Protein Therapeutics for Muscular Dystrophy

Award Information
Agency: Department of Health and Human Services
Branch: N/A
Contract: 1R43AR060019-01
Agency Tracking Number: AR060019
Amount: $300,000.00
Phase: Phase I
Program: SBIR
Awards Year: 2010
Solicitation Year: 2010
Solicitation Topic Code: NIAMS
Solicitation Number: PHS2010-2
Small Business Information
DUNS: 803046676
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 () -
Business Contact
Phone: (732) 729-6255
Research Institution
DESCRIPTION (provided by applicant): Defective membrane repair is associated with the progression of muscular dystrophy that is linked to mutations in caveolin-3 (Cav3) and dysferlin in human patients. Several other forms of muscular dystrophy, including Duchenne muscular dystrophy and dystrophy arising from mutations in the dystroglycan complex have been linked to membrane fragility. Compromised membrane repair and increased membrane fragility are distinct mechanisms leading to increased muscle fiber death, as evidenced by the additive nature of these two pathways. A therapeutic approach to increase the capacity of muscle cells to reseal their membranes following physiological levels of mechanical stress could address both of these mechanisms leading to improvement of the regenerative capacity in muscular dystrophy. Attempts to produce therapeutics targeting membrane resealing have been complicated by the lack of knowledge of the molecular components involved. Recent studies show that Mitsuguimin 53 (MG53), a muscle-specific TRIM-family protein (TRIM72), is an essential component of the acute membrane repair machinery. MG53 acts as a sensor of oxidation to nucleate recruitment of intracellular vesicles to the injury site for membrane patch formation. MG53 can interact with dysferlin to facilitate its membrane repair function, and the membrane trafficking function of MG53 can be modulated through a functional interaction with Cav3. Our data indicate that a molecular complex formed by MG53, dysferlin and Cav3 is essential for repair of muscle membrane damage, thus providing a therapeutic target for treatment of muscular and cardiovascular diseases. In an effort to translate these basic science findings into therapeutic interventions for human diseases, we have formed a biotechnology company named TRIM-edicine, Inc, based on intellectual properties discovered in at UMDNJ-Robert Wood Johnson Medical School. Our research and development effort at TRIM-edicine has provided extensive studies to show that recombinant MG53 purified from E. coli retains efficient membrane repair function, supporting the therapeutic value of targeting MG53 in muscular dystrophy and other human diseases. We have preliminary in vivo animal model data to show that intra-muscular delivery of recombinant MG53 can ameliorate cardiotoxin-induced damage to the muscle fibers. This project will comprise an effort by TRIM-edicine that will leverage our expertise to pursue the proof-of-principle studies for the therapeutic application of MG53 in treatment and/or prevention of various types of muscular dystrophy. PUBLIC HEALTH RELEVANCE: Muscular dystrophies are a family of genetic disorders that all generally include progressive muscle weakness due to degeneration of the muscle fibers, which includes the most common inherited disease, Duchene Muscular dystrophy. Many of these diseases involve either fragility of the membranes that surround muscle cells or a compromised ability to reseal those membranes. Both of these cases lead to compromised integrity of the cell membrane that result in death of muscle fibers, eventual depletion of the muscle regenerative capacity, muscle fibrosis, decreased force production and in many cases death of the patient. If a therapeutic approach could address membrane fragility and reduced resealing capacity it would have efficacy across a large number of different muscular dystrophies. Current efforts within the regenerative medicine field involve examining ways to increase muscle repair in syndromes where there is a reduced regenerative capacity for the skeletal muscle. In this project, TRIM-edicine will leverage our expertise to pursue proof-of- principle studies for the therapeutic application of a novel protein, mitsugumin 53 (MG53) in treatment and/or prevention of various types of muscular dystrophy.

* information listed above is at the time of submission.

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