Associate Surgeon, Division of Plastic and Reconstructive Surgery, Brigham and Women’s Hospital
A closed-loop, durable adipocyte cell therapy to prevent heterotopic ossification
Heterotopic ossification (HO) is a morbid condition in which ectopic bone—the pathologic formation of bone where it does not belong—forms within a patient’s soft tissues. This condition, which often follows severe traumatic injury or orthopedic hip replacement surgery, presents a major barrier to rehabilitation. Patients develop chronic pain at the lesion site, open wounds, ill-fitting prostheses at amputation sites, and restricted range of motion due to joint contractures, limiting normal movements. Although surgical excision may be performed, recurrence is common due to the ensuing inflammatory response.
With his Stepping Strong Innovator Award funding, Shailesh Agarwal, MD, demonstrated that suppression of bone morphogenetic proteins (BMPs)—a unique group of proteins that have pivotal roles in the regulation of bone maintenance and repair—can reduce HO in a pre-clinical mouse model. In particular, he showed that a synthetic peptide that binds BMPs and prevents their activity reduces HO formation. However, clinical translation of this therapeutic agent is challenging due to imprecise dosing strategies, the risk of systemic adverse effects, and difficulty with local delivery for sustained periods of time. To that end, his laboratory has developed a cell therapy capable of producing and secreting the desired therapeutic peptide using a patient’s own adipocytes (fat cells).
For his Stepping Strong Breakthrough Award project, Dr. Agarwal will alter these adipocytes to enable permanent genetic modification and long-term production and secretion of the synthetic peptide. Furthermore, he will develop a strategy that allows the adipocytes to regulate production levels based on a patient’s physiologic need. He anticipates that all patients at risk for HO in sites of musculoskeletal trauma will receive this adipocyte-based therapy, which can turn on or off based on its detection of BMP in the local tissue.
Shailesh Agarwal, MD, received his undergraduate degree in Biochemistry and Mathematics from the University of Michigan (‘02-‘06). He received his medical degree from the University of Chicago Pritzker School of Medicine (‘06-‘10). He completed his residency training in plastic surgery and an NIH-funded post-doctoral research fellowship studying heterotopic ossification and the inflammatory response to trauma at the University of Michigan (‘10-‘18). He subsequently completed a fellowship in microsurgical reconstruction at the University of Chicago (‘18-‘19). Dr. Agarwal’s clinical interests include breast and lymphatic reconstruction, trunk and lower extremity reconstruction, burn reconstruction, and gender-affirming surgery. His laboratory research is centered on genetic and epigenetic re-programming to modify cell function for drug production and tissue regeneration. Dr. Agarwal’s laboratory is funded through the Stepping Strong Innovator Award, the Brigham and Women’s Hospital Department of Surgery, NIH, Harvard Stem Cell Institute, Plastic Surgery Foundation, and the International FOP Association.