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HSCI Retreat 2020 Abstract 6

Engineering Gene Therapies of Aging 

Michael Florea,*1,2,3 Luk H. Vandenberghe,1,4 and Amy Wagers2,5
1 Grousbeck Gene Therapy Center, Mass Eye and Ear, Harvard Medical School, Boston, MA, USA
2 Harvard Stem Cell Institute, Cambridge, MA, USA
3 Harvard Ph.D. Program in Biological and Biomedical Sciences, Division of Medical Sciences, Harvard University, Boston, MA, USA
4 Ocular Genomics Institute, Mass Eye and Ear, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, USA; The Broad Institute of Harvard and MIT, Cambridge, MA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
5 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA; Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA, USA; Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
* Presenting and corresponding author: mflorea@g.harvard.edu

Note: All authors contributed equally to this work

Submitted: Jun 11, 2020; Published online: Jul 27, 2020

 

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ABSTRACT

Over the past decades, research into aging has uncovered numerous genes whose modulation protects against age-related diseases and extends healthy lifespan. However, aging research remains slow and laborious due to the need to generate and age transgenic animals. Furthermore, most discoveries can not easily be translated to the clinic. These problems are major but potentially solvable through the use of gene delivery technologies, to study effects of genes directly in aged mice, and to translate findings directly to patients via gene therapies. However, no known gene delivery technology is able to reach sufficiently wide area of the body while allowing uniform and long-term expression to enable this. To solve these problems, we have developed DAEUS – a high-efficiency body-wide gene delivery system based on AAV. Unlike other gene delivery systems, DAEUS achieves uniform, long-term overexpression of transgenes across multiple major tissues in aged mice and allows expression to be tuned in different tissues. Using DAEUS, we achieve systemic overexpression of three geroprotective genes in aged mice. Furthermore, in a mouse model of Wolfram Syndrome II (a human and mouse progeria caused by loss of Cisd2), delivery of Cisd2 using DAEUS restores Cisd2 expression systemically to wild-type levels and protects against development of progeria in multiple cohorts. Surprisingly, DAEUS-Cisd2 gene therapy also precludes death and rejuvenates multiple tissues in a Wolfram Syndrome mouse with advanced disease. In summary, gene delivery using DAEUS holds promise to speed up aging research and streamline translation to the clinic.