AAV-mediated Gene Therapy and High-Dose, Peri-Gene Therapy Steroid Prescription: Considerations for Monitoring and Management of Adrenal Insufficiency

Topic:

Clinical Management

Poster Number: P211

Author(s):

Diana Bharucha-Goebel, MD, Children's National Hospital and NINDS/NIH, Jaclyn Tamaroff, MD, MSCI, Vanderbilt University, Nadia Merchant, MD, UT Southwestern Medical Center, Cuixia Tian, MD, Cincinnati Children's Hospital Medical Center, Anne Marie Sbrocchi, MD, FRCPC, Department of Pediatrics and Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada, David Weber, MD, MSCE, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvani, Leanne Ward, MD, FRCPC, Children’s Hospital of Eastern Ontario

Adeno-associated virus (AAV) mediated gene transfer (GT) is a rapidly emerging therapeutic approach for targeted gene delivery for the amelioration of inherited diseases, with 8 approved in-vivo AAV gene replacement therapies across the United States, Canada, and European Health Agencies. AAV GT has been associated with side effects including transaminitis, thrombocytopenia, and troponin elevation, largely driven by anti-capsid or anti-transgene innate or adaptive immune responses.
To mitigate these adverse responses, concurrent immune modulation, typically with corticosteroids, is widely utilized for AAV GT in clinical trials and regulatory-approved therapies. Peri-gene transfer prednisone doses typically range from 1-2 mg/kg/day with durations of 7-133 days. Prolonged high dose corticosteroid use poses risks for side effects including weight gain, dysglycemia, mood disturbance, and osteoporosis, even when used for relatively finite periods such as the peri-gene therapy period. Importantly, the doses of corticosteroids used for peri-gene therapy management are associated with adrenal insufficiency due to suppression of the hypothalamic-pituitary-adrenal axis when continued for greater than 14 days. Adrenal insufficiency can cause a life-threatening adrenal crisis during periods of increased physiologic stress if “stress steroid doses” are not administered.
We have developed expert- and evidence-based multicenter interdisciplinary clinical care considerations for peri-gene transfer steroid management including: 1) Pre-steroid counseling about adrenal insufficiency and development of ‘sick plans’ for stress dosing; 2) A steroid tapering strategy to reduce the risk of symptomatic adrenal insufficiency while discontinuing or reducing steroid doses; and 3) Testing for recovery of the adrenal axis once steroids are discontinued. With the expansion of AAV GT for various neuromuscular disorders, it is imperative that clinicians understand the potential risks of peri-gene therapy steroid use and counsel families accordingly to minimize complications of adrenal insufficiency including adrenal crisis during and after gene transfer.