DESCRIPTION (provided by applicant): Our objective is to develop an intravenously delivered protein therapy for treatment of Duchenne muscular dystrophy (DMD), a disease that occurs in 1 of every 3500 male births. DMD is caused by a deficiency of dystrophin, a cytoskeletal protein which tethers the contractile apparatus to the membrane and basal lamina of skeletal and cardiac muscles and protects myofibers from the shear forces of muscle contraction. There are no approved therapies for DMD and the only available treatments are the steroids prednisone or deflazacort. Approaches for treatment of DMD include dystrophin mRNA rescue technologies such PTC124 and exon skipping, and dystrophin replacement through gene and stem cell therapy. Other approaches under consideration employ intravenous proteins or small molecule therapies that upregulate the expression of non- dystrophin surrogates such utrophin or the alpha7 integrin. The laboratory of our academic partner Dr. Dean J. Burkin has generated preliminary data demonstrating that a single intramuscular and systemic dose of a laminin isoform to mdx mice, the mouse model of DMD, distributed to all skeletal and cardiac muscles, remained localized around myofibers for at least 4 weeks, substantially reduced myofiber degeneration, reduced serum creatine kinase and was associated with increased expression of the alpha7 integrin and utrophin. This data supports our main hypothesis that the therapeutic effect of the injected laminin isoform is derived through recruitment of non-dystrophin surrogates which can functionally substitute for dystrophin. This data also demonstrates that the intravenous protein therapy paradigm can restore the structural linkage between the contractile apparatus, the muscle membrane and basal lamina. Alpha7 integrin and utrophin are ubiquitously expressed in mdx and DMD muscles. Their up- regulation and/or functional stabilization in response to the injected laminin isoform, as well as that of other components of the dystrophin/utrophin and integrin complexes, might thus provide a universal mechanism through which the laminin isoform could treat most DMD patients, treat patients with other forms of muscular dystrophy such as MCD1A and LGMD2C-F, and provide an added therapeutic benefit to those DMD patients that respond to the dystrophin mRNA rescue technologies. Phase 1 will employ a series of disease endpoints in exercised mdx, aged (12+ month old) mdx and mdx/utro -/- dKO mice to 1] replicate the preliminary data generated by our academic partner and further test the hypothesis that the therapeutic effect of the laminin isoform is derived through recruitment of non- dystrophin surrogates, 2] determine the minimally effective dose of the laminin isoform that protects mdx skeletal myofibers from degeneration, and 3] determine if the therapeutic benefit of the minimally effective dose of the laminin isoform is sustained following long-term dosing in mdx/utro -/- dKO and aged (12+ month old) mdx mice. Phase 2 will fund the construction of cell lines and production of recombinant human versions of the laminin isoform for completion of IND-enabling pharmacology and toxicology studies. If we successfully complete SBIR phase 1 and 2, we will secure investment to fund canine DMD treatment studies, followed by phase I and II clinical trials. The end result of our efforts will be an intravenously delivered protein therapy for patients with DMD, MCD1A, and LGMD2C-F. PUBLIC HEALTH RELEVANCE: Duchenne muscular dystrophy (DMD) is one of the most common genetic diseases, affecting 1 of every 3500 male births, is ultimately lethal, and there are no approved therapies for these patients. We are investigating a protein therapy that may prevent the breakdown of skeletal and heart muscles of DMD patients and improve their quality of life.