Engineering whole-body gene therapies for aging

Abstract

In the past 30 years, significant progress has been made in understanding the biological and genetic processes of aging, with over 300 genes now known to modulate lifespan. Many of these genes are expressed ubiquitously across the body, are tightly regulated and not easily druggable. Therefore, targeting these genes for research or therapeutic purposes requires controlled genetic modification across many tissues of the body. While multiple gene delivery vectors have been developed in the past, no existing vector system enables the broad and controlled gene delivery required to safely and effectively overexpress or downregulate these genes across the body. In this work, we developed a new gene delivery system based on adeno-associated viruses (AAVs) that enables controlled and broad gene transfer to most tissues of the body. We also developed an improved AAV purification method to streamline the production of this system. We then used this system to develop a gene therapy for the progeria Wolfram Syndrome II (caused by loss of Cisd2 gene) and found that body-wide restoration of Cisd2 expression conferred high therapeutic benefit at every treatment age. Finally, we used these methods to study the effect of over-expression of three putative pro-longevity genes (Atg5, Cisd2 and PTEN) in aged mice, and found that each gene conferred a distinct effect on longevity and health. While many technical challenges remain, this work lays the groundwork for development of whole-body gene therapies for aging.