Multi-organ gene therapy efficiently rescues disease in a mouse model of Wolfram Syndrome II

Michael Florea, Medha K C, David J. Anderson, Luk H. Vandenberghe, Amy J. Wagers

Progeroid syndromes result from single gene mutations that cause accelerated onset of aging-like features in one or more of the body’s organ systems. One such syndrome is Wolfram Syndrome II – a rare human and mouse progeria characterized by sensorineural, metabolic and hormonal defects and caused by genetic disruption of the Cisd2 gene. Cisd2 is of considerable interest in the geroscience community, because its loss or reduction of expression leads to premature aging and has been associated with several prevalent human diseases, while its overexpression protects against age-related diseases and increases lifespan in mice. Gene therapies hold promise for treating progerias, but their application has been hampered by the fact that there are no known gene delivery vectors that have sufficient breadth of tropism and uniformity of expression across tissues to effectively complement disease-causing gene mutations in all of the different cell types that can be affected. Here, we have engineered an adeno-associated virus (AAV) based system that enables efficient and tunable gene expression across multiple organs simultaneously. This system (called DAEUS) combines multiple engineered AAV serotypes and gene regulatory elements with model guided dosing. In recently concluded studies, we find that in Wolfram Syndrome II mice, DAEUS-Cisd2 gene therapy restores near wild-type Cisd2 expression across the major tissues of the body and protects against development of disease in all cohorts tested. Specifically, in mice treated as pups or young adults, DAEUS-Cisd2 therapy prevents the development of frailty, loss of activity, loss of vision and extends post-treatment lifespan by 75% to 140%. Surprisingly, in mice with advanced progeria, DAEUS-Cisd2 gene therapy reverts some disease pathology in multiple tissues, in addition to extending lifespan and protecting against further progression of the disease. These data indicate that DAEUS holds promise as a platform for treatment of multi-organ genetic diseases and that restoration of Cisd2 expression may provide therapeutic benefit to Wolfram Syndrome II patients at any treatment age.

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