Myopathies and other clinical disorders arising from genetic abnormalities of the mitochondrial respiratory chain collectively affect as many as 1 in 8000 individuals, representing in aggregate a significant disease burden, even though the specific underlying genetic lesions are each quite rare. Despite the need for therapeutic strategies to prevent or slow the progression of these often disabling and at times fatal genetic diseases, existing treatment options for mitochondrial disease patients are limited primarily to symptom management. Genetic and clinical heterogeneity make diagnosis, treatment, and therapeutic discovery for these diseases challenging, and disease-modifying treatments remain elusive for the majority of mitochondrial disorders. Inhibition of specific cellular pathology common to multiple mitochondrial diseases could complement approaches targeting the primary genetic defects in individual disorders, and contribute to combination strategies for reducing disease progression. One consequence of mitochondrial dysfunction can be increased permeability of the inner mitochondrial membrane, via opening of a multiprotein channel known as the mitochondrial permeability transition pore (MPTP). Pharmacologic inhibitors of the MPTP modulator cyclophilin D, such as the immunosuppressant cyclosporine A, can reduce the cellular pathology arising from mitochondrial dysfunction in cultured cells derived from mitochondrial disease patients. These observations suggest that cyclophilin D inhibition could be a valid strategy for attenuating the effects of disease-associated mitochondrial dysfunctions. In preliminary studies, SCYNEXIS has identified two non-immunosuppressive cyclophilin D inhibitors that block MPTP opening and are efficacious in protecting cardiac muscle in an in vivo model of acute mitochondrial stress. The key objective of this Phase I SBIR project is to test the ability of these cyclophilin D inhibitors to attenuate cellular phenotypes resulting from chronic mitochondrial dysfunction. Progression to a Phase II project will be justified by attenuation of cellular disease phenotypes in mitochondrial mutant cells by these novel cyclophilin D inhibitors. We will also profile the compounds and newer analogs for selected properties favorable for use in chronic therapeutic administration. The results will inform the design of a full lead discovery and optimization program to be pursued in Phase II, with the long-term goal of identifying a preclinical therapeutic candidate for one or more mitochondrial diseases.

Public Health Relevance

Mitochondrial disorders are a genetically and clinically heterogeneous group of heritable diseases causing myopathies and other organ dysfunctions. Existing treatment options for mitochondrial disease patients are limited and focus primarily on symptom management. This study will evaluate novel therapeutic drug candidates that target a cellular pathology common to multiple of these rare diseases.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZAR1)
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Wang, Xibin
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Scynexis, Inc.
United States
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