Macrophage Depletion via Clodronate Pretreatment Reduces Transgene Expression from AAV Vectors In Vivo

Adeno-associated virus is a popular gene delivery vehicle for gene therapy studies. A potential roadblock to widespread clinical adoption is the high vector doses required for efficient transduction in vivo, and the potential for subsequent immune responses that may limit prolonged transgene express...

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Bibliographic Details
Published in:	Viruses 2021-10, Vol.13 (10), p.2002
Main Authors:	Yu, Darrick L, Chow, Natalie S M, Bridle, Byram W, Wootton, Sarah K
Format:	Article
Language:	eng
Subjects:	adeno-associated virus Adenoviridae - genetics Adenoviruses Animals Bisphosphonates Chemokines clodronate Clodronic acid Clodronic Acid - metabolism Clodronic Acid - pharmacology Cloning Dependovirus - genetics Expression vectors Gene therapy Gene transfer Gene Transfer Techniques Genetic Therapy - methods Genetic Vectors - genetics HEK293 Cells Humans Immune response Immune system Liposomes Liver Liver - metabolism Localization Lymph nodes macrophage Macrophages Macrophages - drug effects Macrophages - metabolism Male Medulla oblongata Mice Mice, Inbred C57BL Mice, Transgenic Phosphatase Pulp Red pulp Regulatory approval Spleen Spleen - metabolism Standard deviation Streptococcus infections Success Transgenes Transgenes - genetics Vectors (Biology) Viruses
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Summary:	Adeno-associated virus is a popular gene delivery vehicle for gene therapy studies. A potential roadblock to widespread clinical adoption is the high vector doses required for efficient transduction in vivo, and the potential for subsequent immune responses that may limit prolonged transgene expression. We hypothesized that the depletion of macrophages via systemic delivery of liposome-encapsulated clodronate would improve transgene expression if given prior to systemic AAV vector administration, as has been shown to be the case with adenoviral vectors. Contrary to our expectations, clodronate liposome pretreatment resulted in significantly reduced transgene expression in the liver and heart, but permitted moderate transduction of the white pulp of the spleen. There was a remarkable localization of transgene expression from the red pulp to the center of the white pulp in clodronate-treated mice compared to untreated mice. Similarly, a greater proportion of transgene expression could be observed in the medulla located in the center of the lymph node in mice treated with clodronate-containing liposomes as compared to untreated mice where transgene expression was localized primarily to the cortex. These results underscore the highly significant role that the immune system plays in influencing the distribution and relative numbers of transduced cells in the context of AAV-mediated gene delivery.
ISSN:	1999-4915 1999-4915