Mitofusin agonists to prevent Charcot-Marie-Tooth disease 2A

Mitofusin agonists to prevent Charcot-Marie-Tooth disease 2A Gerald W Dorn II, MD Mitochondria in Motion, Inc. Washington University in St Louis School of Medicine Abstract: Charcot-Marie-Tooth (CMT) disease type 2A is an incurable, primarily pediatric, autosomal dominant neuromuscular degenerative disease caused by mutations in the mitofusin (MFN) 2 gene. There are currently no disease-altering treatments. With Phase I STTR support, Mitochondria in Motion, Inc. has developed the first pharmaceutically acceptable small molecule mitofusin activator to treat CMT2A and possibly other neurological diseases. In general, mitofusin activation enhances mitochondrial fitness, metabolism, and trafficking within neurons, thus improving homeostatic functioning and injury-responses. Our clinical lead mitofusin activator, trans-MiM111, normalizes mitochondrial abnormalities in CMT2A patient fibroblasts and reprogrammed neurons in vitro, and reverses neuromuscular dysfunction in mice expressing a human CMT2A MFN2 mutant (T105M) in vivo. During STTR Phase I we validated our hypothesis that activating endogenous, genetically normal MFN2 and MFN1 could reverse dominant inhibition by CMT2A MFN2 mutants of neuronal mitochondrial fusion and trafficking, thus preventing CMT2A-induced neuromuscular degeneration. Having identified a pharmaceutically acceptable clinical candidate, trans-MiM111, our Phase II goals are to define optimal dosing levels and schedule using our CMT2A mouse (SA#1), and initiate GLP (non- GMP) pre-IND studies to position us for FDA approval of first-in-human trials. If we are successful, we will fill an unmet healthcare need and build a commercial enterprise to serve the ~10,000 Americans with CMT2A and the andgt;200,000 Americans suffering from other neurodegenerative diseases characterized by mitochondrial degeneration, including CMT type 1, amyotrophic lateral sclerosis, and Huntington’s disease. Our deliverable for this 2 year Phase II STTR will be a mitofusin activator positioned for FDA approval and phase I, first in human, trials.Lay abstract: Charcot-Marie-Tooth disease type 2A (CMT2A) is a tragic genetic childhood condition that causes slowly progressive weakness and atrophy of muscles in the forearm, hand, lower leg and feet, ultimately leading to partial and life-long disability from young adulthood. Despite having identified the genetic cause of this disease over 10 years ago, there is neither a cure nor any way of delaying or ameliorating the disease; the diagnosis can be a sentence to life in a wheelchair. Our biotechnology research and development company, Mitochondria in Motion, Inc., developed the first drug that can directly activate the mitofusin 2 protein which is abnormal in, and that causes, CMT2A. Our mitofusin activator corrected abnormalities in CMT2A patients’ cells and reversed nerve and muscle atrophy in CMT2A mice. Now, with partial support from this STTR grant, we will undertake studies to determine if this drug is safe enough for government (FDA) approval as the first disease-altering therapy for CMT2A, and possibly other neurological diseases.