have taken up and are expressing the nucleic acid delivered by the vector. Such components can be provided as a natural feature of the vector (such as the use of certain viral vectors which have components or functionalities mediating binding and uptake), or vectors can be modified to provide such functionalities. Selectable markers can be positive, negative or bifunctional. Positive selectable markers allow selection for cells carrying the marker, whereas negative selectable markers allow cells carrying the marker to be selectively eliminated. A variety of such marker genes have been described, including bifunctional (i.e., positive / negative) markers (see, e.g., WO 59 24028 / / SLW 875.245WO1 92 / 08796; and WO 94 / 28143). Such marker genes can provide an added measure of control that can be advantageous in gene therapy contexts. A large variety of such vectors are known in the art and are generally available. Vectors for genes within the scope of the invention include, but are not limited to, isolated nucleic acid, e.g., plasmid-based vectors which may be extrachromosomally maintained, and viral vectors. e.g., recombinant adenovirus, retrovirus, lentivirus, herpesvirus, poxvirus, papilloma virus, or adeno-associated virus, including viral and non-viral vectors which are present in liposomes, e.g., neutral or cationic liposomes, such as DOSPA / DOPE, DOGS / DOPE or DMRIE / DOPE liposomes, and / or associated with other molecules such as DNA-anti-DNA antibody-cationic lipid (DOTMA / DOPE) complexes. Exemplary gene viral vectors are described below. Vectors may be administered via any route including, but not limited to, intramuscular, buccal, rectal, intravenous or intracoronary administration, and transfer to cells may be enhanced using electroporation and / or iontophoresis. In one embodiment, vectors are locally administered. Adeno-associated virus (AAV) is a replication-deficient parvovirus, the single stranded DNA genome of which is about 4.7 kb in length including two -145 -nucleotide inverted terminal repeat (ITRs). There are multiple known variants of AAV, also sometimes called serotypes when classified by antigenic epitopes. The nucleotide sequences of the genomes of the AAV serotypes are known. For example, the complete genome of AAV-1 is provided in GenBank Accession No. NC_002077; the complete genome of AAV-2 is provided in GenBank Accession No. NC_001401 and Srivastava et al., J. Virol., 45: 555-564 (1983); the complete genome of AAV-3 is provided in GenBank Accession No. NC_1829; the complete genome of AAV-4 is provided in GenBank Accession No. NC_001829; the AAV-5 genome is provided in GenBank Accession No. AF085716; the complete genome of AAV-6 is provided in GenBank Accession No. NC_001862; at least portions of AAV-7 and AAV-8 genomes are provided in GenBank Accession Nos. AX753246 and AX753249, respectively; the AAV-9 genome is provided in Gao et al., J. Virol., 78: 6381-6388 (2004); the AAV-10 genome is provided in Mol. Then, 13(1): 67-76 (2006); and the AAV-11 genome is provided in Virology, 330(2): 375-383 (2004). The sequence of the AAVrh.74 genome is provided in U.S. Patent 9,434,928, incorporated herein by reference. Cis- acting sequences directing viral DNA replication (rep), encapsidation / packaging and host cell chromosome integration are contained within the AAV ITRs. Three AAV promoters (named p5, pl 9, and p40 for their relative map locations) drive the expression of the two AAV internal open reading frames encoding rep and cap genes. The two rep promoters (p5 and pl 9), coupled with the differential splicing of the single AAV intron (at nucleotides 2107 and 2227), result in the production of four rep proteins (rep78, rep68, rep52, and rep40) from the rep gene. Rep proteins 60 24028 / / SLW 875.245WO1 possess multiple enzymatic properties that are ultimately responsible for replicating the viral genome. The cap gene is expressed from the p40 promoter, and it encodes the three capsid proteins VP1, VP2, and VP3. Alternative splicing and non-consensus translational start sites are responsible for the production of the three related capsid proteins. A single consensus polyadenylation site is located at map position 95 of the AAV genome. The life cycle and genetics of AAV are reviewed in Muzyczka, Current Topics in Microbiology and Immunology, 158: 97- 129 (1992). AAV possesses features that make it attractive as a vector for delivering foreign DNA to cells, for example, in gene therapy. AAV infection of cells in culture is noncytopathic, and natural infection of humans and other animals is silent and asymptomatic. Moreover, AAV infects many mammalian cells allowing the possibility of targeting many different tissues in vivo. Moreover, AAV transduces slowly dividing and non-dividing cells, and can persist essentially for the lifetime of those cells as a transcriptionally active nuclear episome (extrachromosomal element). The AAV proviral genome is inserted as cloned DNA in plasmids, which makes construction of recombinant genomes feasible. Furthermore, because the signals directing AAV replication and genome encapsidation are contained within the ITRs of the AAV genome, some or all of the internal approximately 4.3 kb of the genome (encoding replication and structural capsid proteins, rep-cap) may be replaced with foreign DNA. To generate AAV vectors, the rep and cap proteins may be provided in trans. Another significant feature of AAV is that it is an extremely stable and hearty virus. It easily withstands the conditions used to inactivate adenovirus (56° to 65°C for several hours), making cold preservation of AAV less critical. AAV may even be lyophilized. Finally, AAV-infected cells are not resistant to superinfection. Gene delivery viral vectors useful in the practice of the present disclosure can be constructed utilizing methodologies well known in the art of molecular biology. Typically, viral vectors carrying transgenes are assembled from polynucleotides encoding the transgene, suitable regulatory elements and elements necessary for production of viral proteins, which mediate cell transduction. Such recombinant viruses may be produced by techniques known in the art, e.g., by transfecting packaging cells or by transient transfection with helper plasmids or viruses. Typical examples of virus packaging cells include but are not limited to HeLa cells, SF9 cells (optionally with a baculovirus helper vector), HEK293 cells, etc. A Herpesvirus-based system can be used to produce AAV vectors, as described in US20170218395A1. Detailed protocols for producing such replication-defective recombinant viruses may be found for instance in W095 / 14785, W096 / 22378, U.S. Pat. No.5,882,877, U.S. Pat. No.6,013,516, U.S. Pat. No.4,861,719, U.S. Pat. 61 24028 / / SLW 875.245WO1 No.5,278,056 and W094 / 19478, the complete contents of each of which is hereby incorporated by reference. AAV vectors useful in the practice of the present disclosure can be packaged into AAV virions (viral particles) using various systems including adenovirus-based and helper-free systems. Standard methods in AAV biology include those described in Kwon and Schaffer. Pharm Res. (2008) 25(3):489-99; Wu et al. Mol. Ther. (2006) 14(3):316-27. Burger et al. Mol. Ther. (2004) 10(2):302-17; Grimm et al. Curr Gene Ther. (2003) 3(4):281-304; Deyle DR, Russell DW. Curr Opin Mol Ther. (2009) 11(4): 442-447; McCarty et al. Gene Ther. (2001) 8(16): 1248-54; and Duan et al. Mol Ther. (2001) 4(4):383-91. Helper-free systems included those described in US 6,004,797; US 7,588,772; and US 7,094,604. AAV DNA in the rAAV genomes may be from any AAV variant or serotype for which a recombinant virus can be derived including, but not limited to, AAV variants or serotypes AAV-1, AAV-2, AAV-3, AAV-4, AAV-5, AAV-6, AAV-7, AAV-8, AAV-9, AAV- 10, AAV-11, AAV- 12, AAV-13, AAVrh.74, and AAVrhlO. Production of pseudotyped rAAV is disclosed in, for example, WO 01 / 83692. Other types of rAAV variants, for example rAAV with capsid mutations, are also contemplated. See, for example, Marsic et al., Molecular Therapy, 22(11): 1900-1909 (2014). The nucleotide sequences of the genomes of various AAV serotypes are known in the art. Peptides, Polypeptides and Fusion Proteins The peptide or fusion proteins of the invention can be synthesized in vitro, e.g., by the solid phase peptide synthetic method or by recombinant DNA approaches (see above). The solid phase peptide synthetic method is an established and widely used method. These polypeptides can be further purified by fractionation on immunoaffinity or ion-exchange columns; ethanol precipitation; reverse phase HPLC; chromatography on silica or on an anion-exchange resin such as DEAE; chromatofocusing; SDS-PAGE; ammonium sulfate precipitation; gel filtration using, for example, Sephadex G-75; or ligand affinity chromatography. Once isolated and characterized, chemically modified derivatives of a given peptide or fusion thereof, can be readily prepared. For example, amides of the peptide or fusion thereof of the present invention may also be prepared by techniques well known in the art for converting a carboxylic acid group or precursor, to an amide. One method for amide formation at the C-terminal carboxyl group is to cleave the peptide or fusion thereof from a solid support with an appropriate amine, or to cleave in the presence of an alcohol, yielding an ester, followed by aminolysis with the desired amine. Salts of carboxyl groups of a peptide or fusion thereof may be prepared in the usual manner by contacting the peptide, polypeptide, or fusion thereof with one or more equivalents of a desired 62 24028 / / SLW 875.245WO1 base such as, for example, a metallic hydroxide base, e.g., sodium hydroxide; a metal carbonate or bicarbonate base such as, for example, sodium carbonate or sodium bicarbonate; or an amine base such as, for example, triethylamine, triethanolamine, and the like. N-acyl derivatives of an amino group of the peptide or fusion thereof may be prepared by utilizing an N-acyl protected amino acid for the final condensation, or by acylating a protected or unprotected peptide, polypeptide, or fusion thereof. O-acyl derivatives may be prepared, for example, by acylation of a free hydroxy polypeptide or polypeptide resin. Either acylation may be carried out using standard acylating reagents such as acyl halides, anhydrides, acyl imidazoles, and the like. Both N- and O-acylation may be carried out together, if desired. Formyl-methionine, pyroglutamine and trimethyl-alanine may be substituted at the N- terminal residue of the polypeptide. Other amino-terminal modifications include aminooxypentane modifications. Substitutions may include substitutions which utilize the D rather than L form, as well as other well-known amino acid analogs, e.g., unnatural amino acids such as α, α-disubstituted amino acids, N-alkyl amino acids, lactic acid, and the like. These analogs include phosphoserine, phosphothreonine, phosphotyrosine, hydroxyproline, gamma-carboxyglutamate; hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, omithine, citruline, α-methyl-alanine, para-benzoyl-phenylalanine, phenylglycine, propargylglycine, sarcosine, ε-N,N,N-trimethyllysine, ε-N-acetyllysine, N-acetylserine, N- formylmethionine, 3-methylhistidine, 5-hydroxylysine, ω-N-methylarginine, and other similar amino acids and imino acids and tert-butylglycine. Conservative amino acid substitutions may be employed-that is, for example, aspartic- glutamic as acidic amino acids; lysine / arginine / histidine as polar basic amino acids; leucine / isoleucine / methionine / valine / alanine / proline / glycine non-polar or hydrophobic amino acids; serine / threonine as polar or hydrophilic amino acids. Conservative amino acid substitution also includes groupings based on side chains. For example, a group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic-hydroxyl side chains is serine and threonine; a group of amino acids having amide- containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulfur-containing side chains is cysteine and methionine. For example, it is reasonable to expect that replacement of a leucine with an isoleucine or valine, an aspartate with a glutamate, a threonine with a serine, or a similar replacement of an amino acid with a structurally related amino acid will not have a major effect 63 24028 / / SLW 875.245WO1 on the properties of the resulting peptide, polypeptide or fusion polypeptide. Whether an amino acid change results in a functional peptide, polypeptide or fusion polypeptide can readily be determined by assaying the specific activity of the peptide, polypeptide or fusion polypeptide. Amino acid substitutions falling within the scope of the invention, are, in general, accomplished by selecting substitutions that do not differ significantly in their effect on maintaining (a) the structure of the peptide backbone in the area of the substitution. (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. Naturally occurring residues are divided into groups based on common side-chain properties: (1) hydrophobic: norleucine, met, ala, val, leu, lie; (2) neutral hydrophilic: cys, ser, thr; (3) acidic: asp, glu; (4) basic: asn, gin, his, lys, arg; (5) residues that influence chain orientation: gly, pro; and (8) aromatic; trp, tyr, phe. The invention also envisions a peptide, polypeptide or fusion polypeptide with non- conservative substitutions. Non-conservative substitutions entail exchanging a member of one of the classes described above for another. Acid addition salts of the peptide, polypeptide or fusion polypeptide or of amino residues of the peptide, polypeptide or fusion polypeptide may be prepared by contacting the polypeptide or amine with one or more equivalents of the desired inorganic or organic acid, such as, for example, hydrochloric acid. Esters of carboxyl groups of the polypeptides may also be prepared by any of the usual methods known in the art. Formulations and Dosages The polypeptides or fusions thereof, or nucleic acid encoding the polypeptide or fusion of the invention, can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, e.g., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes. In one embodiment, the polypeptide or nucleic acid encoding the polypeptide is administered to a site of cardiac damage or suspected cardiac damage or is administered prophylactically. In one embodiment, the JP2 polypeptides or fusions thereof, or nucleic acid encoding the polypeptide or fusion, may be administered by infusion or injection. Solutions of the polypeptides or fusions thereof, or nucleic acid encoding the polypeptide or fusion or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, 64 24028 / / SLW 875.245WO1 liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it may be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active agent in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation include vacuum drying and the freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions. Useful solid carriers may include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as antimicrobial agents can be added to optimize the properties for a given use. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user. Useful dosages of the polypeptides or fusions thereof, or nucleic acid encoding the polypeptide or fusion, can be determined by comparing their in vitro activity and in vivo activity 65 24028 / / SLW 875.245WO1 in animal models thereof. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No.4,938,949. Generally, the concentration of the polypeptides or fusions thereof, or nucleic acid encoding the polypeptide or fusion, in a liquid composition, may be from about 0.1-25 wt-%, e.g., from about 0.5-10 wt-%. The concentration in a semi-solid or solid composition such as a gel or a powder may be about 0.1-5 wt-%. e.g., about 0.5-2.5 wt-%. The amount of the polypeptides or fusions thereof, or nucleic acid encoding the polypeptide or fusion required for use alone or with other agents will vary with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. The polypeptides or fusions thereof, or nucleic acid encoding the polypeptide or fusion, may be conveniently administered in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, or conveniently 50 to 500 mg of active ingredient per unit dosage form. In general, however, a suitable dose may be in the range of from about 0.5 to about 100 mg / kg, e.g., from about 10 to about 75 mg / kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, for example in the range of 6 to 90 mg / kg / day, e.g., in the range of 15 to 60 mg / kg / day. In some embodiments, the AAV vector is administered at a dose of between about 1 x 1012and 5x 1014vector genomes (vg) or between about 1 x 1012and 6x 1014vg of the AAV vector per kilogram (vg) of total body mass of the subject (vg / kg). In some embodiments, the AAV vector is administered at a dose of between about 1 x l013and 5x l014vg / kg. In some embodiments, the AAV vector is administered at a dose of between about 5 x 1013and 3 x 1014vg / kg. In some embodiments, the AAV vector is administered at a dose of between about 5x 1013and I x 1014vg / kg. In certain embodiments, the AAV vector is administered at a dose of between about 5x 1013and 5x 1014vg / kg. In certain embodiments, the AAV vector is administered at a dose of between about 1 x l013and I x l015vg / kg. In certain embodiments, the AAV vector is administered at a dose of between about 5x 1013and I x l014vg / kg. In certain embodiments, the AAV vector is administered at a dose of between about 8x 1013and 1 x l014vg / kg. The invention will be described by the following non-limiting examples. EXAMPLES Example 1 Preventing Site-specific Calpain Proteolysis of Junctophilin-2 Protects Against Stress-induced E-C Uncoupling and Heart Failure Development 66 24028 / / SLW 875.245WO1 Introduction Dysfunctional excitation-contraction (E-C) coupling and asynchronous Ca2+handling events in cardiomyocytes are recognized as defining hallmarks of failing human hearts (1-4) as well as in animal models of heart failure (HF) (5-12). In healthy ventricular cardiomyocytes, excitation of the plasmalemma through depolarization triggers uniform myofilament contraction through a process called Ca2+induced Ca2+release (CICR). CICR occurs within well-organized cardiac dyads that position CaV1.2 L-type Ca2+entry channels (LTCC) on plasma membrane transverse tubule (or T-tubules) with Ryanodine receptor Ca2+release channels (RyR2) on the sarcoplasmic reticulum (SR) (13,14). Pathological stress promotes T-tubule remodeling that causes the dissociation of dyad structures, E-C uncoupling, and abnormal Ca2+homeostasis (4,8,12). Over time, the heart adapts to these changes through structural and functional remodeling that involves cellular and pathological hypertrophy, fibrosis, and transcriptional remodeling, among other changes. Compensatory ionotropic and chronotropic changes are commonly targeted by current HF medications but fail to address changes inherent to E-C coupling dysfunction. Direct restoration of E-C coupling machinery in the diseased heart can be one way to improve cardiac function. Cardiac dyad integrity and efficient CICR utilizes Junctophilin-2 (JP2), a multi-faceted E- C coupling structural protein that tethers T-tubules with SR membranes while interacting with and regulating both CaV1.2 and RyR2 channels (15). JP2 is downregulated during HF (12,16-22) and genetic studies demonstrate JP2 loss of function in the mouse heart promotes T-tubule disorganization and Ca2+handling dysfunction leading to a lethal cardiomyopathy (12,23-26). The decrease in JP2 levels in failing hearts is attributed to Ca2+-dependent and site-specific proteolysis by calpain proteases (22,27,28). Calpains are activated by Ca2+and are thought to contribute to HF by proteolytically cleaving proteins needed for normal cardiac function, such as sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) (29-31), LTCCs (32) and JP2 (21,22,27,28), in addition to being implicated in processes such as inflammation, oxidative stress, apoptosis and remodeling. Preclinical studies conducted in animal models have demonstrated the beneficial effects of calpain inhibitors in treating HF (21). Translational use of calpain inhibitors in treating HF in patients, however, has not been attempted and may be prohibitive due to concerns over the broad specificity, potential off-target effects, and long-term safety of this class of drugs (33,34). While achieving specificity when targeting calpains is challenging, the identification of specific calpain substrates that initiate and promote HF progression would be an important first step toward more specialized therapies that mitigate the complex pathophysiology of HF. 67 24028 / / SLW 875.245WO1 It was recently reported that JP2 can be one such target as pharmacological inhibition of calpain activity with MDL-28170 preserves JP2, myocyte T-tubule integrity, E-C coupling and protects against development of HF in multiple murine HF models (21). However, a limitation of these findings is that the specific contribution of JP2 cleavage on cardiac remodeling processes cannot be discerned from those of other proteolytic substrates. Provided herein, evidence is presented that preventing site-specific cleavage of JP2 in vivo is sufficient to reduce HF development. Calpain-resistant mutant JP2 knockin mice (JP2CR) were generated in which the primary calpain-cleavage site of JP2 (a.a. 563-568) (27,34) is deleted. It is shown that cardiac functional decline, E-C coupling dysfunction, structural remodeling and transcriptional reprogramming are significantly lessened during pressure overload stress in JP2CRmice as compared to wildtype animals. JP2CRexpressing adeno-associated viruses (AAVJP2CRversus AAV-JP2) was administered to mice with established moderate HF from pressure overload stress and it was demonstrated that JP2CRgene therapy effectively attenuates HF progression and demonstrates much better protection than wildtype JP2. It was concluded that site-specific and stress-dependent JP2 cleavage represents a critical proximal event in development of HF and preventing its proteolysis is important in preserving cardiomyocyte E-C coupling during HF progression. Thus, gene therapy targeting site-specific cleavage of JP2 represents a novel therapeutic approach for precision medicine in treating human HF. Materials & Methods Calpain-resistant JP2 knockin mice (JP2CR) were generated by deleting the primary JP2 calpain cleavage site. Stress dependent JP2 cleavage was assessed via in vitro cleavage assays and in isolated cardiomyocytes treated with 1 μM isoproterenol by immunofluorescence. Cardiac outcomes were assessed in WT and JP2CRmice five weeks after transverse aortic constriction (TAC) versus sham surgery using echocardiography, histology, and RNA-sequencing methods. E- C coupling efficiency was measured by in situ confocal microscopy. E-C coupling proteins were evaluated by calpain assays and Western blotting. The effectiveness of adeno-associated virus (AAV) gene therapy with JP2CR, JP2, or GFP to slow HF progression was evaluated in mice with established cardiac dysfunction. All animal experiments were approved by the Institutional Animal Care and Use Committee of the University of Iowa and were performed by following ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines and in accordance with the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health (NIH publication 85-23, revised 1996). 68 24028 / / SLW 875.245WO1 Data were analyzed in GraphPad Prism version 9.4.1. Data are expressed as mean ± standard error of the mean (SEM). Data were tested for normality using the Shapiro-Wilk test and were considered normally distributed when the P value was higher than 0.05. Statistical analyses used for different datasets were described in detail in their corresponding figure legends. P-values and adjusted p-values of <0.05 were considered statistically significant. All quantified Western blot data are shown as values relative to control. Images with quantified values approximating the group average were chosen as representative. The RNA-seq raw data have been uploaded to the Gene Expression Ominibus (www.ncbi.nlm.nih.gov / geo), under accession No. GSE235601. Animal studies: All animal experiments were approved by the Institutional Animal Care and Use Committee of the University of Iowa and were performed in accordance with according to the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health (NIH publication 85-23, revised 1996). JP2CRknockin mice were generated using CRISPR-Cas9 technology by the University of Iowa Genome Editing Facility. Cas9 nuclease, crRNA directed to Jph2 exon4 and purified repair template lacking codons encoding amino acids 563-568 were pronuclear injected into zygotes. Correctly targeted founders were identified by DNA sequencing and backcrossed more than ten generations into the C57Bl / 6N background. Routine genotyping was performed using forward (5’-CCGGAGCGTCAAAGGAC-3’; SEQ ID NO: 64) and reverse (5’- TCCAGAGTGGCTTGCTTG-3’ (SEQ ID NO: 65) primers. To maintain model consistency and avoid hormonal interference, male mice were preferred over female. Nine to ten-week-old male mice were subjected to pressure overload by transverse aortic constriction (TAC) surgery, as described previously. (31) Briefly, mice were anesthetized with ketamine (100 mg / kg) / xylazine (5 mg / kg) by i.p. injection and isoflurane inhalation. Aortic constriction was performed by tying a 7–0 nylon suture ligature against a 27-gauge needle. For the sham group, the aortic arch was visualized but not banded. Hearts were harvested from anesthetized mice (ketamine / xylazine (100 mg / kg / 5 mg / kg, i.p.)) 5 or 8 weeks after TAC or sham surgery and processed for biochemical, cellular and histological analyses. All animal experiments were performed in accordance with NIH policies and approved by the University of Iowa Institutional Animal Care and Use Committee (IACUC approval #1101529). Transthoracic Echocardiography: Transthoracic echocardiograms were performed in the University of Iowa Cardiology Animal Phenotyping Core Laboratory, using a Vevo 2100 Imager (VisualSonics), as described 69 24028 / / SLW 875.245WO1 previously. (33) Briefly, conscious sedation was achieved with midazolam (0.2 - 0.3 mg s.c.).2D images were acquired in left ventricle (LV) short- and long-axis planes with a 40-MHz sector- array probe, yielding 100 frames per second. LV mass, volumes, and ejection fractions were calculated with the area-length method. All echocardiographic images were analyzed by an experienced operator blinded to genotypes or treatments. Hemodynamic analysis Hemodynamic analysis was performed on 6-month-old JP2CR and WT mice by using a pressure volume loop according to manufacturers’ protocols. Briefly, a polyethylene pressure transducer catheter (Millar Spr-8391.4F; Millar Instruments, Houston, TX) was inserted from the right carotid artery into LV for hemodynamic study. LV maximum and minimum ascending rates of pressure (+dp / dt and –dp / dt), heart rate (HR), LV end-diastolic pressure (LVEDP), LV development pressure (LVDP), LV end-systolic volume (LVESV), LV end-diastolic volume (LVEDV), LV relaxation time (Tau), left ventricle ejection fraction (LVEF) were recorded simultaneously. Chart software (AD Instrument Ltd., Australia) was used for data processing. Histology: Hearts from mice were fixed by perfusion with 4% paraformaldehyde (PFA) for 15-20 min, cut longitudinally and fixed with fresh 4% PFA at 4°C for an additional 24hrs. Fixed heart tissue was then incubated in 15% and 30% sucrose sequentially at 4°C for cryoprotection before cryo-embedding with optimal cutting temperature (OCT) compound. The heart tissues were longitudinally sectioned (5 µm) in a cryostat at -20°C and stained with hematoxylin and eosin (H&E) using standard protocols. H&E staining was used for measurement of cross-sectional area of cardiomyocytes. Masson's trichrome staining was used for the detection of collagen fibers in the heart tissues. ImageJ (NIH, Bethesda, Maryland) was used to quantify the relative area of fibrosis (blue staining in the myocardial tissue), by measuring the ratio of blue staining region to total myocardial area in the image. Immunofluorescence Immunofluorescence of isolated cardiomyocytes was performed as described previously. (44) Briefly, isolated cardiomyocytes were plated on laminin-coated slides with a concentration of 1x104cells / mL for 2 hours then fixed in 4% paraformaldehyde (PFA) at room temperature for 15 min. For immunofluorescent staining, samples were washed 3 times with PBS for 10 min each, and then permeabilized with 0.3% Triton-X 100 in PBS for 30 min. Following 1% BSA blocking for 30 min at room temperature, samples were incubated with custom made JP2 primary antibody (1:200, N-terminal epitope, Pacific Immunology Inc.), (19,31) or commercial antibodies against type 2 ryanodine receptors (1:200, RyR2, Thermo Fisher Scientific, Catalog #MA3-916) and 70 24028 / / SLW 875.245WO1 voltage-gated L-type Ca2+ channels (1:200, CaV1.2, Alomone Labs, Catalog #ACC-003) at 4°C overnight followed by incubation with fluorescent-labeled secondary antibody (1:500, anti-rabbit IgG-Alexa 488, Thermo Fisher Scientific, Catalog #A-11034)) at room temperature for 1 hour. TO-PRO-3 (1:2000, Thermo Fisher Scientific) was added at room temperature for 30 min to stain the nucleus. A Zeiss LSM510 confocal microscope using a 63x (NA=1.4) oil immersion lens (Carl Zeiss MicroImaging Inc., Germany) was used for immunofluorescence imaging. Super resolution imaging of CaV1.2-RyR2 colocalization was executed with a ZEISS LSM980 Airyscan 2 system (Carl Zeiss MicroImaging Inc., Germany). Adult mouse ventricular myocytes isolation and Isoproterenol (ISO) treatment: Mouse ventricular myocytes were isolated via enzymatic digestion. Briefly, hearts were quickly excised from isofluorane anesthetized mice and perfused on a Langendorff apparatus at 37 °C with normal Ca2+free Tyrode’s solution (containing the following in mM: NaCl, 137; KCl, 5.4; MgCl2, 2.0; NaH2PO4, 0.33; D-Glucose, 10.0; and HEPES, 10.0; pH 7.40 at 37 ℃). After ~5 min of perfusion, the perfusate was switched to Tyrode’s solution containing collagenase (Type 2, 1mg / ml, Worthington) and protease (0.05 mg / ml, Sigma-Aldrich) for the digestion of the connective tissue. After ~20 min of digestion, single ventricular myocytes were isolated from the dissected and triturated ventricles and stabilized in Tyrode’s solution containing BSA (1%). After gradually reintroducing Ca2+, the final Ca2+tolerant cardiomyocytes were resuspended in 1.8 mM Ca2+Tyrode’s solution and maintained at room temperature. Isolated cardiomyocytes were suspended in Minimum Essential Medium (MEM) with 10% fetal bovine serum (FBS) and plated on Laminin (10 ug / ml) coated cover slides for 2 hours. The myocytes were cultured in 5% CO2incubator at 37 ℃ for 2 hours (hrs), then the medium was changed to FBS-free MEM. For some experiments, ISO (1 uM) and additional Ca2+(total 4 mM) was added to the culture medium for 24 hours. Single myocyte Calcium imaging Laser scanning confocal imaging of single myocytes was performed as previously reported.46 Mouse ventricular myocytes isolated from WT or JP2CRmice were loaded with Rhod- 2 AM (5 µM, AAT BioQuest, Catalog # 21062) at room temperature for 30 min. After 10 min of de-esterification, the myocytes were placed in a recording chamber and perfused with Tyrode solution (1.8 mM Ca2+) at 36 ±1 °C (Temperature Controller, TC2BIP, Cell MicroControls). Ca2+imaging was acquired with a laser scanning confocal microscope (LSM 510, Carl Zeiss) equipped a 63 × lens with numerical aperture (NA) 1.35. Images of Ca2+transients and sparks were acquired at a sampling rate of 1.93 ms per line along the longitudinal axis of the myocytes. All digital images were processed with IDL 8.0 program (Research System Inc.). 71 24028 / / SLW 875.245WO1 Cardiomyocyte diastolic calcium level was measured using a ratiometric Ca2+imaging system. (47) Myocytes were loaded with 1µM Fura-2 AM (Invitrogen) for 20 min at room temperature. Myocytes were washed twice with Tyrode’s solution and de-esterified for 10 min. Myocytes were placed in a recording chamber and perfused with Tyrode’s solution (1.8 mM Ca2+) at room temperature. Fura-2 was excited at 340 and 380 nm wavelengths with fluorescence signal intensity acquired at 510 nm. Real-time shifts in Fura-2 AM fluorescence ratio were recorded in 30 s intervals using a Zeiss Observer A1 inverted fluorescence microscope. T-tubule imaging Isolated cardiomyocyte T-tubules were stained with Di-8-ANEPPS (10 μmol / L, AAT BioQuest, USA) in Ca2+free Tyrode solution at room temperature for 30 mins. The structure of T-tubules was visualized by the LSM510 confocal microscope. Quantitative analysis of T-tubule integrity was processed with AutoTT, a custom program compiled with MatLab. (34) The power value (TTpower) reflects the strength of T-tubule organization regularity. In situ imaging of T-tubules in perfused hearts was described previously. (8,48) Briefly, intact mouse hearts were retrogradely Langendorff-perfused at room temperature with 0 Ca2+Tyrode's solution (NaCl 137, KCl 5.4, HEPES 10, Glucose 10, MgCl21, NaH2PO40.33, pH adjusted to 7.4 with NaOH), containing 2.5 µM MM 4-64, a lipophilic fluorescence indicator of membrane structure (AAT Bioquest, Inc, USA) for 30 min. Hearts were then transferred to another Langendorff apparatus (37 ºC) attached to the confocal microscope system and perfused with indicator free / Ca2+free solution. The membrane structure of epicardial myocyte membrane structures were imaged and the regularity of T-tubules within each 202 x 202 μm2image frame were analyzed as described above for isolated myocytes. In Situ Confocal Ca2+Imaging in Intact Hearts In situ confocal Ca2+imaging in intact hearts were performed as described previously (49) and similar to in situ T-tubule imaging above. Briefly, excised hearts were perfused with Rhod-2 AM (0.3 mM, AAT Bioquest, CA, USA) containing Kreb-Henseleit’s solution (in mM: 120 NaCl, 24 NaHCO3, 11.1 Glucose, 5.4 KCl, 1.8 CaCl2,1 MgCl2, 0.42 KH2PO4, oxygenated with 95% O2 and 5% CO2) at room temperature for 60 min via retrograde Langendorff perfusion system. Hearts were transferred to the second confocal-attached Langendorff apparatus (37ºC) and placed onto a recording chamber for in situ confocal imaging (line scan) of Ca2+signals from epicardial myocytes under sinus rhythm. To avoid motion artifacts during Ca2+imaging, blebbistatin (10 μM, Sigma) and BDM (2,3-butanedione monoxime, 10 mM, Sigma) were added to the perfusion solution. The confocal line scan images were acquired at a rate of 3.07 ms per line. Unless otherwise specified, Ca2+transients were autonomously elicited by electrical signals from the 72 24028 / / SLW 875.245WO1 sinoatrial node and analyzed by using IDL8.0. Molecular Cloning and Mutagenesis The cDNAs of mouse CaV1.2 (Addgene, #26572) and human SERCA2a (Addgene, #75187) were cloned into pCMV6-XL5 and fused with a C-terminal HA tag. A pcDNA3 plasmid expressing Myc-tagged mouse RyR2 was provided by Dr. S.R. Wayne Chen (University of Calgary, Canada). The pCMV6-XL5-CAPN1 and pCMV6-entry-CAPN2 plasmids expressing human CAPN1 and CAPN2 were provided by Dr. Tianqing Peng (Western University, Canada). In Vitro Calpain-mediated Proteolysis Reaction Mouse heart tissues were washed with PBS and homogenized in lysis buffer (20 mM Tris- HCl, 150 mM NaCl, 2 mM EDTA, and 1% Triton X-100), followed by sonication. Homogenates were centrifuged for 15 min at 13,000 rpm at 4 °C. Cell extracts were added into ice-cold calpain reaction buffer (to a final concentration of 135 mM NaCl, 5 mM KCl, 1mM MgCl2, 10mM glucose, 10 mM HEPES (pH 7.25), 0.3 µM MG132, and 10 mM 2-mercaptoethanol). Just prior to starting the calpain reaction, CaCl2 was added to achieve a final concentration of 50 µM, 200 µM, 500 µM or 2 mM free Ca2+(in the presence of EDTA), as calculated by Winmax32 version 2.50 (Chris Patton, Stanford University, USA; www.stanford.edu / ~cpatton / maxc.html). 10 µM MDL-28170 (Sigma-Aldrich) was added into reactions as indicated to inhibit calpain. Reactions were incubated at 30 °C for 10 mins and stopped by adding EDTA to a final concentration of 10 mM. The reaction products were mixed with 4X LDS Sample Buffer (Thermo Fisher Scientific, NP0007) and 10X Sample Reducing Agent (Thermo Fisher Scientific, NP0004), incubated at 95 °C for 5 min and then subjected to Western blotting. Calpain Activity Assay Calpain activity in heart lysates was determined using a calpain activity assay kit (ab65308, Abcam, Cambridge, Massachusetts), according to the manufacturer’s protocol. Heart lysates were obtained from mice treated with TAC or sham surgery for 5 weeks. Immunoblotting Heart tissues and cultured HEK293T cells were homogenized using RIPA and sonicated. The antibody used for detecting JP2 was custom made by Pacific Immunology Inc (N-terminal epitope). Commercial antibodies were directed against type 2 ryanodine receptors (RyR2, Thermo Fisher Scientific, Catalog #MA3-916), voltage-gated L-type Ca2+channels (CaV1.2, Alomone Labs, Catalog #ACC-003), CSQ2 (Thermo Fisher Scientific, Catalog # PA1-913) , SERCA2 (Thermo Fisher Scientific, Catalog #MA3-919), Phospholamban (PLN, Cell Signaling, Catalog #14562), phospho-PLN-Ser16 (Badrilla, Catalog # A010-12), phospho-PLN-Thr17 (Badrilla, 73 24028 / / SLW 875.245WO1 Catalog #A010-13), ANP (Thermo Fisher Scientific, Catalog #702539), Fibronectin (Abclonal, #A12977), Flag tag (Cell Signaling, #14793), Myc tag (Cell Signaling, #2276), HA tag (Cell Signaling, #3724), CAPN1 (Cell Signaling, #2556S), CAPN2 (Cell Signaling, #2539S), CAPNS1 (Abcam, # ab92333) and GAPDH (Cell Signaling, Catalog #5174). HRP-linked anti-Mouse IgG (Thermo Fisher Scientific, Catalog #62-6520), and anti-rabbit IgG (Cell Signaling, Catalog #7074) were used to visualize bound primary antibodies with the ECL substrate (Thermo Fisher Scientific, Catalog #32106) and visualized on a BioRad ChemiDoc Touch Imaging Station. RNA-sequencing Ventricular tissue was isolated from mice five weeks after sham or TAC surgery (n=4 per group). Total RNA was purified after homogenizing tissue in Trizol reagent using a Percellus Evolution homogenizer (Bertin Corp.). RNA libraries were generated by the University of Iowa Institute for Human Genetics using a TruSeq Stranded mRNA kit (Illumina) and sequenced on a Novaseq 6000 instrument (SP flowcell, 200 cycles). Raw sequencing files were uploaded and processed on the BaseSpace Sequence Hub (Illumina). RNA reads were aligned to the mm10 genome using STAR default options and TruSeq adapter trimming via the BaseSpace RNA Seq Alignment app (v1.1.1). Differential expression analysis was performed with the DESeq2 app (v.1.1.0) with differentially expressed genes (DEGs) defined by a false discovery rate (FDR) <0.05 and >1.5-fold change (absolute log2 fold change>0.585). RNA sequencing files have been deposited into the Gene Expression Ominibus (Accession: GSE235601). Heatmaps were generated using MORPHEUS Gene-E (software.broadinstitute.org / morpheus / ) via k-means clustering of DEGs. Ingenuity Pathway Analysis (QIAGEN) was used to determine enriched pathways annotated for cardiovascular diseases within its Diseases and Functions analysis. The RNA-seq raw data have been uploaded to the Gene Expression Ominibus (www.ncbi.nlm.nih.gov / geo), under accession No. GSE235601. Adeno-associated virus gene delivery: Mouse cDNAs of full-length JP2 and JP2CR(Δ563-568) was cloned into an AAV2 / 9 shuttle vector (pFBAAVCMVmcswtIRESGFPBgHpA, G0692, provided by University of Iowa Viral Vector Core). The vector contains the structural Rep proteins from AAV2 and the capsid serotype 9. AAV viruses were generated by the University of Iowa Viral Vector Core. For AAV injections in the established HF model, 11–12-week-old mice (2 weeks post TAC) were intravenously injected with a total volume of 100 μl saline containing 1 × 1012vg AAV-GFP, AAV-JP2 or AAV- JP2CRviruses. Measurements of Plasma Factors 74 24028 / / SLW 875.245WO1 Blood was collected from 6-month-old WT and JP2CRmice or TAC-induced heart failure mice and centrifuged (6000 rpm, 10 mins) to obtain the serum fraction. ELISA kits were used to measure plasma levels of mouse TNNT2 (RK03251, Abclonal) and N‐terminal (NT)‐pro‐ANP (ab267800; Abcam). All ELISA procedures were done according to manufacturers’ protocols. Three technical replicates were measured. Statistics Data were analyzed in GraphPad Prism version 9.4.1. Data are expressed as mean ± standard error of the mean (SEM). Sample size selected based on previous data. The sample size was chosen based on previous experience and standards in the field. Data were tested for normality using the Shapiro-Wilk test and were considered normally distributed when the P value was higher than 0.05. A parametric test was made when the data set met the normality test. Multiple group comparisons were performed by 2-way ANOVA followed by Tukey post hoc test (for 3 or more groups of data) when the data exhibited a normal distribution (Figures 1, 2, 3, 4, 5). Unpaired two- tailed Student’s t-tests were used to determine statistical significance for Figure S1. For data sets that did not meet the normality test, nonparametric Kruskal-Wallis test followed by Dunn post hoc test was used (Figures 3B and 3C). Enrichment and IPA analysis were performed using a right- tailed Fisher’s exact test (^ of 0.05) and Benjamini-Hochberg multiple testing correction. P- values and adjusted p-values of <0.05 were considered statistically significant. All quantified Western blot data are shown as values relative to control. Images with quantified values approximating the group average were chosen as representative. Results and Discussion JP2CRknock-in prohibits Calpain-mediated cleavage of JP2. Endogenous ~100 kDa JP2 protein undergoes likely site-specific proteolysis under a variety of cardiac stress events in generating ~75 kDa N-terminal and ~25 kDa C-terminal fragments (22,35-37). Previous studies show that the primary calpain cleavage site in JP2 lies between R565and T566and deletion of residues 563-568 preserves the integrity of JP2 against in vitro cleavage by Calpain-1 and Calpain-2 (22,28). A homologous site is present in human JP2 (between R572and T573) that is also cleaved by Calpain-1 and Calpain-2 (22). It was hypothesized herein that pathological stress initiates E-C coupling dysfunction and promotes HF through in vivo JP2 cleavage at R565 / T566. To determine the physiological relevance of this site, a calpain-resistant mutant JP2 knockin mouse model (JP2CR) was generated by deleting codons within the Jph2 gene that encode amino acids 563-568 (Fig. 1A; FIG. S1). Confocal microscopy, echocardiography analysis and ex vivo heart weight / body weight and lung weight / body weight data show that there is no significant difference in JP2 subcellular localization, heart function, or heart morphology at 75 24028 / / SLW 875.245WO1 baseline between JP2CRand wildtype (WT) littermate mice (FIGS. S2-S4). The CR deletion mutant appears to be chronically well tolerated; cardiac function remained unaltered in JP2CRmice through at least 24 months of age (Table S1). To verify that JP2CRexpressed from the knockin allele is resistant to calpain, heart lysates from WT and homozygous JP2CRmice were subjected to in vitro calpain cleavage assays. Addition of recombinant Calpain-1 and 2 mM Ca2+produced a 75 kD N-terminal JP2 fragment (JP2NT) in WT, but not JP2CR, lysates (Fig.1B). Cleavage of WT JP2 was inhibited by the calpain inhibitor MDL-28170. Based on previous findings that JP2NT translocates to nuclei after stress-dependent cleavage (36) it was asked whether JP2CRcould protect JP2 integrity at its known localization at cardiomyocyte Z-lines and prevent its nuclear enrichment in response to isoproterenol (ISO). Treatment of isolated adult cardiomyocytes with 1 μM Isoproterenol + 5 mM Ca2+for 24 hrs 76 24028 / / SLW 875.245WO1 caused an increase in JP2 nuclear localization in WT cells compared to freshly isolated and vehicle treated cells (FIG. S5). No detectable nuclear translocation was observed in JP2CRcells treated with ISO and Ca2+. As a quantitative index of JP2 immunostaining regularity, peak JP2 power values were calculated at the dominant frequency in Fourier transformed images (JP2power) using the AutoTT algorithm (38). The organized JP2 distribution was similar in both WT and JP2CRhearts in freshly isolated cardiomyocytes but altered obviously in WT cells during culturing and even worse upon ISO plus high [Ca2+]o treatment, while JP2CRpattern was preserved with better integrity under the same conditions (Fig. 1C-D). Since JP2 is a structural protein that tethers T- tubules to the SR and is required to maintain T-tubule integrity (12,26), it was examined whether JP2CRcould similarly preserve T-tubule organization in cultured cardiomyocytes under similar conditions. The regularity of T-tubule network (TTpower) was similar in freshly isolated WT and JP2CRmyocytes but degenerated in WT cells after culturing, and was more severe with ISO plus high [Ca2+]o(Fig. 1E-F). These data, together with the above in vitro calpain cleavage assay, demonstrate that JP2CRis indeed cleavage resistant, protecting both JP2 integrity and T-tubule architecture from cardiac stress. JP2CRprotects against TAC-induced cardiac dysfunction and adverse cardiac remodeling. The improved integrity of JP2 and T-tubules suggests that E-C coupling and ensuing cardiac function may also be preserved in JP2CRhearts during cardiac stress. To test this, JP2CRand WT mice were subjected to TAC or sham surgery at 9-10 wks of age. It was found that a significantly larger fraction of JP2CRmice (18 of 26, 69.2%) survived from 5 weeks of pressure overload stress compared to WT (19 of 38, 50%, p<0.05) mice (Fig. 2A). Cardiac function was evaluated in surviving animals via echocardiographic assessments of left ventricular ejection fraction (LVEF), end-diastolic volume (LVEDV), end-systolic volume (LVESV), and mass (Fig.2B-D; Tables S2 and S3). In sham operated groups, WT and JP2CRmice had similar cardiac function. Under pressure overload conditions that promote cardiac hypertrophy and HF, however, JP2CRmice displayed significantly less TAC-induced contractile dysfunction. Furthermore, while WT and JP2CRmice had similar heart and lung weights under sham conditions when normalized to body weight, JP2CRanimals exhibited significantly less cardiac hypertrophy and lung edema in response to TAC compared to WT littermates (Fig. 2E-F). Histological hematoxylin & eosin staining for gross heart morphology and myocyte cross-sectional area (CSA) analysis also revealed that TAC- induced hypertrophy is attenuated in JP2CRmice (Fig.2G-H). As extracellular matrix remodeling is frequently found in failing hearts, histological analysis was performed of hearts with Masson’s trichrome staining and found that JP2CRhearts had reduced LV fibrosis after TAC compared with 77 24028 / / SLW 875.245WO1 WT hearts (Fig. 2I-J). These results demonstrate that JP2CR protects the heart against TAC- induced pathological remodeling. 78 24028 / / SLW 875.245WO1 JP2CRprotects against T-tubule remodeling and abnormalities in Ca2+handling during TAC induced HF. It was next asked whether the improved cardiac outcomes observed in JP2CRhearts after TAC correlate with improvements in JP2 function in stabilizing cardiac dyad junctions and maintaining EC coupling function. Using confocal microscopy of intact Langendorff-perfused hearts, the morphology of the cardiomyocyte membrane network and intracellular Ca2+dynamics from WT and JP2CR animals 5 weeks after sham and TAC surgery were assessed. The degree to which organized T-tubules deteriorate during HF can be effectively quantified in membrane- stained cardiomyocytes using T-tubule analysis algorithms (38,39). Consistent with results in isolated cardiomyocytes, JP2CRdid not affect T-tubule integrity in either the left (LV) or right (RV) ventricles of sham-operated mice (Fig. 3A-C). By contrast, JP2CRmice had significantly better organized T-tubule structures in both ventricles following pressure overload compared to WT mice. Line scan confocal Ca2+images recorded from intact hearts under spontaneous beating revealed there was no difference in Ca2+handling properties in sham-operated WT and JP2CRhearts (Fig.3D-G), suggesting that and JP2CRhas no influence on CICR at baseline. WT hearts have markedly impaired Ca2+handling after TAC as indicated by a significant decrease in Ca2+79 24028 / / SLW 875.245WO1 transient amplitude, an increase in Ca2+transient time to peak (Tpeak), and a prolongation in the 50%, 75% and 90% Ca2+transient decay time (T50, T75, and T90, respectively) (Fig. 3D-G). Consistent with attenuated T-tubule remodeling after TAC, JP2CRhearts had a significantly higher Ca2+transient amplitude with shorter time to peak and faster decay rates as compared to WT TAC hearts. To obtain a more complete assessment of intracellular Ca2+handling, Ca2+dynamics were isolated in isolated cardiomyocytes. Consistent with decreased colocalization between CaV1.2 and RyR2 and E-C uncoupling (FIG. S6), it was found that WT myocytes after TAC have an increase in SR Ca2+spark frequency that was not found in JP2CR myocytes (Figure 3H and 3I). No difference in other Ca2+parameters, including amplitude, duration, or width of Ca2+sparks, was observed between genotypes (Figure 3J through 3L), indicating that expression of JP2CRlimits RyR2 activation under stress conditions without altering SR Ca2+release events once initiated. Parallel experiments with Fura-2 revealed that the increase in diastolic Ca2+levels in response to TAC is also blunted by JP2CRexpression (Figure 3M). Taken together, these data support the notion that JP2CRpreserves T-tubule organization, cardiac dyad integrity, and Ca2+handling homeostasis during pressure-overload stress. JP2CRmitigates the degradation of E-C coupling proteins and the induction of hypertrophic and fibrotic factors during TAC-induced HF. The above physiological, histological, and cellular data show that JP2CRmice have significantly better cardiac outcomes and E-C coupling function after TAC than wild-type mice. It was next examined whether there are molecular changes in E-C coupling proteins and hypertrophic markers that could explain JP2CRmediated cardioprotection. Western blotting of LV lysates supports a widespread downregulation in E-C coupling proteins in WT hearts after TAC including JP2, RyR2, sarcoplasmic reticulum calcium ATPase-2a (SERCA2a), CaV1.2, Calsequestrin-2 (CSQ-2) and phospholamban (PLN) (Fig.4A-H). It should be noted that the JP2 R565 / T566 cleavage site is used for in vivo JP2 proteolysis as the increase in the 75 kD JP2 proteolytic fragment in response to TAC and at the expense of the full-length protein does not occur in JP2CRhearts (Fig.4A-C). While no significant differences were found in the expression levels of E-C coupling proteins in sham samples in WT versus JP2CRmice, TAC-induced downregulation of RyR2, CaV1.2, and SERCA2a was significantly reduced in JP2CRLV lysates (Fig.4D-F). While the expression of Fibronectin-1 (FN1) and atrial natriuretic protein (ANP) were induced by TAC in both genotypes, changes were less dramatic in JP2CRhearts (Fig. 4I-J), supporting the attenuated cardiac fibrosis and hypertrophy phenotype of JP2CRmice (Fig.2). A difference in total PLN levels was not found between TAC operated groups, but significant changes in PLN phosphorylation was observed at two canonical regulatory sites: PKA- 80 24028 / / SLW 875.245WO1 phosphorylated Ser16 and CaMKII-phosphorylated Thr17. Phosphorylation at either site relieves PLN inhibition of SERCA2a to increase Ca2+reuptake into the SR. It was found that phospho- Ser16 levels were reduced after TAC in both genotypes but is more modest in JP2CRhearts (Fig. 4K), consistent with the degree of Ca2+handling dysfunction that was observed in these hearts after TAC (Fig. 3). Phospho-Thr17 levels, however, were dramatically increased in response to TAC in both genotypes, but to a less extent in JP2CRmice as compared to WT mice (Fig.4L). Protection of E-C coupling related proteins in JP2CRhearts correlates with diminished calpain activity. Calpain activation in response to cytosolic [Ca2+]ioverload has been implicated in pathogenesis of myocardial remodeling and HF and likely contributes to the proteolysis of E-C coupling related proteins. To investigate the potential contribution of calpain activation in the differential downregulation of RyR2, SERCA2a and CaV1.2 in TAC-treated wildtype versus JP2CRhearts, first calpain activity was measured in ventricular lysates. Calpain activity was increased in response to TAC and was greater in WT hearts compared to JP2CR(Fig.5A). Western blotting for calpain subunits shows that calpain-1 (CAPN1), calpain-2 (CAPN2), and their regulatory subunit calpain-S1 (CAPNS1) were upregulated after TAC and CAPN1 and CAPNS1 are ameliorated in JP2CRhearts (Fig. 5B-E). It was also examined whether cleavage of RyR2, SERCA2a and CaV1.2 is differentially sensitive to calpain-1 and calpain-2 that are activated by μM and mM [Ca2+]i, respectively. HEK293T cells were co-transfected with CAPN1 or CAPN2 and full-length, tagged RyR2, SERCA2a and CaV1.2 and in vitro cleavage assays were performed from cell lysates. Both calpain-1 and calpain-2 can similarly cleave RyR2 and SERCA2a when supplemented with 50 μM and 2 mM Ca2+, respectively (Fig. 5F, and G). CaV1.2, however, is more sensitive to calpain-1 than calpain-2 as the full length is completely degraded by calpain-1 but only partially by calpain 2 (Fig. 5H). However, CaV1.2 is more sensitive to calpain-1 than calpain-2; the full length is completely degraded by calpain-1 but only partially by calpain 2 (Figure 5I). Taken together, these data suggest that the preserved E-C coupling that was observed in JP2CRhearts is due to diminished TAC-induced Ca2+handling dysfunction that lessens calpain activation and the subsequent cleavage of RyR2, SERCA2a and CaV1.2. JP2CRprotects against TAC-induced transcriptional reprogramming. It was previously discovered that the generation of the nuclear translocating JP2NT fragment resulting from stress induced cleavage of JP2 provides the heart with a salutary excitation transcriptional mechanism for repressing maladaptive gene expression (36). The JP2CRmutation prevents this mechanism by preserving the integrity of JP2 and maintaining JP2 at E-C coupling sites (Fig. 1C-D). Since changes in gene expression accompany and facilitate cardiac 81 24028 / / SLW 875.245WO1 structural remodeling under chronic stress, it was asked how stress-dependent transcriptional changes might be affected in JP2CRmice. Applying significance and magnitude thresholds to RNA sequencing results of padj<0.05 and >1.5-fold change in expression (absolute log2 foldchange >0.58) indicate the JP2CRallele has minimal effect on basal transcription in sham operated mice (6 differentially expressed genes (DEGs)) (Fig. 6A-B). Pressure overload stress with TAC, however, induced a large transcriptional response in both genotypes relative to sham producing 1883 DEGs in WT (1025 up, 858 down) and 1502 DEGs in JPCR(947 up, 555 down) (Fig.6C). The response to TAC in JP2CRventricles is generally similar in scope to WT, but less in magnitude as observed in the volcano plot (Fig.6B) and by linear regression analysis (slope=0.66, r2=0.77). Ingenuity Pathway Analysis indicates there is a reduction in transcription of genes enriching in cardiovascular related disease signaling pathways including those involved in dilated cardiomyopathy, cardiac hypertrophy, calcium, beta-adrenergic, and calcineurin / NFAT (nuclear factor of activated T cells) signaling (Fig. 6D; FIG. S7). Although calcium signaling is differentially enriched, consistent with the Ca2+imaging studies, it was found that mRNA expression of major Ca2+handling genes in JP2CRhearts is similar to that in WT at baseline and in response to TAC (FIG. S8), providing evidence that differences in protein levels for these genes after TAC (Figure 4) occur by posttranscriptional or posttranslational mechanisms. To gain a broader perspective on other potential contributing processes attributable to transcriptional remodeling, upregulated versus downregulated DEGs were separately analyzed. In general, implicated enriched pathways in response to TAC were less significant for JP2CRthan for WT, particularly for downregulated DEGs (Figures 6E and 6F; FIG. S9). For upregulated DEGs, there is less significant enrichment in extracellular and adhesion pathways and cardiomyopathy signaling. With respect to downregulated DEGs, the TAC response in JP2CRhearts had less significant enrichment in calcium signaling, metabolic, adrenergic / cAMP, and contractile pathways. These results demonstrate that JP2CRindirectly reduces stress-dependent transcriptional remodeling by sustaining E-C coupling function despite not being able to produce the cardioprotective JP2NT transcriptional repressor fragment. JP2CRgene therapy attenuates heart failure progression in mice with pre-established cardiac dysfunction. JP2CRGene Therapy Attenuates HF Progression in Mice with Pre-Established Cardiac Dysfunction The above JP2CRknock-in approach demonstrated that JP2CRis a novel therapeutic for treating hypertrophy and HF. The Wehrens’ group demonstrated adeno-associated virus type 9 (AAV9) mediated overexpression of JP2 in mice with HF attenuates T-tubular, E-C coupling, and 82 24028 / / SLW 875.245WO1 cardiac dysfunction arising from TAC stress (40). To explore whether the AAV-JP2CRmay be better than wildtype AAV-JP2 at rescuing or reducing the HF progression, the effects of JP2CRgene delivery was tested in an intervention-based pre-clinical trial in mice after moderate cardiac hypertrophy and dysfunction was established (FIG. S10). Echocardiograms were performed 2 weeks post-TAC to identify mice with moderate cardiac dysfunction. Forty-one mice were identified by echocardiography to have a decrease in EF to between 40% and 60% with an average EF of 49.22% compared to baseline (80.14%, p<0.0001). These mice were then entered into the prospective, randomized trial to receive AAV-GFP (N=16), AAV-JP2 (N=14) or AAV-JP2CR(N=11) treatment. Immunofluorescence and immunoblot assays demonstrate gene delivery after TAC surgery in mice provides for long-lasting cardiac-specific JP2 and JP2CRexpression that continues throughout the experimental time course with modest or no expression in other tissues (Fig.7B; FIGS. S11 and S12). Immunoblot assays further demonstrate that virally expressed Flag-tagged JP2CRis resistant to TAC-induced cleavage relative to endogenous and Flat-tagged wildtype JP2 (Fig. 7B). Cardiac function was again evaluated 5 and 8 weeks after TAC by serial echocardiography (Tables S4 to S6). Following AAV delivery, the EF of AAV-GFP treated mice continued to decline (Fig. 7C). The decline in the EF over a six-week timeframe was modestly attenuated in AAV-JP2 treated mice (p=0.0310) but robustly slowed in AAV-JP2CRtreated mice (p<0.0001) that was also significantly different from AAV-JP2 (p=0.0282). The dramatic attenuation of cardiac dysfunction with AAV-JP2CRrelative to AAV-GFP administration was attributed to significant differences in both LVEDV and LVESV (Fig. 7D and E). AAV-JP2 and AAV-JP2CRdelivery also conferred resistance to hypertrophy and lung edema relative to AAV- GFP controls with AAV-JP2CRproviding superior protection (Fig. 7G, H). Through histological analysis of hearts with H&E and Masson’s trichrome staining, it was found that that AAVJP2 lead to an attenuated increase in cardiomyocyte size and LV fibrosis compared to GFP control hearts that was further blunted with AAV-JP2CR(Fig.7I and J). These results suggest that while JP2 gene therapy intervention after the onset of cardiac dysfunction slows the progression of heart failure, JP2CRgene therapy is a significantly better intervention approach. 83 24028 / / SLW 875.245WO1 84 24028 / / SLW 875.245WO1 Discussion 85 24028 / / SLW 875.245WO1 It is demonstrated herein that preventing a single proteolytic event in vivo is sufficient to significantly improve HF related outcomes. Based on previous evidence suggesting stress- dependent cleavage of JP2 may be an important precipitating event in E-C uncoupling and HF, CRISPRCas9 technology was used to generate calpain-resistant JP2 knock-in (JP2CR) mice by removing the primary calpain cleavage site from JP2. The importance of this site was confirmed by showing that cardiac JP2CRis insensitive to purified calpain and to pathological conditions known to result in JP2 proteolysis. Pathologically, JP2CRhearts and cardiomyocytes exhibit a significant amelioration in T-tubule degeneration, abnormal Ca2+homeostasis, cardiac dysfunction, hypertrophy, lung edema and fibrosis in response to pressure overload, relative to WT mice. Molecularly, JP2CRhearts have reduced calpain activity and preserved RyR2, LTCC, and SERCA2a levels that likely result from improved Ca2+homeostasis. JP2CRfurther protects the heart by modestly attenuating hypertrophic and HF-related gene transcription. Finally, JP2CRgene therapy is a treatment for HF as it dramatically slows cardiac remodeling and dysfunction in response to pressure overload. Taken together, the data presented here demonstrate that protection against stress-induced HF can be achieved by preventing JP2 site-specific cleavage. JP2 plays a role in efficient E-C coupling and cardiac function as has been demonstrated through knockout (23) and knockdown (24-26) studies. Reciprocally, JP2 protein expression is lower in failing heart samples from humans and in animal models of HF (12,16). Decreased JP2 expression correlates with the disruption of the T-tubule system, dysfunctional Ca2+handling, and remodeling of the myocardium (12,16) while JP2 overexpression inhibits these changes and protects against the development of HF (39) The primary determinant of JP2 downregulation in HF is now believed to be due to Ca2+-dependent and site-specific proteolysis of JP2 that coincides with calpain activation and results in the generation of a 75 kDa N-terminal fragment (27,35). Although the exact identity of the cardiac protease responsible for cleaving JP2 in vivo has yet to be established, it is likely one or more calpain isoforms are responsible. Using in vitro assays, the primary calpain-1 and calpain-2 recognition site in mouse JP2 was mapped and verified as R565 / T566 and R572 / T573 in human JP2 (22,28). Provided herein it was established that the R565 / T566 site of mouse JP2 is responsible for pathological JP2 cleavage in vivo. Evidence in support of calpain-dependent JP2 cleavage in the heart comes from studies showing that administration of calpain inhibitors preserve JP2 integrity and provides cardioprotection from TAC, myocardial infarction, ISO infusion, and ischemia / reperfusion injury (21,41). Further, cardiac overexpression of calpain-1 promotes the downregulation of JP2 and causes a lethal cardiomyopathy that can be partially rescued through JP2 overexpression (21). RNA-seq results indicate the heart expresses at least 11 different calpain catalytic genes including 86 24028 / / SLW 875.245WO1 ubiquitously expressed Capn1 and Capn2. As calpain inhibitors cannot distinguish between different calpain enzymes, the contribution of one or more these isoforms in cleaving JP2 cannot be ruled out. Furthermore, MDL-28170 and other so-called calpain inhibitors, however, are not entirely specific to the calpain family as several have been shown to inhibit metalloproteinase-2 protein (MMP2) (42). MMP2 also has activity for JP2 but appears to cleave JP2 at one or more sites distinct from those that produce the 75 kDa JP2NT fragment (43). The approach provided herein using knockin mice devoid of the R565 / T566 cleavage site shows the JP2CRprotein is insensitive to calpain and other potential proteases that are responsible for cleaving JP2 in response to HF stress. The data also show specific cleavage of JP2 is a major initiator of pathology. Given the improved HF outcomes that were observed in JP2CRmice, it was hypothesized that improving E-C coupling in failing hearts using therapies specifically designed to maintain JP2 function will be more effective and elicit fewer side effects than protease inhibitors. As discussed above, current inhibitors lack specificity and have the potential to produce potential harmful side effects (33) by affecting multiple substrates and processes. JP2 has already been demonstrated as a potential gene therapy agent. Cardiotropic adeno-associated virus-9 (AAV9)- mediated JP2 gene delivery into mice with early-stage HF from TAC decreases T-tubule degeneration, abnormal SR Ca2+leak, and cardiac dysfunction compared to control virus (40). Provided herein it is shown that a similar approach using AAV-JP2CRproduces better outcomes by preventing the degradation of exogenously expressed JP2. The results add an additional layer of complexity to the stress-dependent cleavage of JP2 as JP2 cleavage is not entirely detrimental to the heart. Although it is shown herein that intact JP2 maintains CICR and E-C coupling at the myocyte periphery, it was previously demonstrated that the cleaved JP2NT fragment acts as a salutary transcription factor that enters the nucleus to repress maladaptive gene expression (36). Transgenic JP2NT overexpression or injection of cardiotropic AAV-JP2NT is effective at blunting HF-related gene expression and cardiac remodeling processes (36,37). It is interesting, then, that the protective proteolytic JP2NT fragment and the proteolytic resistant allele of JP2 are both serve as cardioprotective gene therapy agents in the context of pressure overload. While the former is a direct repressor of transcriptional reprogramming in the E-C uncoupled heart, the latter sustains E-C coupling and appears to prevent a full transcriptional response from being reached. This difference in transcriptional responses to TAC is exemplified in a meta-analysis of the data from the two genetic mouse models. After applying the same RNA-seq thresholds used here, JP2NT overexpressing mice had a 53.5% reduction in the number of significant DEGs in response to TAC (935) relative to littermate controls (2012) while JP2CRmice had a 20.2% reduction (1503 versus 1883). 87 24028 / / SLW 875.245WO1 The cardioprotective effects of JP2CRextend beyond a straightforward interpretation that E-C coupling function is improved in stressed hearts solely by stabilizing the cardiac dyad and CICR. It is surprising that it was found that preventing calpain from cleaving JP2 led to a reduction in total calpain activity in ventricular homogenates even though the cardiac stress was the same between WT and JP2CRanimals. Similar findings are observed by Peng and colleagues in work yet to be peer reviewed (44). They find that cardiomyocytes undergoing apoptosis in response to palmitate stress coincides with calpain activation and JP2 downregulation and that adenoviral expression of JP2 protects against apoptosis while also limiting calpain activation. It was proposed that the reason for reduced calpain activity seen in JP2CRhearts is likely due to less available Ca2+levels that are needed for calpain activation. The T-Tubule and Ca2+imaging observations suggest JP2CRcardiomyocytes may have more efficient CICR and / or cytosolic Ca2+clearance mechanisms that could result from diastolic Ca2+normalization during TAC. Diastolic Ca2+levels that are closer to unstressed conditions would be expected to limit CaMKII activation and CaMKII- dependent PLN Thr-17 phosphorylation, which was also observed. Changes in PLN-Ser16 phosphorylation levels in JP2CRTAC homogenates was also more normalized compared to WT TAC samples. It is unexpected, however, that while TAC promoted increased PLN Thr-17 phosphorylation, PLN-Ser16 levels decreased. Phospho-Ser16 and -Thr17 levels typically change in the same direction. These results were interpreted to mean that PLN-Ser16 is a beneficial post- translational modification, while PLN-Thr17 is detrimental during cardiac stress. Therapies that specifically prevent the cleavage of JP2 can be superior to that of other EC coupling protein cleavage events. JP2 is the only known protein that physically stabilizes the cardiac dyad while also being of a size amenable for AAV approaches. Cleavage of other E-C coupling candidates have yet to be shown to promote T-tubule degeneration and supported by the finding that LTCCs become dissociated from RyR2 receptors in the absence of JP2 (23,45). In addition, the length of the coding sequences of LTCCs and RyR2 channels are too large to be packaged into a single AAV vector. However, new strategies have recently been developed that allow for reconstitution of large proteins by the trans-splicing of gene fragments expressed from separate AAV vectors (e.g., PMID: 30509897, 36383253). The small size of SERCA2a is amenable for single AAV incorporation, but clinical gene therapy trials using SERCA2a have been unsuccessful in producing a measurable benefit in patients (46). The fact that JP2CRexpression blunts stress-induced calpain activation and the degradation of other Ca2+handling proteins suggests JP2CRcan effectively mimic cleavage resistance in other E-C coupling proteins. In summary, the state of current gene therapy technologies combined with the data presented herein demonstrate that JP2CRis a novel therapeutic for treating HF. 88 24028 / / SLW 875.245WO1 Conclusion Demonstrated herein is that preserving JP2-dependent E-C coupling by prohibiting the site-specific calpain cleavage of JP2 offers multi-faceted beneficial effects, conferring cardiac protection against stress-induced proteolysis, hypertrophy and HF. The data also indicate that specifically targeting the primary calpain cleavage site of JP2 by gene therapy approaches provides a novel therapeutic for precision medicine for treating HF. Example 2 Combination Therapy Provided herein is the expression of JP2CR, optionally combined with JP2NT and other therapeutic proteins in the heart, which improves HF outcomes beyond the expression of either alone. Discussed herein is the production and use of clinically relevant gene therapy agents, such as JP2CRand JP2NT, and others. Currently, state-of-the-art gene therapy technology involves: 1) the incorporation of therapeutic genetic material of interest into a tissue-selective adeno- associated virus (AAV), 2) in vivo administration of the AAV agent(s) and 3) tissue-selective take- up and expression of the AAV cargo. To selectively express JP2CRand JP2NT in cardiomyocytes of living organisms, existing technology based on AAV serotype 9 was applied. AAV9 (also AAV2 / 9) is widely used for selectively and efficiently delivering genes of interest in the hearts of experimental animals resulting in stable expression that lasts at least several months (e.g., PMID: 18548221, 19715530, 28356340, 26358504, 31981493, 36695318). As discussed above, JP2CRgene therapy after the onset of cardiac dysfunction was found to be effective at slowing the progression of HF and superior to wildtype JP2. Generation of AAV vectors and viruses The generation of AAV-JP2CRand AAV-JP2NT viruses was enabled in part by services provided by the University of Iowa Viral Vector Core (https: / / medicine.uiowa.edu / vectorcore / ). A parental replication deficient cis-acting AAV shuttle plasmid that co-expresses a fluorescent eGFP protein via an internal ribosome entry site (IRESeGFP) was acquired from the Viral Vector Core (#G0692, pFBAAVCMVmcswtIRESeGFPBgHpA). JP2 gene fragments generated by PCR amplification and were cloned into the AAV shuttle vector using SacI + BamHI restriction sites (Fig.9). JP2 PCR products contained a Kozak sequence to facilitate transcription and N-terminal FLAG and C-terminal HA tags to validate in vivo expression. Subsequent steps in virus production were performed by the University of Iowa Viral Vector Core and included: Triple transfection of HEK-293 cells with the cloned cis-acting AAV plasmid containing JP2, JP2CR, JP2NT, or shorter variants of each, a second plasmid providing the genes for the AAV structural proteins, rep and cap, and a third pHelper plasmid providing the 89 24028 / / SLW 875.245WO1 adenovirus helper genes, and transduced titer by FACS when expressing fluorescent reporters and of the appropriate serotype for the cell line; Amplification and purification of the AAV vectors; Quality control assays, e.g., determination of physical titer (viral genomes / ml) by digital droplet PCR, silver stain to assess viral titer and purity, and Reconstitution of virus in a physiological compatible buffer (F68 / PBS: 1XPBS adjusted to 180mM NaCl, pH 7.4, 0.001% Poloxamer 188). Adeno-associated viruses (AAVs) were developed that selectively target cardiomyocytes for expressing an N-terminal fragment of the Junctophilin-2 protein (JP2NT) that therapeutically represses maladaptive transcription in the hearts of mice subjected to cardiac pressure overload stress (Wang et al, Circ Res, 2022). The specific application of JP2NT as a therapeutic is provided in US Pat No.11,351,270 but is shown here to demonstrate that is has been effectively developed to target an HF mechanism and can now be combined with therapeutic constructs targeting other HF mechanisms (i.e., JP2CR). AAV-JP2 viruses were first injected into the hearts of 3-day-old postnatal mice with tissue expression analyzed 8 weeks later (Fig. 10). AAV2 / 9 particles were intraventricularly injected with using a 30-gauge insulin syringe (BD, Ultra fine needle) with a total volume of 30 μl saline containing 5 × 1011viral genomes. Mice administered AAV-JP2NT and DNA-binding deficient JP2NTΔbNLS / ΔARRdemonstrated expression in heart and skeletal muscle, but not other tissues. Immunofluorescence of heart tissue for the C-terminal HA-tag revealed expected nuclear- localized expression of hemagglutinin (HA)-tagged JP2NT and JP2NTΔbNLS / ARRwhile JP2 remained cytosolic. This proof-of-principle experiment demonstrates AAV-dependent expression in the myocardium is sustained over months allowing for preventative gene therapy studies in animal models. Preventative and therapeutic effectiveness of AAV-JP2NT in treating HF. A transaortic constriction (TAC) model of cardiac pressure overload stress was evaluated to investigate the therapeutic effectiveness of AAV-JP2NT injected at 3 days of age followed by Sham or TAC surgeries at 8 weeks of age. Transthoracic echocardiography and tissue analyses were performed 5 weeks after surgery (Fig.11). Gene delivery provided long-lasting JP2NT and JP2NTΔbNLS / ARRexpression throughout the experimental TAC time course. In sham groups, AAV- JP2NT and AAV-JP2NTΔbNLS / ARRhad no effect on cardiac function or morphology relative to AAV-eGFP. Under pressure overload conditions that promote cardiac hypertrophy and HF, AAV- eGFP–infected mice displayed typical TAC-induced responses including contractile dysfunction (left ventricular [LV] ejection fraction [EF]) and hypertrophy (increased heart weight / body weight ratio). AAV-JP2NT transduced mice were more resistant to TAC-induced pressure overload, having significantly less cardiac dysfunction and hypertrophy relative to AAV-eGFP controls. 90 24028 / / SLW 875.245WO1 Deletion of the DNA-binding domain significantly worsened cardiac dysfunction compared to AAV-JP2NT supporting the idea that AAV-JP2NT mediates cardioprotection via a transcriptional mechanism. To be clinically relevant, one should know whether the application of AAV-JP2NT rescues or reduces the detrimental effects of TAC after the onset of cardiac dysfunction. Therefore, the effects of JP2NT gene delivery was tested in an intervention-based preclinical trial after moderate cardiac hypertrophy and dysfunction (40<EF%<60) was established by 2-week pressure overload. TAC (n=64) or sham (n=10) surgery was performed on 9- to 10-week-old C57BL / 6N male mice (Fig. 12). Six TAC mice died during or after surgery, leaving 58 surviving TAC mice. Subsequently, echocardiograms at 2 weeks post-TAC were used to assess cardiac dysfunction of 53 surviving mice. Twenty-three mice were excluded from the study as EFs were outside of the 40% to 60% range. Thirty mice with EFs between 40% and 60% entered the prospective, randomized trial in which mice were assigned either AAV-JP2NT (n=15) or AAV-eGFP (n=15) treatment. AAV viruses (1x1012viral genomes in 100 µl saline) were delivered by tail-vein injection at 2 weeks post-TAC just after echocardiographic analysis. Following AAV treatment, mice underwent serial echocardiography at 5- and 8-weeks post-surgery. It was confirmed that the AAV-JP2NT vector provides cardiac selective expression of HA-tagged JP2NT 8 weeks after tail- vein injection. As evidenced by the selection criteria, TAC caused a significant decline in cardiac function by 2 weeks post-TAC with an average EF of 50.9% compared with baseline (84.9%; P<0.0001). Following AAV delivery at this 2-week time point, the EF of AAV-eGFP treated mice continued to decline. Although the average EF of AAV-JP2NT treated mice also declined, it did so at a significantly slower rate at 5 and 8 weeks after TAC relative to AAV-eGFP mice. AAV- JP2NT delivery also conferred resistance to hypertrophy relative to AAV-eGFP controls. Through histological analysis of hearts with Masson trichrome staining, it was found that JP2NT decreased LV fibrosis compared to eGFP control hearts. These results suggest that JP2NT gene therapy intervention after the onset of cardiac dysfunction remarkably slowed the progression of HF in the mouse model. Therapeutic effectiveness of AAV-JP2CRin treating established HF. To investigate whether therapeutically targeting JP2-dependent E-C coupling mechanisms is amenable to JP2CRexpression, a similar experiment as for AAV-JP2NT described above was performed. A model of established HF was performed via Sham or TAC surgery in 9- to 10-week- old mice followed by echocardiographic evaluation two weeks later (Fig.13A-C). TAC operated mice with an ejection fraction between 40% and 60% were randomly assigned to received AAV- GFP, AAV-JP2, or cleavage resistant AAV-JP2CR. Sham operated mice were used as a reference 91 24028 / / SLW 875.245WO1 control. Additional echocardiography was performed 5 and 8 weeks after surgery. In AAV-GFP administered mice, TAC induced considerable HF as indicated by a dramatic decrease in ejection fraction that paralleled increases in left ventricular end systolic volume (LVESV), end diastolic volume (LVEDV), and mass (LV mass) (Fig.13C-F). AAV-JP2CRblunted each of these changes in response to TAC while AAV-JP2 had intermediate effects. Data indicate that constitutive expression of JP2CRtherapeutically treats HF in a pressure overload model in mice more so than stress cleavable wildtype JP2. Genetic co-expression of JP2CRand JP2NT Genetic co-expression of JP2CRand JP2NT synergistically improves HF-related transcriptional changes. Supporting evidence shows that HF outcomes can be improved either by transgenic overexpression of the JP2NT transcriptional repressor, or in JP2CRknock-in animals after deleting the calpain cleavage site in the endogenous Jph2 gene. To determine whether HF responses can be further reduced, changes in Sham vs. TAC transcription in ventricular tissues from WT, JP2CR, and double JP2CR + JP2NT-OE mice were investigated. RNA-sequencing results show that while WT mice had 1902 significant differentially regulated genes (DEGs, pAdj<0.05 and >1.5-fold change (Log2>0.585)) from TAC, JP2CRmice had 1526 DEGs, a 20% reduction (FIG.14). Since JP2CRcannot be cleaved or enter the nucleus, transcriptional changes are indirectly related to improvements in Ca2+homeostasis and cardiac contractility. In hearts that express JP2CRand overexpress JP2NT (JP2CR+ JP2NT-OE), the number of DEGs fell to 294, an 85% reduction compared to WT and an 80% reduction relative to JP2CRalone. It was observed that the combination of JP2CR+ JP2NT-OE reduces the number of TAC sensitive DEGs by an additional 35% over JP2NT-OE alone. Taken together, these results indicate that combining JP2CRwith JP2NT provides is a synergistic benefit in diminishing HF over either alone. BIBLIOGRAPHY 1. Kaprielian RR, et al. Distinct patterns ofdystrophin organization in myocyte sarcolemma and transverse tubules of normal and diseased human myocardium. Circulation.2000;101:2586- 2594. 2. Cannell MB, Crossman DJ, Soeller C. Effect of changes in action potential spike configuration, junctional sarcoplasmic reticulum micro-architecture and altered t-tubule structure in human heart failure. J Muscle Res Cell Motil.2006;27:297-306. doi:10.1007 / s10974-006-9089-y. 3. Lyon AR, et al. Loss of T-tubules and other changes to surface topography in ventricular myocytes from failing human and rat heart. Proc Natl Acad Sci U S A.2009;106:6854-6859. doi: 0809777106 [pii] 10.1073 / pnas.0809777106. 92 24028 / / SLW 875.245WO1 4. Zhang HB, et al. Ultrastructural uncoupling between T-tubules and sarcoplasmic reticulum in human heart failure. Cardiovasc Res.2013;98:269-276. doi: 10.1093 / cvr / cvt030. 5. Gomez AM, et al. Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science.1997;276:800-806. doi:10.1126 / science.276.5313.800. 6. Gomez AM, et al. Heart failure after myocardial infarction: altered excitation-contraction coupling. Circulation.2001;104:688-693. 7. Balijepalli RC, et al. Depletion of T-tubules and specific subcellular changes in sarcolemmal proteins in tachycardia-induced heart failure. Cardiovasc Res.2003;59:67-77. 8. Song LS, et al. Orphaned ryanodinereceptors in the failing heart. Proc Natl Acad Sci U S A. 2006;103:4305-4310. doi:10.1073 / pnas.0509324103. 9. Louch WE, et al. T-tubule disorganization and reduced synchrony of Ca2+ release in murine cardiomyocytes following myocardial infarction. J Physiol.2006;574:519-533. doi: jphysiol.2006.107227 [pii] 10.1113 / jphysiol.2006.107227. 10. Bito V, et al. Crosstalk between L-type Ca2+ channels and the sarcoplasmic reticulum: alterations during cardiac remodelling. Cardiovasc Res.2008;77:315-324. doi: cvm063 [pii] 10.1093 / cvr / cvm063. 11. Heinzel FR, et al. Remodeling of T-tubules and reduced synchrony of Ca2+ release in myocytes from chronically ischemic myocardium. Circ Res.2008;102:338-346. doi: CIRCRESAHA.107.160085 [pii] 10.1161 / CIRCRESAHA.107.160085. 12. Wei S, et al. T-tubule remodeling during transition from hypertrophy to heart failure. Circ Res.2010;107:520-531. doi: CIRCRESAHA.109.212324 [pii] 10.1161 / CIRCRESAHA.109.212324. 13. Song LS, et al. beta-Adrenergic stimulation synchronizes intracellular Ca(2+) release during excitation-contraction coupling in cardiac myocytes. Circ Res.2001;88:794-801. doi: 10.1161 / hh0801.090461. 14. Wang SQ, et al. Ca2+ signalling between single L-type Ca2+ channels and ryanodine receptors in heart cells. Nature.2001;410:592-596. doi: 10.1038 / 35069083 15. Hall DD, et al. Structure, Function, and Regulation of the Junctophilin Family. Annu Rev Physiol.2024;86:123-147. doi: 10.1146 / annurev-physiol-042022-014926. 16. Chen B, et al. beta-Adrenergic receptor antagonists ameliorate myocyte T-tubule remodeling following myocardial infarction. FASEB J.2012;26:2531-2537. doi: fj.11-199505 [pii] 10.1096 / fj.11-199505. 17. Xu M, et al. Mir-24 regulates junctophilin-2 expression in cardiomyocytes. Circ Res. 2012;111:837-841. doi: CIRCRESAHA.112.277418 [pii] 10.1161 / CIRCRESAHA.112.277418. 93 24028 / / SLW 875.245WO1 18. Lyon AR, et al. Plasticity of surface structures and beta(2)-adr...

Claims

24028 / / SLW 875.245WO1 WHAT IS CLAIMED IS:

1. A mutant JP2 protein comprising a deletion of a calpain cleavage site at amino acids R572 / T573 of SEQ ID NO: 1, wherein the mutant protein has at least 80%, 85%, 87%, 90%, 92%, 93%, 94%, 95%, 98%, 99% or more amino acid identity to SEQ ID NO:

4.

2. The mutant JP protein of claim 1, wherein at least some or all of amino acids 570 to 575 are deleted or mutated so as prevent calpain cleavage.

3. An expression vector comprising a polynucleotide sequence which codes for the mutant JP2 protein of claim 1 or 2 (e.g., an adeno-associated virus (AAV).

4. The expression vector of claim 3, wherein the polynucleotide sequence comprises SEQ ID NO:

3.

5. The expression vector of claim 3 or 4, wherein the expression vector is a viral vector.

6. The expression vector of claim 5, wherein the viral vector is a recombinant adeno- associated virus (rAAV) vector.

7. The expression vector of claim 6, wherein the rAAV vector is an AAV9 or a functional variant thereof.

8. The expression vector of any one of claims 3 to 7, wherein the polynucleotide sequence is operatively linked to a promoter.

9. The expression vector of claim 8, wherein the promotor is a cardiac-specific promoter (e.g., TNNT2, MLC-2v, MYH6), a muscle specific promoter (e.g., MCK, DES, SPc5-12), or a ubiquitously recognized promoter (e.g., CMV, CAG, PGK, EF1α, UbC, MP-84, MP-135).

10. The expression vector of claim 8 or 9, wherein the promoter is a cardiomyocyte- specific promoter.

11. The expression vector of claim 10, wherein the cardiomyocyte specific promoter comprises TnnT2, Tpm1 or Myl2. 9824028 / / SLW 875.245WO1 12. A pharmaceutical composition comprising the expression vector of any one of claims 3 to 11 and a carrier.

13. A method to prevent, inhibit or treat a cardiac disease or condition comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 11.

14. A method for treating or preventing stress-induced cardiac dysfunction in a subject comprising administering to subject in need thereof a gene therapy vector comprising a nucleic acid encoding a calpain-resistant embodiment of junctophilin-2 (JP2), the nucleic acid lacking codons encoding amino acids 572 and 573 so as to render the JP2 embodiment resistant to calpain- mediated proteolytic cleavage; expressing the calpain-resistant JP2 embodiment in the subject’s cardiomyocytes, wherein expression of the calpain-resistant JP2 embodiment sustains T-tubule structural integrity and excitation–contraction coupling under conditions of cardiac stress.

15. The method of claim 13 or 14, wherein the vector is an adeno-associated virus (AAV) vector.

16. The method of claim 15, wherein the AAV vector is serotype 9.

17. The method of any one of claims 13 to 16, wherein the calpain-resistant JP2 is operably linked to a cardiomyocyte-specific promoter.

18. The method of any one of claims 13 to 17, wherein the gene therapy vector is administered via intravenous injection.

19. The method of any one of claims 13 to 18, wherein the cardiac disease, dysfunction or condition is cardiac hypertrophy, cardiac fibrosis, cardiac inflammation, heart failure, or myocardial infarction.

20. The method of any one of claims 13 to 19, wherein the administration inhibits the progression of heart failure. 9924028 / / SLW 875.245WO1 21. The method of any one of claims 13 to 20, wherein a second therapeutic polynucleotide sequence is administered.

22. The method of claim 21, wherein the second therapeutic polynucleotide sequence comprises one or more of JP2NT, CaV1.2, SERC2a, RyR2, DMD, DES, UTRN, SPTBN2, ITBG3, ANK2, ACTN2, PPP3CA, CAMK2D, PRKCA, PTK2, TNNI3, TNNT2, MYBPC3, LAMP2, or AIFM1.

23. The method of claim 21, wherein the second active therapeutic polynucleotide sequence comprises JP2NT (SEQ ID NO: 5).

24. The method of any one of claims 21 to 23, wherein the second active therapeutic polynucleotide sequence encodes a polypeptide sequence variant that is resistant to calpain cleavage.

25. The method of any one of claims 13 to 24, wherein the subject is a mammal.

26. The method of any one of claims 13 to 25, wherein the subject is a human.

27. A composition comprising the expression vector of any one of claims 3 to 11 and an expression vector comprising a polynucleotide sequence which codes for JP2NT.

28. Use of the composition of claim 27 to treat prevent, inhibit or treat a cardiac disease, dysfunction or condition in a subject in need thereof. 100

Images