Dr. Marks’ work on the mechanisms of action of drugs that inhibit vascular smooth muscle proliferation and migration has been translated into novel therapeutics including drug-eluting stents for treatment of coronary artery disease that have substantially reduced the incidence of in-stent restenosis, as well as effective therapy to reduce accelerated arteriopathy following cardiac transplantation. Dr. Marks has defined how macromolecular signaling complexes regulate ion channel function in muscle and non-muscle systems. His work has contributed new understandings of fundamental mechanisms that regulate muscle contraction.
He discovered that “leaky” intracellular calcium release channels (ryanodine receptors, RyR) contribute to heart failure, fatal cardiac arrhythmias, and impaired exercise capacity particularly in muscular dystrophy. Dr. Marks discovered a new class of small molecules (rycals), developed in his laboratory, that effectively treat cardiac arrhythmias, heart failure, and muscular dystrophy in pre-clinical studies. His new approach, based on fixing the “leak” in the ryanodine receptor/calcium release channels, is in Phase II clinical trials for the treatment of heart failure and cardiac arrhythmias, and is being developed for the treatment of muscular dystrophy. Dr. Marks found that RyR channels develop a stress-induced diastolic SR calcium leak that contributes to heart failure progression and sudden cardiac death. To address this problem, he developed a novel class of small molecule compounds called “rycals” that prevent the calcium leak by stabilizing the closed state of the channel, without impairing its normal function. He has shown that rycals reduce heart failure progression, prevent arrhythmias, and improve exercise capacity in animal models. A rycal is now in Phase II clinical trials in patients for prevention of heart failure progression and sudden cardiac death.
Muscle fatigue is one of the most fundamental physiological processes. Fatigue of skeletal muscle determines the outer limits of physical activity and explains, for example, why an elite athlete who can run 100 meters in under 10 seconds cannot run 1,000 meters in 100 seconds. Severe muscle fatigue is a life threatening problem for millions of patients suffering from chronic diseases, including heart failure, cancer, kidney failure, AIDS, as well as rarer genetic abnormalities including muscular dystrophies. Moreover, millions of individuals over the age of 70 suffer from unexplained muscle weakness that limits their quality of life. Muscle fatigue has been described and studied in enormous detail for centuries but mechanistic understandings remain obscure. Indeed, the prevailing theory of the past 100 years, that build up of lactic acid causes muscle fatigue, has only recently been refuted with convincing data. Attention has now turned to potential abnormalities in calcium handling as the most likely cause of skeletal muscle fatigue. In particular, several groups have observed defective intracellular calcium release from the sarcoplasmic reticulum in fatigued skeletal muscle, although no mechanisms have been established. Dr. Marks has tackled the new problem of the molecular basis of skeletal muscle fatigue, particularly as it relates to loss of muscle function with aging. These new understandings may lead to a novel therapeutic approach that improves muscle function in older individuals and in those with chronic diseases. There is no effective therapy for muscle fatigue, and the same type of Rycal drugs that Dr. Marks is testing for heart failure also improve exercise capacity in aged mice. Thus, one outcome could be a completely novel and effective treatment that improves muscle performance. This would be revolutionary in the field of muscle fatigue.
Dr. Marks has also discovered that intracellular Ca2+ leak represents a key pathology that impairs memory storage and alters signaling in the brain required for normal behavior (e.g. threat avoidance) and contributes to post-traumatic stress disorder (PTSD), Alzheimer’s Disease (AD), and possible Parkinson’s Disease (PD). A novel drug called a Rycal that we have developed that prevents intracellular Ca2+ leak prevents symptoms associated with PTSD and AD.
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