Clinical Trials in Duchenne Muscular Dystrophy

Principal Investigator:  John Day, M.D., Ph.D.

The genetic cause of Duchenne muscular dystrophy (DMD), a mutation of the dystrophin gene and absence of that cytoskeletal protein, leads to a cascade of events resulting in muscle fiber death.  That myonecrosis in DMD is not simply due to loss of a critical protein, but actually involves several downstream pathogenic mechanisms, is indicated by several clinical features: 1) Muscle functions normally early in life; 2) Some muscles continue to function normally throughout life despite absence of dystrophin – for example extraocular muscles; 3) Pharmacologic treatment with prednisone or creatine can alter muscle function without affecting dystrophin content.  Pathogenic processes involved in DMD appear to include failure of energy production in affected muscle fibers, inability to regulate calcium in muscle fibers, inflammation of muscle, and activation of cell death programs.

We have established collaborative relationships with MD investigators for multicenter studies, and will use the NASH grant support to further these studies and to initiate pilot studies on novel approaches to diminish inflammation, and to study the effects of cord blood transplants in humans.   In these ways we will develop better immediately available treatments for DMD while laying the groundwork for more definitive treatments in the future.  Specifically for this proposal, we will investigate the use of a novel source of enhanced muscle energy production, a synthetic fat (triheptanoin) containing 7 carbon atoms.  Because of the limitations of initially studying such novel compounds in children, we propose to study an adult form of metabolic myopathy, carnitine palmitoyl transferase deficiency, which is highly likely to respond to trieheptanoin; we will use the experience of that study to initiate a study of adults with Becker muscular dystrophy, and then boys with Duchenne.

Subjects will be studied monthly to assess strength and function.  After a 3 month period to define the natural history, patients will be studied after giving them either a conventional form of fat supplementation, or the novel form, triheptanoin.  In addition to muscle function, we will monitor various amino acids in urine and blood that reflect the state of muscle fiber degeneration.  By verifying that increased muscle energy production improves muscle function in DMD, we would then also follow patients to see if it slows progression of muscle degeneration.