Novel AAV variants with improved tropism for human Schwann cells

Matthieu Drouyer; Tak-Ho Chu; Elodie Labit; Florencia Haase; Renina Gale Navarro; Deborah Nazareth; Nicole Rosin; Jessica Merjane; Suzanne Scott; Marti Cabanes-Creus; Adrian Westhaus; Erhua Zhu; Rajiv Midha; Ian E Alexander; Jeff Biernaskie; Samantha L Ginn; Leszek Lisowski

doi:10.1016/j.omtm.2024.101234

Novel AAV variants with improved tropism for human Schwann cells

Mol Ther Methods Clin Dev. 2024 Mar 11;32(2):101234. doi: 10.1016/j.omtm.2024.101234. eCollection 2024 Jun 13.

Authors

Matthieu Drouyer¹, Tak-Ho Chu², Elodie Labit³, Florencia Haase¹, Renina Gale Navarro¹, Deborah Nazareth¹, Nicole Rosin³, Jessica Merjane¹, Suzanne Scott¹, Marti Cabanes-Creus¹, Adrian Westhaus¹, Erhua Zhu⁴, Rajiv Midha², Ian E Alexander^{4

5}, Jeff Biernaskie^{2

3

6}, Samantha L Ginn⁴, Leszek Lisowski^{1

7

8}

Affiliations

¹ Translational Vectorology Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia.
² Department of Clinical Neurosciences and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
³ Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada.
⁴ Gene Therapy Research Unit, Children's Medical Research Institute and Sydney Children's Hospitals Network, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia.
⁵ Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
⁶ Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
⁷ Australian Genome Therapeutics Centre, Children's Medical Research Institute and Sydney Children's Hospitals Network, Westmead, NSW, Australia.
⁸ Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Warsaw, Poland.

Abstract

Gene therapies and associated technologies are transforming biomedical research and enabling novel therapeutic options for patients living with debilitating and incurable genetic disorders. The vector system based on recombinant adeno-associated viral vectors (AAVs) has shown great promise in recent clinical trials for genetic diseases of multiple organs, such as the liver and the nervous system. Despite recent successes toward the development of novel bioengineered AAV variants for improved transduction of primary human tissues and cells, vectors that can efficiently transduce human Schwann cells (hSCs) have yet to be identified. Here, we report the application of the functional transduction-RNA selection method in primary hSCs for the development of AAV variants for specific and efficient transgene delivery to hSCs. The two identified capsid variants, Pep2hSC1 and Pep2hSC2, show conserved potency for delivery across various in vitro, in vivo, and ex vivo models of hSCs. These novel AAV capsids will serve as valuable research tools, forming the basis for therapeutic solutions for both SC-related disorders or peripheral nervous system injury.

Keywords: AAV; Schwann cells; adeno-associated vector; directed evolution; gene therapy; vector engineering.