Novel Therapies for Duchenne Muscular Dystrophy

Project Summary Myologica is a small business focused on developing therapeutics for neuromuscular diseases Started in collaboration with the University of Maryland Myologica maintains a vigorous in house pre clinical discovery program in Duchenne Muscular Dystrophy DMD while providing consultation and specialized neuromuscular function testing for non profit and corporate clients The objective of this proposal is to demonstrate the feasibility of our novel therapeutic strategy developed through years of expertise and careful research to slow the progression and reduce the severity of DMD DMD is the most common X linked neuromuscular disease affecting approximately in male births in the US Although the genetic basis for this deadly disease is known lack of dystrophin there are currently no cures At Myologica we have identified the disease altered microtubule network as a novel therapeutic target in DMD and that acute treatment with colchicine can prevent muscle and cardiac injury during stress Despite growing evidence for the utility of colchicine as a drug its pharmacokinetic PK profile is less than ideal with plasma concentration peaking within minutes with a half life of to hours Additionally colchicine absorption across the intestinal mucosa is impacted by its ability to depolymerize microtubules within the epithelial cells of the mucosa This has led to the necessity to establish dosing thresholds in the treatment of gout dose escalation until GI distress However it is the impact on the GI tract that is often dose limiting in the treatment of chronic diseases Together these factors result in large variability in absorption and bioavailability between individuals to median which presents challenges in establishing an optimal dosing paradigm in patients Further complicating the clinical picture is the relatively narrow therapeutic window of colchicine lethal dose approximately to times therapeutic dose As such colchicine dosing is used only acutely in response to gout flare up or limited to twice a day dosing Given the significant clinical potential for microtubule targeting in DMD we have recently developed a family of colchicine pro drugs These pro drugs are pharmacologically inactive until they are activated by enzymatic or non enzymatic hydrolysis in the body These new pro drug formulations will allow for more clinically tolerated dosing once a day for example and more consistent therapeutic effects at the tissue level due to increased half life and a delayed peak plasma concentration This approach will open novel therapeutic avenues in DMD as well as chronic diseases that benefit from colchicine therapies such as Limb Girdle Muscular Dystrophy sarcopenia osteoporosis and atrial fibrillation Therefore the goal of this proposal is to test the feasibility of our novel therapy in DMD In our first aim we suggest to synthesize and test efficacy and PK of different pro drugs of colchicine to tailor an ideal PK profile with a lower Cmax than colchicine and increased half life In our second aim we will then test the efficacy of our lead therapeutic in a mouse model of DMD If shown effective our drug can be rapidly advanced to IND enabling studies for use in DMD as part of a Phase II SBIR and represent a new class of drugs for the treatment of neuromuscular disorders Project Narrative Duchenne Muscular Dystrophy is a devastating debilitating neuromuscular disease affecting approximately in male births in the US that currently does not have a cure At Myologica LLC we have developed a novel therapeutic strategy that targets the structural network of muscle cells which becomes dysregulated early in the progression of Duchenne Muscular Dystrophy and contributes to loss of muscle function as the disease progresses In this proposal we posit that safer alternative pro drugs of colchicine a regulator the structural network of muscle cells can be used innovatively to slow the progression and reduce the severity of Duchenne Muscular Dystrophy