Targeted, safe, and efficient gene delivery to human hematopoietic stem and progenitor cells in vivo using the engineered AVID adenovirus vector platform.

Targeted delivery and cell-type-specific expression of gene-editing proteins in various cell types in vivo represent major challenges for all viral and non-viral delivery platforms developed to date. Here, we describe the development and analysis of artificial vectors for intravascular delivery (AVIDs), an engineered adenovirus-based gene delivery platform that allows for highly targeted, safe, and efficient gene delivery to human hematopoietic stem and progenitor cells (HSPCs) in vivo after intravenous vector administration. Due to a set of refined structural modifications, intravenous administration of AVIDs did not trigger cytokine storm, hepatotoxicity, or thrombocytopenia. Single intravenous administration of AVIDs to humanized mice, grafted with human CD34 ⁺ cells, led to up to 20% transduction of CD34 ⁺ CD38 ^- CD45RA ^- HSPC subsets in the bone marrow. Importantly, targeted in vivo transduction of CD34 ⁺ CD38 ^- CD45RA ^- CD90 ^- CD49f ⁺ subsets, highly enriched for human hematopoietic stem cells (HSCs), reached up to 19%, which represented a 1,900-fold selectivity in gene delivery to HSC-enriched over lineage-committed CD34-negative cell populations. Because the AVID platform allows for regulated, cell-type-specific expression of gene-editing technologies as well as expression of immunomodulatory proteins to ensure persistence of corrected HSCs in vivo, the HSC-targeted AVID platform may enable development of curative therapies through in vivo gene correction in human HSCs after a single intravenous administration.
Competing Interests: Declaration of interests The AVID vector platform was co-developed by Emory University and AdCure Bio and described in the provisional patent application 63/497,106, which was licensed to AdCure Bio. D.M.S. and N.C.D.P. are listed as co-inventors on provisional patent application 63/497,106 and issued US patents #10,376,549 and #9,982,276 and European patent #3247807. D.M.S. and N.C.D.P. are co-founders and shareholders of AdCure Bio, which develops adenovirus technologies for therapeutic use.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)