Identification of a myotropic AAV by massively parallel in vivo evaluation of barcoded capsid variants

Jonas Weinmann, Sabrina Weis, Josefine Sippel, Warut Tulalamba, Anca Remes, Jihad El Andari, Anne-Kathrin Herrmann, Quang H. Pham, Christopher Borowski, Susanne Hille, Tanja Schönberger, Norbert Frey, Martin Lenter, Thierry VandenDriessche, Oliver J. Müller, Marinee K. Chuah, Thorsten Lamla and Dirk Grimm ()
Additional contact information
Jonas Weinmann: Heidelberg University Hospital, Dept. of Infectious Diseases/Virology, Cluster of Excellence CellNetworks
Sabrina Weis: Heidelberg University Hospital, Dept. of Infectious Diseases/Virology, Cluster of Excellence CellNetworks
Josefine Sippel: Heidelberg University Hospital, Dept. of Infectious Diseases/Virology, Cluster of Excellence CellNetworks
Warut Tulalamba: Vrije Universiteit Brussel, Department of Gene Therapy & Regenerative Medicine
Anca Remes: University Hospital Schleswig-Holstein, Campus Kiel, Innere Medizin III
Jihad El Andari: Heidelberg University Hospital, Dept. of Infectious Diseases/Virology, Cluster of Excellence CellNetworks
Anne-Kathrin Herrmann: Heidelberg University Hospital, Dept. of Infectious Diseases/Virology, Cluster of Excellence CellNetworks
Quang H. Pham: Vrije Universiteit Brussel, Department of Gene Therapy & Regenerative Medicine
Christopher Borowski: University Hospital Schleswig-Holstein, Campus Kiel, Innere Medizin III
Susanne Hille: University Hospital Schleswig-Holstein, Campus Kiel, Innere Medizin III
Tanja Schönberger: Boehringer Ingelheim Pharma GmbH & Co. KG, Drug Discovery Sciences
Norbert Frey: University Hospital Schleswig-Holstein, Campus Kiel, Innere Medizin III
Martin Lenter: Boehringer Ingelheim Pharma GmbH & Co. KG, Drug Discovery Sciences
Thierry VandenDriessche: Vrije Universiteit Brussel, Department of Gene Therapy & Regenerative Medicine
Oliver J. Müller: University Hospital Schleswig-Holstein, Campus Kiel, Innere Medizin III
Marinee K. Chuah: Vrije Universiteit Brussel, Department of Gene Therapy & Regenerative Medicine
Thorsten Lamla: Boehringer Ingelheim Pharma GmbH & Co. KG, Drug Discovery Sciences
Dirk Grimm: Heidelberg University Hospital, Dept. of Infectious Diseases/Virology, Cluster of Excellence CellNetworks

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Adeno-associated virus (AAV) forms the basis for several commercial gene therapy products and for countless gene transfer vectors derived from natural or synthetic viral isolates that are under intense preclinical evaluation. Here, we report a versatile pipeline that enables the direct side-by-side comparison of pre-selected AAV capsids in high-throughput and in the same animal, by combining DNA/RNA barcoding with multiplexed next-generation sequencing. For validation, we create three independent libraries comprising 183 different AAV variants including widely used benchmarks and screened them in all major tissues in adult mice. Thereby, we discover a peptide-displaying AAV9 mutant called AAVMYO that exhibits superior efficiency and specificity in the musculature including skeletal muscle, heart and diaphragm following peripheral delivery, and that holds great potential for muscle gene therapy. Our comprehensive methodology is compatible with any capsids, targets and species, and will thus facilitate and accelerate the stratification of optimal AAV vectors for human gene therapy.

Date: 2020
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DOI: 10.1038/s41467-020-19230-w

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