Lee Sweeney

Lee Sweeney, Ph.D.

PRG DIR & EMIN SCHOLAR

Department: MD-PHARMACOLOGY / THERAPEUTICS
Business Phone: (352) 273-9416
Business Email: lsweeney@ufl.edu

About Lee Sweeney

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.

Honors & Awards

Co-President
2016 · AFM Myology Conference
Thomas H. Maren Eminent Scholar Chair
2015-Current · University of Florida
RARE Champion of Hope, Nominee
2013 · Global Genes
Stanley N. Cohen Biomedical Research Award
2010 · University of Pennsylvania
Hamdan Award for Medical Research Excellence
2008 · Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
First Annual Arthur C. Guyton Memorial Lecturer
2007 · Association of Chairs of Departments of Physiology
Director
2005-2014 · Wellstone Muscular Dystrophy Cooperative Center
Named among “America’s Best and Brightest”
2004 · Esquire Magazine
Fellow
2001 · American Heart Association
William Maul Measey Professor of Physiology (Endowed Chair)
1998 · University of Pennsylvania
Established Investigator
1990-1995 · American Heart Association

Research Profile

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.

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

Publications

2016 Proceedings of the National Academy of Sciences of the United States of America
2016 Proceedings of the National Academy of Sciences of the United States of America
2015 Proceedings of the National Academy of Sciences of the United States of America
2010 American Journal of Physiology-Endocrinology and Metabolism

Grants

Apr 2020 ACTIVE
Myosin 18 and its role in skeletal muscle
NATL INST OF HLTH NIAMS · Principal Investigator
Jul 2019 ACTIVE
Myo10-Driven Filopodia in Skeletal Muscle
NATL INST OF HLTH NIAMS · Principal Investigator
Jul 2019 ACTIVE
Impact and Interplay of Corticosteroid Regimen and Exercise Training on DMD Muscle Function
US ARMY MED RES ACQUISITION ·
Jul 2018 ACTIVE
Structure and Function of Myosin VI
NATL INST OF HLTH NIDCD · Principal Investigator
Feb 2018 ACTIVE
Targeting senescent stroma in DMD
MUSCULAR DYSTROPHY ASSO · Mentor
May 2016 – Jul 2016
PPMD conference
PARENT PROJECT MUSCULAR DYSTROPHY · Principal Investigator
Apr 2016 – Apr 2017
New directions in biology and disease of skeletal muscle
BRISTOL MYERS SQUIBB CO · Principal Investigator
Apr 2016 – Dec 2016
MDA Conference Support
MUSCULAR DYSTROPHY ASSO · Principal Investigator
Feb 2016 ACTIVE
wellstone supplement: PPMD therapeutic evaluations
PARENT PROJECT MUSCULAR DYSTROPHY · Principal Investigator
Jan 2016 ACTIVE
ufhcc-ioa cancer-aging collaborative team grants
UF HEALTH SHANDS HOSPITAL · Project Manager
Sep 2015 ACTIVE
Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy
NATL INST OF HLTH NIAMS ·
Sep 2015 – Aug 2017
Rescue Nebulin-KO mice from NM
A FOUNDATION BUILDING STRENGTH · Principal Investigator
Aug 2015 – Jul 2017
Mutations in Smooth Muscle Contractile Proteins: Pathways to Vascular Diseases
UNIV OF TEXAS HLTH SCI CTR HOUSTON · Principal Investigator
Aug 2015 – Jul 2016
Modulation of Calcium Handling in Mouse Models
MUSCULAR DYSTROPHY ASSO · Principal Investigator
Aug 2015 ACTIVE
Failed Regeneration in the Muscular Dystrophies: Inflammation, Fibrosis and Fat
NATL INST OF HLTH NIAMS · Principal Investigator
Jul 2015 – Jun 2018
Structure and function of Myosin VI
NATL INST OF HLTH NIDCD · Principal Investigator
Jul 2015 ACTIVE
Mechanical Triggers to Programmed Cell Death in Cardiomyocytes- and how to prevent their Action in Failing Hearts
Fondation Leducq · Principal Investigator
Jul 2015 ACTIVE
Muscular Dystrophy Research
UF FOU · Principal Investigator
Jul 2015 ACTIVE
MUSCULAR DYSTROPHY MEETING
UF FOU · Principal Investigator
Jan 2015 ACTIVE
Sweeneyh-Maren Chair
UF FOU UNRESTRICTED DONATION · Principal Investigator
Sep 2013 – Aug 2018
The relationship between genomic variants and MRI/MRS markers in DMD
NATL INST OF HLTH NIAMS · Project Manager

Education

Post Doc – Physiology
1985 · University of Texas Southwestern
Ph.D. – Physiology & Biophysics
1984 · Harvard University
A.M. – Physiology
1980 · Harvard University
S.B. – Biochemistry
1975 · Massachusetts Institute of Technology

Contact Details

Phones:
Business:
(352) 273-9416
Emails:
Business:
lsweeney@ufl.edu