A7 - AAV Vectors - Immune Modulation
1551: Engineering Human CNS Receptor-Targeted Capsids for Improved Antibody Evasion
Type: Poster Session
Poster Board Number: 1551
Presentation Details
Session Title: Friday Posters: AAV Vectors - Immune Modulation
Adeno-associated virus (AAV) capsids have been successfully engineered via surface loop modifications to target different organs such as the central nervous system (CNS), muscle, retina, and liver following systemic delivery. However, the population of patients that can benefit from AAV-based gene therapies is limited by pre-existing neutralizing antibodies (NAbs) to AAV capsids. NAbs not only activate the complement system but can hinder AAV transduction and thus the gene therapy’s efficacy. Therefore there is a need for capsids with reduced sensitivity to antibodies that are compatible with surface loop modifications that confer enhanced in vivo tropisms. In this work, we aimed to reduce the NAb sensitivity of novel capsids developed by our group that cross the blood-brain barrier (BBB) via interactions with human CNS receptors such as human Transferrin Receptor (TfR1). Through sequential steps, we generated a library of TfR1-targeting capsids diversified at five distributed surface locations. We then subjected the library to high-throughput neutralization assays, in the presence of increasing concentrations of human intravenous immunoglobulin (IVIG), with transduction of human brain endothelial cells as a readout. Based on library screening data, we identified several capsid variants that (1) exhibited decreased neutralization by human IVIG, (2) retained their ability to transduce human cells via interactions with TfR1, and (3) possessed production fitness scores that were comparable to AAV9. We are now evaluating these capsids individually for their manufacturability, TfR1-dependent transduction, BBB crossing in vitro and in vivo, and maintained transduction efficiency in the presence of human sera. Ultimately, this work should yield novel antibody-evading capsids that can be used in combination with other capsid modifications that confer enhanced in vivo functionalities.
Simon Pacouret, William Donahoe, John W. Harvey, Pamela P. Brauer, Qingxia Zheng, Chin-Yen Lin, Binhui Zhao, Gabrielle Clouse, Qin Huang, Jencilin Johnson, Casey Keyes, Catherine P. Pirtle, Jarrett Rios, Albert T. Chen, Fatma Elzahraa Eid, Andrew J. Barry, Yujia A. Chan, Ken Y. Chan, Benjamin E. Deverman
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA"
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