About

H. Lee Sweeney, Ph.D., is an Emeritus Professor of Physiology at the University of Pennsylvania's Perelman School of Medicine, within the Department of Physiology. His research program addresses the molecular basis of cellular movement and force generation, focusing on investigations at the level of single molecules, cells, and whole organisms. His work examines the design and function of molecular motors, particularly myosin, through protein engineering, biochemical, and structural analyses. At the cellular level, his studies explore the role of various proteins in force generation and transmission, as well as the assembly of the contractile apparatus in cultured myocytes. His research extends to whole animal models, involving gene transfer into muscle to assess structural and functional changes, especially in the context of muscle diseases such as Duchenne muscular dystrophy and hypertrophic cardiomyopathy. Dr. Sweeney's contributions have advanced understanding of muscle cell design and disease mechanisms, utilizing innovative gene transfer techniques to evaluate potential treatments.

Research topics

• Internal medicine
• Medicine
• Nuclear medicine
• Physical medicine and rehabilitation

Selected publications

• Functional and structural pathologies in skeletal muscle of a rat model of Duchenne muscular dystrophy

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-16

  preprintOpen accessSenior author

  Background-: Duchenne muscular dystrophy (DMD) is a lethal pediatric degenerative muscle disease for which there is no cure. Robust preclinical models that recapitulate major clinical features of DMD are required to investigate efficacy of potential DMD therapeutics. Rat models of DMD have emerged as promising small animal models to accomplish this; however, there have been no comprehensive studies investigating the functional skeletal muscle decrements associated with the modeling of DMD in rats. Methods-: muscle function was assessed in wild-type (WT) and MDR muscles at 3, 6, and 12 months of age, followed by histopathological analyses. Results-: MDR muscle tissues exhibited loss of full-length dystrophin and reduced content of other dystrophin glycoprotein complex members. MDR extensor digitorum longus (EDL) muscles and diaphragms displayed pronounced and progressive muscle weakness beginning at 3 months of age, compared to WT littermates. EDLs also exhibit susceptibility to eccentric contraction-induced damage. Functional deficits in soleus muscles were less severe and were associated with a right shift in force-frequency relationship and a muscle fiber-type shift. MDR muscles display progressive histopathology including degenerative lesions, fibrosis, regenerative foci, and modest adipose deposition. Conclusions-: MDR is a preclinical model of DMD that exhibits many translational features of the human disease, including a large dynamic range of muscle decrements, that has high utility for the evaluation of potential therapeutics for DMD.

  PublisherOA PDFDOI

• Dual S100A1 and ARC gene therapy as a treatment for DMD cardiomyopathy

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-23

  preprintOpen accessSenior author

  ABSTRACT Duchenne muscular dystrophy (DMD) is a lethal pediatric striated muscle disease caused by loss of dystrophin for which there is no cure. Cardiomyopathy is the leading cause of death amongst individuals with DMD, and effective therapeutics to treat DMD cardiomyopathy are a major unmet clinical need. This work investigated adeno-associated viral (AAV) gene therapy approaches to treat DMD cardiomyopathy by overexpression of the calcium binding proteins S100A1 and apoptosis repressor with caspase recruitment domains (ARC). Using the severe D2 .mdx mouse model of DMD, we identified that S100A1 gene therapy improves the diastolic dysfunction associated with DMD cardiomyopathy, whereas ARC gene therapy prolongs survival. The combination of both S100A1 and ARC in a single bicistronic vector improves the long-term cardiac outcome of D2. mdx mice, development of heart failure caused by micro-dystrophin expression, and exhibits safety via intracoronary delivery in a canine model of DMD. Furthermore, S100A1-ARC gene therapy provides functional benefits when expressed in D2. mdx skeletal muscle. Together, these findings indicate that S100A1-ARC gene therapy represents an effective treatment for DMD cardiomyopathy and may be effective in treating other forms of cardiomyopathy and muscle pathologies. SIGNIFICANCE STATEMENT Cardiomyopathy is the leading cause of death amongst individuals with Duchenne muscular dystrophy (DMD). Effective therapeutics to treat DMD cardiomyopathy represent a major unmet clinical need. This work identifies the dual gene therapy approach of S100A1 and ARC as an effective treatment that improves long-term cardiac function and life-expectancy in severe mouse model of DMD. Intracoronary delivery of this AAV-based gene therapy also exhibits safety and evidence of efficacy in dystrophic canines. Furthermore, functional benefits in skeletal muscle are also incurred via S100A1-ARC expression in striated muscle. These findings indicate that S100A1-ARC therapy is an effective treatment for DMD cardiomyopathy whose benefits may be applicable for other forms of cardiac and muscle disease.

  PublisherOA PDFDOI

• Effect of Tadalafil on cardiac function and left ventricular dimensions in Duchenne muscular dystrophy: safety and cardiac MRI substudy results from a randomized, placebo-controlled trial

  BMC Cardiovascular Disorders · 2025-04-11 · 1 citations

  articleOpen accessSenior author

  BACKGROUND: Inhibition of phosphodiesterase 5 (PDE5) was hypothesized to slow disease progression in Duchenne muscular dystrophy (DMD). Tadalafil, a once-daily PDE5 inhibitor, did not slow loss of ambulation in a phase 3 placebo-controlled trial. This report details the cardiac findings from this study. METHODS: Patients with DMD (N = 331) aged 7 to 14 years on stable glucocorticoids were randomized to tadalafil 0.3 mg/kg/day, 0.6 mg/kg/day, or placebo. Ejection fraction (EF), fractional shortening, and M-mode ventricular dimensions were measured on echocardiograms. 12-lead ECGs were centrally evaluated for heart rate and intervals, and qualitative diagnoses. Vital signs and unsolicited adverse events were collected throughout the study. Cardiac MRI (CMR) was collected in a subset of 27 patients. Z-scores for ventricular dimensions and volumes were calculated based on published age-normative reference values. Treatment differences for change in continuous ECG parameters and vital signs were compared using Wilcoxon rank-sum tests. Echocardiogram and CMR parameters were analyzed with an ANCOVA model. RESULTS: Tadalafil had no adverse effects on echocardiographic left ventricular (LV) EF or fractional shortening, ECG findings, or vital signs. Mean diastolic LV internal dimension (LVIDd) was increased in the tadalafil 0.6 mg/kg group versus placebo at Week 24 (+ 0.13 cm, p =.019) and Week 48 (+ 0.18 cm, p =.008), with a similar pattern observed for LV systolic dimensions (LVIDs). Mean LV end diastolic volume (EDV) measured by CMR also increased at Week 48 in the tadalafil 0.3 mg/kg (+ 13.0 ml, p =.047 vs. placebo) and 0.6 mg/kg (+ 12.0 ml, p =.08 vs. placebo) groups, with numerically smaller increases in LV EDV and commensurate increases in stroke volume and cardiac output. Z-scores for LVIDd and LV EDV were generally below the normal range at baseline and increased toward or within the normal range in the tadalafil groups but not in the placebo group. CONCLUSIONS: No adverse effects of tadalafil on cardiovascular function were evident based on adverse events, echocardiograms, ECG, or vital sign measurements through 48 weeks in patients with DMD. The small mean increases in LVID and LV volume observed with tadalafil are consistent with PDE5 inhibitor pharmacology, but their clinical relevance in the context of LV tonic contraction in DMD is unknown and deserve further study. GOV IDENTIFIER: NCT01865084 (first registration date: 24-May-2013).

  PublisherOA PDFDOI

• Development of clinically viable non-muscle myosin II small molecule inhibitors

  Cell · 2025-07-02 · 7 citations

  article
  PublisherDOI

• Developing Social Worker Student Belonging, Engagement and Confidence Through Peer Mentoring: A Case Study Exploration

  2025-10-28

  book-chapter

  Abstract Peer mentoring in higher education can benefit mentees, mentors and institutions. For mentees, it can support their transition into higher education, clarifies academic and professional expectations, reduces worries and boosts confidence and engagement. Mentors can develop interpersonal and professional skills, build confidence and learn through shared experiences. Both mentors and mentees can develop a sense of shared identity and belonging. For institutions, peer mentoring schemes are linked to reduced attrition, improved retention, higher grades, and increased student engagement. This chapter explores a peer mentoring scheme within the BA (Hons) Social Work programme at the University of Sunderland, designed to provide additional support for students on a demanding, professionally regulated course. The scheme supplements existing support systems and fosters communities of practice and learning among students at different stages of study. Reflections from mentors and mentees are considered to highlight the significant benefits, some of the challenges of the scheme and its role in fostering a sense of belonging.

  PublisherDOI

• Evaluation of a control paradigm allowing heart rate guided rehabilitative exercise  for boys with Duchenne muscular dystrophy 

  Research Square · 2025-06-10

  preprintOpen access
  PublisherOA PDFDOI

• Cardiomyopathy in Duchenne Muscular Dystrophy and the Potential for Mitochondrial Therapeutics to Improve Treatment Response

  Cells · 2024-07-09 · 13 citations

  reviewOpen access

  Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations to the dystrophin gene, resulting in deficiency of dystrophin protein, loss of myofiber integrity in skeletal and cardiac muscle, and eventual cell death and replacement with fibrotic tissue. Pathologic cardiac manifestations occur in nearly every DMD patient, with the development of cardiomyopathy-the leading cause of death-inevitable by adulthood. As early cardiac abnormalities are difficult to detect, timely diagnosis and appropriate treatment modalities remain a challenge. There is no cure for DMD; treatment is aimed at delaying disease progression and alleviating symptoms. A comprehensive understanding of the pathophysiological mechanisms is crucial to the development of targeted treatments. While established hypotheses of underlying mechanisms include sarcolemmal weakening, upregulation of pro-inflammatory cytokines, and perturbed ion homeostasis, mitochondrial dysfunction is thought to be a potential key contributor. Several experimental compounds targeting the skeletal muscle pathology of DMD are in development, but the effects of such agents on cardiac function remain unclear. The synergistic integration of small molecule- and gene-target-based drugs with metabolic-, immune-, or ion balance-enhancing compounds into a combinatorial therapy offers potential for treating dystrophin deficiency-induced cardiomyopathy, making it crucial to understand the underlying mechanisms driving the disorder.

  PublisherOA PDFDOI

• Draft Guidance for Industry Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Related Dystrophinopathies – Developing Potential Treatments for the Entire Spectrum of Disease

  Journal of Neuromuscular Diseases · 2024-02-13 · 10 citations

  articleOpen accessSenior author

  Background: Duchenne muscular dystrophy (DMD) and related dystrophinopathies are neuromuscular conditions with great unmet medical needs that require the development of effective medical treatments. Objective: To aid sponsors in clinical development of drugs and therapeutic biological products for treating DMD across the disease spectrum by integrating advancements, patient registries, natural history studies, and more into a comprehensive guidance. Methods: This guidance emerged from collaboration between the FDA, the Duchenne community, and industry stakeholders. It entailed a structured approach, involving multiple committees and boards. From its inception in 2014, the guidance underwent revisions incorporating insights from gene therapy studies, cardiac function research, and innovative clinical trial designs. Results: The guidance provides a deeper understanding of DMD and its variants, focusing on patient engagement, diagnostic criteria, natural history, biomarkers, and clinical trials. It underscores patient-focused drug development, the significance of dystrophin as a biomarker, and the pivotal role of magnetic resonance imaging in assessing disease progression. Additionally, the guidance addresses cardiomyopathy's prominence in DMD and the burgeoning field of gene therapy. Conclusions: The updated guidance offers a comprehensive understanding of DMD, emphasizing patient-centric approaches, innovative trial designs, and the importance of biomarkers. The focus on cardiomyopathy and gene therapy signifies the evolving realm of DMD research. It acts as a crucial roadmap for sponsors, potentially leading to improved treatments for DMD.

  PublisherOA PDFDOI

• Potential limitations of microdystrophin gene therapy for Duchenne muscular dystrophy

  JCI Insight · 2024-05-07 · 32 citations

  articleOpen accessSenior author

  Clinical trials delivering high doses of adeno-associated viruses (AAVs) expressing truncated dystrophin molecules (microdystrophins) are underway for Duchenne muscular dystrophy (DMD). We examined the efficiency and efficacy of this strategy with 4 microdystrophin constructs (3 in clinical trials and a variant of the largest clinical construct), in a severe mouse model of DMD, using AAV doses comparable with those in clinical trials. We achieved high levels of microdystrophin expression in striated muscles with cardiac expression approximately 10-fold higher than that observed in skeletal muscle. Significant, albeit incomplete, correction of skeletal muscle disease was observed. Surprisingly, a lethal acceleration of cardiac disease occurred with 2 of the microdystrophins. The detrimental cardiac effect appears to be caused by variable competition (dependent on microdystrophin design and expression level) between microdystrophin and utrophin at the cardiomyocyte membrane. There may also be a contribution from an overloading of protein degradation. The significance of these observations for patients currently being treated with AAV-microdystrophin therapies is unclear since the levels of expression being achieved in the DMD hearts are unknown. However, these findings suggest that microdystrophin treatments need to avoid excessively high levels of expression in the heart and that cardiac function should be carefully monitored in these patients.

  PublisherOA PDFDOI

• Mitochondria in Duchenne Muscular Dystrophy-induced Cardiomyopathy: A Prospective Therapeutic Target to Improve Treatment Response

  Preprints.org · 2024-01-31 · 1 citations

  preprintOpen access

  Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations to the dystrophin gene - resulting in deficiency of dystrophin protein, loss of myofiber integrity in skeletal and cardiac muscle, and eventual cell death and replacement with fibrotic tissue. Pathologic cardiac manifestations occur in nearly every DMD patient, with development of cardiomyopathy - the leading cause of death - inevitable by adulthood. As early cardiac abnormalities are difficult to detect, timely diagnosis and appropriate treatment modalities remain a challenge. There is no cure for DMD – treatment is aimed at delaying disorder progression and alleviating symptoms. A comprehensive understanding of the pathophysiological mechanisms is crucial to development of targeted treatments. While established hypotheses of underlying mechanisms include sarcolemmal weakening, upregulation of pro-inflammatory cytokines, and perturbed ion homeostasis, mitochondrial stress has recently come into focus as a potential key contributor. Several experimental compounds targeting the skeletal muscle pathology of DMD are in development, but effects of such agents on cardiac function remain unclear. Synergistic integration of small molecule- and gene-target-based drugs with metabolic, immune, or ion balance-enhancing compounds into a combinatorial therapy offers potential for treating dystrophin deficiency-induced cardiomyopathy, making it crucial to understand the underlying mechanisms driving the disorder.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01AR047292

  NIH · $3.3M · 2006

• Structure and Function of Myosin VI

  NIH · $6.0M · 2002–2024

• NIH Grant P01AR043648

  NIH · $7.4M · 2001

• NIH Grant R01AR048868

  NIH · $1.8M · 2008

• NIH Grant R01AR035661

  NIH · $6.1M · 2011

Frequent coauthors

• Richard S. Finkel

  St. Jude Children's Research Hospital

  324 shared

• Barry J. Byrne

  University of Florida

  271 shared

• Krista Vandenborne

  University of Florida

  259 shared

• Craig M. McDonald

  UC Davis Health System

  225 shared

• Nathalie Goemans

  KU Leuven

  216 shared

• Haluk Topaloğlu

  213 shared

• Alberto Dubrovsky

  Favaloro University

  210 shared

• Glenn A. Walter

  University of Florida

  167 shared