Senior Principal Scientist Pfizer Cambridge, Massachusetts
Adeno-associated viruses (AAVs) are rapidly emerging as the leading platform for in vivo delivery of gene therapies for chronic and debilitating monogenetic diseases. Characterization of the in vivo biodistribution and tissue transduction profile has become a limiting factor for the development of AAV based gene therapies since transduction can vary widely depending on AAV serotype/construct, species, target tissue, and study design. To address this key gap, we have used current knowledge of the biology of AAV gene therapy pharmacology analysis of compiled pre-clinical and clinical data on AAV-based gene therapy treatments to develop a Quantitative Systems Pharmacology (QSP) species translation framework for AAV Gene Therapies. Using, this approach we were able to robustly characterize the serotype, construct, target tissue, and species dependencies of AAV treatment response as measured in terms of key endpoints like vector genome transduction, tissue coverage %, transcription/translation, and functional protein expression. These results guided the construction of a minimal physiologically-based pharmacokinetic model that can explain the observed kinetics, serotype, and dose-dependence of AAV tissue biodistribution as well as transcription/translation of the target gene across multiple serotypes and species. Here we show how this QSP modeling platform can be used to design key aspects of AAV biodistribution/pharmacology studies including species, dose, and study duration even for novel AAV therapies where minimal information about the construct is available by leveraging key insights from historical data and physiological constraints. We further show how this platform can serve as an effective screening tool for capsids by providing species-specific quantitative predictions of tissue-transduction efficiency and variability that can serve as benchmarks for novel capsid performance. We show how this model can serve as potential platform for projecting biodistribution/pharmacology thereby reducing the reliance on preclinical biodistribution studies and optimizing AAV dose-translation between species and clinical study designs.
Learning Objectives:
Appreciate the key challenges, mitigation strategies, and translational considerations for prediction of FIH doses for gene therapy
Understand the value of QSP M&S approach in discovery and development of novel AAV gene therapies
Understand how QSP M&S approaches can be applied for pre-clinical to clinical dose-translation of novel AAV gene therapies
