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.

Accomplishments

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

2021
Assessment of rAAVrh.74.MHCK7.micro-dystrophin Gene Therapy Using Magnetic Resonance Imaging in Children With Duchenne Muscular Dystrophy.
JAMA network open. 4(1) [DOI] 10.1001/jamanetworkopen.2020.31851. [PMID] 33394000.
2021
Current state of cardiac troponin testing in Duchenne muscular dystrophy cardiomyopathy: review and recommendations from the Parent Project Muscular Dystrophy expert panel.
Open heart. 8(1) [DOI] 10.1136/openhrt-2021-001592. [PMID] 33762424.
2020
Glucocorticoids counteract hypertrophic effects of myostatin inhibition in dystrophic muscle.
JCI insight. 5(1) [DOI] 10.1172/jci.insight.133276. [PMID] 31830002.
2020
Myosin Structures.
Advances in experimental medicine and biology. 1239:7-19 [DOI] 10.1007/978-3-030-38062-5_2. [PMID] 32451853.
2020
The D2.mdx mouse as a preclinical model of the skeletal muscle pathology associated with Duchenne muscular dystrophy.
Scientific reports. 10(1) [DOI] 10.1038/s41598-020-70987-y. [PMID] 32826942.
2018
DMD genotype correlations from the Duchenne Registry: Endogenous exon skipping is a factor in prolonged ambulation for individuals with a defined mutation subtype.
Human mutation. 39(9):1193-1202 [DOI] 10.1002/humu.23561. [PMID] 29907980.
2017
Altered Smooth Muscle Cell Force Generation as a Driver of Thoracic Aortic Aneurysms and Dissections.
Arteriosclerosis, thrombosis, and vascular biology. 37(1):26-34 [DOI] 10.1161/ATVBAHA.116.303229. [PMID] 27879251.
2017
Duchenne Regulatory Science Consortium Meeting on Disease Progression Modeling for Duchenne Muscular Dystrophy.
PLoS currents. 9 [DOI] 10.1371/currents.md.83071bbd728982f2f1073f4950e03586. [PMID] 28228973.
2017
Supraphysiological levels of GDF11 induce striated muscle atrophy.
EMBO molecular medicine. 9(4):531-544 [DOI] 10.15252/emmm.201607231. [PMID] 28270449.
2016
Cardiac myosin light chain is phosphorylated by Ca2+/calmodulin-dependent and -independent kinase activities.
Proceedings of the National Academy of Sciences of the United States of America. 113(27):E3824-33 [DOI] 10.1073/pnas.1600633113. [PMID] 27325775.
2016
Disease-Modifying Effects of Orally Bioavailable Nf-Kappa B Inhibitors in Dystrophin-Deficient Muscle
JCI insight. 1(21) [DOI] 10.1172/jci.insight.90341. [PMID] 28018975.
2016
Force-producing ADP state of myosin bound to actin.
Proceedings of the National Academy of Sciences of the United States of America. 113(13):E1844-52 [DOI] 10.1073/pnas.1516598113. [PMID] 26976594.
2016
Increased collagen cross-linking is a signature of dystrophin-deficient muscle.
Muscle & nerve. 54(1):71-8 [DOI] 10.1002/mus.24998. [PMID] 26616495.
2016
Osteopontin ablation ameliorates muscular dystrophy by shifting macrophages to a pro-regenerative phenotype.
The Journal of cell biology. 213(2):275-88 [DOI] 10.1083/jcb.201510086. [PMID] 27091452.
2016
Tadalafil Treatment Delays the Onset of Cardiomyopathy in Dystrophin-Deficient Hearts.
Journal of the American Heart Association. 5(8) [DOI] 10.1161/JAHA.116.003911. [PMID] 27506543.
2016
The myosin X motor is optimized for movement on actin bundles.
Nature communications. 7 [DOI] 10.1038/ncomms12456. [PMID] 27580874.
2015
Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy.
Proceedings of the National Academy of Sciences of the United States of America. 112(23):7153-8 [DOI] 10.1073/pnas.1507719112. [PMID] 26039989.
2014
Assessment of intramuscular lipid and metabolites of the lower leg using magnetic resonance spectroscopy in boys with Duchenne muscular dystrophy.
Neuromuscular disorders : NMD. 24(7):574-82 [DOI] 10.1016/j.nmd.2014.03.013. [PMID] 24798221.
2014
Longitudinal measurements of MRI-T2 in boys with Duchenne muscular dystrophy: effects of age and disease progression.
Neuromuscular disorders : NMD. 24(5):393-401 [DOI] 10.1016/j.nmd.2013.12.012. [PMID] 24491484.
2014
Magnetic Resonance Imaging and Spectroscopy Assessment of Lower Extremity Skeletal Muscles in Boys With Duchenne Muscular Dystrophy: a Multicenter Cross Sectional Study
PLoS One. 9(9) [DOI] 10.1371/journal.pone.0106435. [PMID] 25338055.
2013
Magnetic Resonance Imaging and Spectroscopy Detect Changes With Age, Corticosteroid Treatment, and Functional Progression in Dmd
Neuromuscular Disorders. 23(9-10) [DOI] 10.1016/j.nmd.2013.06.599.
2013
Overexpression of insulin-like growth factor-1 attenuates skeletal muscle damage and accelerates muscle regeneration and functional recovery after disuse.
Experimental physiology. 98(5):1038-52 [DOI] 10.1113/expphysiol.2012.070722. [PMID] 23291913.
2013
Skeletal muscles of ambulant children with Duchenne muscular dystrophy: validation of multicenter study of evaluation with MR imaging and MR spectroscopy.
Radiology. 269(1):198-207 [DOI] 10.1148/radiol.13121948. [PMID] 23696684.
2013
T₂ mapping provides multiple approaches for the characterization of muscle involvement in neuromuscular diseases: a cross-sectional study of lower leg muscles in 5-15-year-old boys with Duchenne muscular dystrophy.
NMR in biomedicine. 26(3):320-8 [DOI] 10.1002/nbm.2851. [PMID] 23044995.
2012
A proteasome inhibitor fails to attenuate dystrophic pathology in mdx mice.
PLoS currents. 4 [PMID] 22866241.
View on: PubMed
2012
Long-Term Restoration of Cardiac Dystrophin Expression in Golden Retriever Muscular Dystrophy Following Raav6-Mediated Exon Skipping
Molecular Therapy. 20(3):580-589 [DOI] 10.1038/mt.2011.264. [PMID] 22146342.
2012
MRI/MRS evaluation of a female carrier of Duchenne muscular dystrophy.
Neuromuscular disorders : NMD. 22 Suppl 2:S111-21 [DOI] 10.1016/j.nmd.2012.05.013. [PMID] 22980762.
2012
Relationships of thigh muscle contractile and non-contractile tissue with function, strength, and age in boys with Duchenne muscular dystrophy.
Neuromuscular disorders : NMD. 22(1):16-25 [DOI] 10.1016/j.nmd.2011.06.750. [PMID] 21807516.
2011
Design of a Multi-Center Study To Examine Skeletal Muscles of Children With Duchenne Muscular Dystrophy Using Mri/Mrs
Neuromuscular Disorders. 21(9-10):653-654 [DOI] 10.1016/j.nmd.2011.06.801.
2011
Long-Term Systemic Myostatin Inhibition Via Liver-Targeted Gene Transfer in Golden Retriever Muscular Dystrophy
Human Gene Therapy. 22(12):1499-1509 [DOI] 10.1089/hum.2011.102. [PMID] 21787232.
2010
Age-related differences in lower-limb muscle cross-sectional area and torque production in boys with Duchenne muscular dystrophy.
Archives of physical medicine and rehabilitation. 91(7):1051-8 [DOI] 10.1016/j.apmr.2010.03.024. [PMID] 20599043.
2010
Impact of viral-mediated IGF-I gene transfer on skeletal muscle following cast immobilization.
American journal of physiology. Endocrinology and metabolism. 299(5):E730-40 [DOI] 10.1152/ajpendo.00230.2010. [PMID] 20739512.
2005
Changes in inorganic phosphate and force production in human skeletal muscle after cast immobilization.
Journal of applied physiology (Bethesda, Md. : 1985). 98(1):307-14 [PMID] 15333614.
View on: PubMed
2005
Noninvasive monitoring of gene correction in dystrophic muscle.
Magnetic resonance in medicine. 54(6):1369-76 [PMID] 16261578.
View on: PubMed
2004
Noninvasive monitoring of stem cell transfer for muscle disorders.
Magnetic resonance in medicine. 51(2):273-7 [PMID] 14755651.
View on: PubMed

Grants

Aug 2021 ACTIVE
Potential therapies for the muscular dystrophies
Role: Principal Investigator
Funding: PARENT PROJECT MUSCULAR DYSTROPHY
Aug 2021 ACTIVE
Understanding and Improving Therapies for the Muscular Dystrophies
Role: Principal Investigator
Funding: NATL INST OF HLTH NIAMS
Jul 2021 ACTIVE
Seven tesla preclinical MRI/S scanner for structural, functional and molecular imaging
Role: Other
Funding: NATL INST OF HLTH OD
Sep 2020 ACTIVE
Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy
Role: Co-Investigator
Funding: NATL INST OF HLTH NIAMS
Sep 2020 – Jul 2021
Understanding and Improving AAV Gene Therapy for DMD
Role: Principal Investigator
Funding: PARENT PROJECT MUSCULAR DYSTROPHY
May 2020 – Sep 2021
Task Order #2 – Preclinical work to enable clinical trials with AAV delivery of genes to prevent heart failure
Role: Principal Investigator
Funding: SAREPTA THERAPEUTICS
Apr 2020 ACTIVE
Myosin 18 and its role in skeletal muscle
Role: Principal Investigator
Funding: NATL INST OF HLTH NIAMS
Jul 2019 ACTIVE
Myo10-Driven Filopodia in Skeletal Muscle
Role: Principal Investigator
Funding: NATL INST OF HLTH NIAMS
Jul 2019 ACTIVE
Impact and Interplay of Corticosteroid Regimen and Exercise Training on DMD Muscle Function
Role: Co-Investigator
Funding: US ARMY MED RES ACQUISITION
Jul 2018 ACTIVE
Structure and Function of Myosin VI
Role: Principal Investigator
Funding: NATL INST OF HLTH NIDCD
Feb 2018 – Jul 2021
Targeting senescent stroma in DMD
Role: Other
Funding: MUSCULAR DYSTROPHY ASSO
May 2016 – Jul 2016
PPMD conference
Role: Principal Investigator
Funding: PARENT PROJECT MUSCULAR DYSTROPHY
Apr 2016 – Apr 2017
New directions in biology and disease of skeletal muscle conference
Role: Principal Investigator
Funding: BRISTOL MYERS SQUIBB CO
Apr 2016 – Dec 2016
MDA Conference Support
Role: Principal Investigator
Funding: MUSCULAR DYSTROPHY ASSO
Feb 2016 – Jan 2021
wellstone supplement: PPMD therapeutic evaluations
Role: Principal Investigator
Funding: PARENT PROJECT MUSCULAR DYSTROPHY
Jan 2016 ACTIVE
ufhcc-ioa cancer-aging collaborative team grants
Role: Project Manager
Funding: UF HEALTH SHANDS HOSPITAL
Sep 2015 – Sep 2020
Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy
Role: Co-Investigator
Funding: NATL INST OF HLTH NIAMS
Sep 2015 – Aug 2017
Identification of factors that rescue Nebulin-KO mice from NM
Role: Principal Investigator
Funding: A FOUNDATION BUILDING STRENGTH
Aug 2015 – Jul 2021
Failed Regeneration in the Muscular Dystrophies: Inflammation, Fibrosis and Fat
Role: Principal Investigator
Funding: NATL INST OF HLTH NIAMS
Aug 2015 – Jul 2017
Mutations in Smooth Muscle Contractile Proteins: Pathways to Vascular Diseases
Role: Principal Investigator
Funding: UNIV OF TEXAS HLTH SCI CTR HOUSTON via NATL INST OF HLTH NHLBI
Aug 2015 – Jul 2016
Modulation of Calcium Handling in Mouse Models
Role: Principal Investigator
Funding: MUSCULAR DYSTROPHY ASSO
Jul 2015 ACTIVE
Muscular Dystrophy Research
Role: Principal Investigator
Funding: UF FOU
Jul 2015 – Jul 2021
MUSCULAR DYSTROPHY MEETING
Role: Principal Investigator
Funding: UF FOU
Jul 2015 – Aug 2020
Mechanical Triggers to Programmed Cell Death in Cardiomyocytes- and how to prevent their Action in Failing Hearts
Role: Principal Investigator
Funding: Fondation Leducq
Jul 2015 – Jun 2018
Structure and function of Myosin VI
Role: Principal Investigator
Funding: NATL INST OF HLTH NIDCD
Sep 2013 – Aug 2018
The relationship between genomic variants and MRI/MRS markers in DMD
Role: Project Manager
Funding: NATL INST OF HLTH NIAMS

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

Teaching Profile

Courses Taught
2017,2019-2021
GMS6847 Translational Research and Therapeutics: Bench, Bedside, Community, & Policy
2018-2021
GMS6560 Molecules to Man: Past, Present and Future Therapeutic Strategies for Disease
2019-2021
GMS6476 Fundamentals of Skeletal Muscle
2020-2021
GMS5905 Special Topics in Biomedical Sciences
2018
GMS7593 Topics in Pharmacology and Toxicology
2018
GMS7980 Research for Doctoral Dissertation
2018
GMS7979 Advanced Research
2017-2018
DEN6262 Prin of Pharmacology
2016
GMS7794 Neuroscience Seminar

Contact Details

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