A3 - AAV Vectors - Capsid Engineering
217: An AAV Capsid Programmed to Bind Human and Macaque Receptors Mediates Enhanced Gene Delivery to the CNS and Skeletal Muscle In Vivo
Type: Oral Abstract Session
Presentation Details
Session Title: Developing the Next Generation of Muscle-Targeted Gene Delivery Vehicles via AAV Capsid Engineering
Gene therapies for multisystem disorders require efficient gene delivery to many organs. However, natural adeno-associated viruses (AAVs) have limited extrahepatic tissue tropisms, and capsid engineering has largely focused on targeting specific organs such as the central nervous system (CNS), liver, retina, or muscle. To target multiple organs, we used our recently described receptor-targeting platform to target peptide-modified AAV9 capsids to a human receptor that is broadly expressed across diverse cell types, including the CNS and muscle. These receptor-targeting capsids exhibited enhanced binding and transduction of cells in transgenic mice that expressed the human receptor. Two of the capsids, BI-TBA1 and BI-TBA2, efficiently transduced the CNS to an extent comparable to AAV-PHP.eB, a mouse CNS-targeting capsid, when intravenously administered to mice overexpressing the human receptor in the brain microvasculature (Fig. 1A). This enhanced tropism was absent in transgenic mice treated with wild type AAV9 or in mice not expressing the human receptor. When BI-TBA1 was intravenously administered to transgenic mice ubiquitously expressing the human receptor, it achieved substantially enhanced CNS and muscle transduction compared to wild type mice or transgenic mice injected with AAV9 (Fig. 1B). BI-TBA1 was also dramatically de-targeted from the liver compared to AAV9, even in animals where the human receptor was ubiquitously expressed (Fig. 1B). Notably, we demonstrated that BI-TBA1 can more efficiently transduce cells that express human or macaque, but not mouse, orthologs of the targeted receptor (Fig. 1C). Our findings show that BI-TBA1 has the potential to be a cross-species receptor-targeting AAV that can mediate enhanced in vivo gene delivery in a receptor-dependent manner. Based on the broad expression of the receptor in humans, BI-TBA1 and similar capsids may mediate enhanced gene delivery to multiple organs after systemic administration.
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Figure 1. Human receptor-targeted AAVs efficiently transduced the brain and muscle but were de-targeted from the liver in transgenic mice. (A) Representative images show the luciferase signal in brain tissue from transgenic mice expressing the targeted human receptor in the brain vasculature injected with ssAAV-CAG-NLS-mScarlet-P2A-Luciferase-SV40pA packaged into human receptor-targeting capsids (BI-TBA1 or BI-TBA2) or AAV-PHP.eB. (B) Representative images show the luciferase signal in brain, muscle, and liver tissue from wild type mice or transgenic mice ubiquitously expressing the human receptor that were injected with BI-TBA1 or AAV9. (C) BI-TBA1 transduced CHO cells stably expressing the human or macaque orthologs of the targeted human receptor more efficiently than AAV9.
Jason Wu, Nuria R. Botticello-Romero
, Ken Y. Chan
, Chin-Yen Lin
, Qin Huang
, Thomas Beddow
, Pamela Brauer
, Yujia A. Chan
, Benjamin E. Deverman
Broad Institute of MIT and Harvard, Cambridge, MA"