Beverly L. Davidson, Ph.D.

Katherine A. High Chair in Cell and Gene Therapy
Director, Raymond G. Perelman Center for Cellular and Molecular Therapeutics 
Chief Scientific Strategy Officer
Children’s Hospital of Philadelphia 
Professor of Pathology and Laboratory Medicine
Perelman School of Medicine at the University of Pennsylvania

“Engineering newer generations of AAVs for brain delivery and therapy”

Abstract:
Management of neurodegenerative diseases can benefit from brain delivery of therapeutically relevant proteins including recombinant antibodies and their derivatives, growth factors, or pro-enzymes delivered either indirectly from intravenous injection or directly by infusion into the cerebral spinal fluid (CSF). These include adult and childhood onset disorders such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and lysosomal storage disorders (LSDs). Gene therapy provides an alternative method for sustained expression of therapeutic proteins. Indeed, recent work shows that prolonged expression of recombinant proteins after adeno-associated virus (AAV) delivery to long-lived, ventricle-lining ependymal cells can profoundly impact disease phenotypes in AD mice and LSD dogs. To advance this work to human application, we embarked on a capsid discovery project using a large library of AAV variants screened through relevant models, with the goal of identifying a capsid with improved therapeutic utility.  Through this work, we discovered an AAV capsid with unprecedented potency in transducing ependymal cells and cerebral neurons in NHPs. The identified capsid’s potency was conserved in three species of NHP, two mouse strains, and human neurons derived from induced pluripotent stem cells (iPSCs). Importantly, this capsid provided for robust and therapeutically relevant protein expression in NHPs and mice after CSF delivery at doses well below those currently used in the clinic, showing efficacy delivering two different types of payloads for treatment of recessive lysosomal storage diseases or a genetic form of ALS.