Duchenne muscular dystrophy (DMD) is a lethal, X-linked recessive disorder with no known cure that afflicts 1in 5,000 newborn males. Patients carry a mutation in the dystrophin (DMD) gene, resulting in aberrant or absentexpression of the dystrophin protein. Affected individuals experience progressive wasting of skeletal musclesand cardiac dysfunction leading to loss of ambulation and premature death, primarily due to cardiac or respiratoryfailure. Only palliative treatments are available, although gene therapy approaches for DMD have beeneffectively applied in dystrophic animal models by either directly targeting a class of mutations (as with exonskipping or gene editing) or by delivering a synthetic version of the dystrophin gene. The lack of scalable, human-based pre-clinical screening models is a significant roadblock to developing new therapies for these patients.Simple single molecule assays can be readily scaled, but lack the complexity needed to model musclecontraction which relies on a symphony of many biological systems working in concert to produce movement. Atthe other end of the spectrum, animal (particularly mouse) models have generated much that is known about thedisease, but they are costly, slow, and in notable instances have given false positives for new treatments thatfailed to translate to humans. In this FastTrack SBIR proposal, Curi Bio and its partners will develop a novelpreclinical screening platform for DMD that directly measures the contraction of stem cell-derived muscle tissueconstructs from both human and murine cells. Because the contractility of tissue constructs is directly measured,therapies can be tested in the complex context of the mosaic of phenotypes that constitute muscle contraction.Further, the use of both murine and human cells will allow direct comparison of results to understand species-specific biology as well as to translate past results from animal models. Successful completion of this proposalwill validate the platform's ability to model contractile dysfunction in the dish, and to measure the degree ofrecovery after application of a novel therapeutic strategy that has been shown to restore the expression of healthydystrophin in patient cells. The company will also leverage this platform by measuring the therapeutic effect of arevolutionary adeno-associated virus-based gene therapy that will be superior in both safety and efficacycompared to current approaches. The deliverables of this project will greatly improve the field's ability topreclinically test novel therapeutics and will speed to market new lifesaving drugs for devastating diseases.
Public Health Relevance Statement: PROJECT NARRATIVE Gene therapies for the disease of contractile muscle are extraordinarily difficult to develop and have a track record of significant adverse effects during clinical trials, including patient death. We will develop an in vitro model of contractility using both human and murine cells that can be used to pre-clinically test these therapies in a way that can translate results from animal to human studies. We will also use the platform to assess the viability of a revolutionary novel genetic medicine for Duchenne muscular dystrophy.
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