Lee Sweeney, Ph.D.

Dr. Sweeney’s basic research interests are focused on molecular motors of the myosin superfamily. Notable among his accomplishments on molecular motors was the first visualization of structural rearrangement of the myosin lever arm, a detailed analysis of how processive myosins are engineered, a demonstration of the structural changes induced by actin-binding and nucleotide release, and the discovery and molecular dissection of the only known reverse-direction myosin.

Much of Dr. Sweeney’s research program is translational in focus, and has produced highly cited research on inherited forms of cardiovascular disease, and on the skeletal and cardiac aspects of muscular dystrophy. Dr. Sweeney was elected as a Fellow of the American Heart Association in 2001. He has been the Director of a NIH-funded Paul Wellstone Muscular Dystrophy Cooperative Center (one of the six) since 2005, which he relocated to the University of Florida (UF) in 2015. Dr. Sweeney is actively developing therapeutics for rare diseases that include both small molecule and gene therapy approaches. He serves as a consultant to a number of industry therapeutic development efforts for Duchenne muscular dystrophy and Spinal Muscular Atrophy.

Dr. Sweeney is also heavily involved in small molecule therapy development for muscle disease. In 2007, he and his collaborators at PTC Therapeutics (a small NJ biotech company) published the development of a compound (PTC 124 or ataluren) that allows read-through of nonsense mutations (premature stop codons) in a variety of genetic disease models. Dr. Sweeney was awarded a Hamdan Award for Medical Research Excellence from Sheikh Hamdan of Dubai in 2008. On May 23, 2014, ataluren was granted conditional European approval for the treatment of Duchenne muscular dystrophy (DMD), making it the first approved drug for this disease.

Dr. Sweeney is well known in the popular press for his gene-therapy approaches to permanently block the loss of age-related muscle size and strength in mice. The technique suggests that therapies for humans could reverse the feebleness associated with old age or slow the muscle-wasting effects of muscular dystrophies. In 2004, this work led to Dr. Sweeney being among those chosen by Esquire Magazine as the “Best and Brightest” in America. Based on the enhancement this creates in healthy young animals, Dr. Sweeney has been widely sought as an expert commentator on the potential for gene “doping” in sports, as well as on the bioethical issues surrounding genetic enhancement. He currently serves as an advisor to the World Anti-doping Association on these matters.

There are two broad focuses of Dr. Sweeney’s current research program. The first grew out of his desire to understand the molecular basis of muscle contraction, and the molecular motor powering muscle contraction, myosin. He has been working in the area of myosin structure and function since the mid-1980s, and has authored a large number of papers on the subject, beginning in 1986. His lab was the first to publish the use of the baculovirus-SF9 expression system for the heterologous expression of myosin in the early 1990s. They published the first structural evidence for the lever arm hypothesis for myosin in 1995, and at the same time discovered the mechanism for ADP-release-associated load sensing in myosin. In the late 1990’s they hypothesized that myosin VI might be a reverse-direction myosin motor based on its primary sequence, which they were able to demonstrate experimentally. It was a paradigm-shifting discovery and remains the only know reverse-direction myosin. They also unraveled the kinetic basis for the processivity of myosin V, which applies to many classes of unconventional myosins. Recently, they described how actin activates the motor activity of all myosin classes. They are currently focused on the role of unconventional myosins in hearing, as well as evaluating the possibility that they may be drug targets in certain forms of cancer.

The second focus of his research is on muscle disease. This evolved from his desire to understand the processes involved in force generation and transmission by muscle, and diseases that result from defects in the proteins involved. This has included congenital forms of cardiomyopathy as well as muscular dystrophies. He has been working in the area of muscular dystrophy since 1992 and has authored a number of papers on evaluating potential therapeutic targets, beginning in the late 1990s. His lab has been working on the development of AAV gene transfer to liver, skeletal muscle, and to the heart in dogs, as well as small molecule therapies for inherited human diseases. He is the senior author on the paper describing their development of the nonsense suppression drug, PTC 124 (ataluren). His lab continues to work on the development of small molecules for the treatment of muscular dystrophies.

• AAV vectors
• Dystrophin
• Force generation
• Gene therapy
• MR imaging
• Molecular motors
• Muscle
• Muscular dystrophy
• Myosin
• Sarcopenia
• Small molecule therapy

0000-0002-6290-8853