Compositions for reducing sarcolipin expression and preventing and treating muscular dystrophy and cardiomyopathy and methods of use

A composition, recombinant virus technology, applied in the fields of molecular biology, virology, and medicine, can solve problems such as incurable DMD

Pending Publication Date: 2019-11-19
RUTGERS UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is currently no cure for DMD

Method used

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  • Compositions for reducing sarcolipin expression and preventing and treating muscular dystrophy and cardiomyopathy and methods of use
  • Compositions for reducing sarcolipin expression and preventing and treating muscular dystrophy and cardiomyopathy and methods of use
  • Compositions for reducing sarcolipin expression and preventing and treating muscular dystrophy and cardiomyopathy and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0087] The compositions, vectors, viruses and methods described herein can be used to reduce SLN expression in any tissue in which SLN is elevated. For example, because SLN is also elevated in the ventricles of patients with mitral regurgitation and in the muscles of patients with Tako-Tsubo cardiomyopathy and in patients with Emery-Dreifuss muscular dystrophy, the SLN could serve as a target for these diseases, and SLN expression can be reduced by administering the compositions, viruses and vectors described herein.

[0088] effective dose

[0089] The compositions, viruses, and vectors described herein are preferably present in effective amounts (i.e., capable of producing desired results (e.g., reducing SLN expression, restoring SERCA function, improving LV systolic function and cardiac remodeling, improving forelimb muscle) in the treated mammal. Strength, life-prolonging amount)) administered to mammals (eg, humans). Such a therapeutically effective amount can be determ...

Embodiment 1

[0097] Example 1 - Reduction of Sarcolipin Expression Alleviates DMD and Associated Cardiomyopathy in Mice

[0098] Here it is shown that reduction of SLN levels ameliorates dystrophic pathology in a severe dystrophin / utrophin double mutant (mdx:utr- / -) mouse model of DMD. Germline inactivation of one-allele of the SLN gene normalized SLN expression, restored SERCA function, attenuated skeletal muscle and cardiac pathology, improved muscle regeneration, and extended lifespan. To translate these findings into therapeutic strategies, SLN expression was knocked down by AAV9-mediated RNA interference in one-month-old mdx:utr- / - mice. AAV treatment significantly reduced SLN expression, attenuated muscle pathology and improved diaphragmatic, skeletal muscle and cardiac function. Taken together, these findings suggest SLN reduction as a therapeutic approach for DMD.

[0099] To determine whether SLN upregulation is a common molecular change in skeletal muscle and heart in DMD, SLN ...

Embodiment 2

[0134] Example 2 - Increased SLN protein levels in canine dystrophic myoblasts

[0135] SLN was upregulated in dystrophic canine myoblasts ( Figure 16 ). Canine-specific shSLN expressed using AAV9 (5'-ctgtttctcaacttcactattgtttcaagagaacaatagtgaagttgagaaacag-3') (SEQ ID NO:5) reduced SLN expression in dystrophic canine myoblasts ( Figure 17 ).

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Abstract

Compositions, recombinant viruses, and recombinant viral vectors for inhibiting sarcolipin (SLN) expression or activity in a cell and for preventing or treating Duchenne Muscular Dystrophy (DMD) in asubject (e.g., a human patient having or predisposed to having DMD) and in some embodiments additionally cardiomyopathy, include a therapeutically effective amount of an inhibitor of SLN. Methods of using these compositions, recombinant viruses, and recombinant viral vectors are also described herein. These compositions, recombinant viruses, and recombinant viral vectors and methods of use providenovel therapies for DMD and associated cardiomyopathy based on the reduction of SLN expression and / or activity.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 62 / 449,371 filed January 23, 2017, U.S. Provisional Application No. 62 / 575,089 filed October 20, 2017, and U.S. Provisional Application No. 62 / 589,273, the disclosures of these provisional applications are hereby incorporated by reference in their entirety. [0003] sequence listing [0004] This application contains a Sequence Listing, which has been submitted in ASCII format via EFS-Web, and is hereby incorporated by reference in its entirety. The ASCII copy, created on January 22, 2018, is named 096738-00567_ST25.txt and has a size of 3.7 kilobytes. [0005] Federally Funded Research [0006] This invention was made with Government support. 1R01AR069107-01A1 was awarded by the National Institutes of Health. The government has certain rights in this invention. [0007] field of invention [0008] The present invention relates generally to the fields of medi...

Claims

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Application Information

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IPC IPC(8): A61K48/00C12N15/11C12N15/00C07H21/04
CPCC12N15/1138C12N2310/14C12N2310/531C12N2320/32C12N2330/51A01K2217/075A01K2227/105A01K2267/0306A61P21/04A61P43/00A61P9/00C12N15/113C12N15/86C12N2750/14141
Inventor G·J·巴布
Owner RUTGERS UNIVERSITY
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