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A - Viral Vector Development -> AAV Vectors – Clinical/Non-Human Primate Studies

1481: High Throughput Discovery of Optimized Human Genomic Regulatory Elements That Selectively Decrease Off-Target Expression in Dorsal Root Ganglion and Liver in Mice and Non-Human Primates

Type: Poster Session

Poster Board Number: 1481
Presentation Details
Session Title: Friday Poster Session
Start Time: 5/19/2023 12:00
End Time: 5/19/2023 14:00

Adeno-associated virus (AAV)-mediated gene therapy (GT) has demonstrated transformative potential in treating genetic disorders, but off-target transgene expression remains an important safety issue. Encoded’s next generation sequencing (NGS)-based functional screening and model-based sequence enrichment platform efficiently identifies regulatory elements (REs) from human genomic sequences to modulate transgene expression. Previously, we identified and validated 3’UTR elements that selectively reduced off-target liver expression to undetectable levels while maintaining central nervous system (CNS) expression in mice. We also applied our high-throughput screening method to achieve a specific transgene expression profile: selective de-targeting of dorsal root ganglion (DRG) expression, while maintaining CNS expression. We simultaneously tested >10,000 genomic REs and identified and validated top 3’UTR genomic sequences that achieved robust DRG de-targeting and maintained CNS expression in mice. Here, we used this large-scale functional data for predictive modeling to identify sequence features that contributed to DRG de-targeting and designed second-generation libraries (GEN2) to further improve performance. Using these GEN2 AAV libraries, we developed RE sequences that simultaneously de-target expression in DRG and liver, discovered novel candidate DRG de-targeting sequences, and achieved further improvement in de-targeting efficiency. Finally, multiplex GEN2 library screening in non-human primates (NHPs) showed conserved function across species for top de-targeting REs. In conclusion, we applied high-throughput functional and computational screening to efficiently discover, optimize, and validate multiple de-targeting REs to drive potency and specificity in cell types and organ systems, including DRG neurons and liver. These human genomic REs have the potential to improve gene therapy constructs and may enable optimized safety and efficacy profiles for patients through increased flexibility in GT modality, dose, and route of administration.

Anne Tanenhaus1, Steven A. Tan1, Serena X. Liu1, Puja Dhanota1, Ben Zhao1, Hana Lejmi1, John McLaughlin1, Gregory M. Lucey1, Camille G. Artur1, Ming Chen1, Dixon Hoffelt1, James S. Griffin1, Mitchell Lopez1, Tulasi I. Solanki1, Andrew Kim2, Raghu Hosur1, Martin Moorhead1

1Encoded Therapeutics, South San Francisco, CA,2Encoded Therapeutics (at the time study was conducted), South San Francisco, CA
  A. Tanenhaus: 1; Commercial Interest i.e. Company X; Encoded Therapeutics. 1; What was received? i.e. Honorarium; Employee Salary. 1; For what role? i.e. Speaker; Employee Salary.

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