AAV-8 and AAV-9 Vectors Cooperate with Serum Proteins Differently Than AAV-1 and AAV-6

Molecular Therapy. Methods & Clinical Development
Jérôme DenardFedor Svinartchouk

Abstract

Under intravenous delivery, recombinant adeno-associated vectors (rAAVs) interact with blood-borne components in ways that can critically alter their therapeutic efficiencies. We have previously shown that interaction with human galectin 3 binding protein dramatically reduces rAAV-6 efficacy, whereas binding of mouse C-reactive protein improves rAAV-1 and rAAV-6 transduction effectiveness. Herein we have assessed, through qualitative and quantitative studies, the proteins from mouse and human sera that bind with rAAV-8 and rAAV-9, two vectors that are being considered for clinical trials for patients with neuromuscular disorders. We show that, in contrast to rAAV-1 and rAAV-6, there was a substantial similarity in protein binding patterns between mouse and human sera for these vector serotypes. To establish an in vivo role for the vector binding of these sera proteins, we chose to study platelet factor 4 (PF4), which interacts with both vectors in both mouse and human sera. Experiments using PF4-knockout mice showed that a complete lack of PF4 did not alter skeletal muscle transduction for these vectors, whereas heart transduction was moderately improved. Our results strongly support our position that the impact of serum protei...Continue Reading

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Citations

Feb 3, 2019·Nature Reviews. Drug Discovery·Dan WangGuangping Gao
Feb 12, 2020·Nature Reviews. Genetics·Chengwen Li, R Jude Samulski
Jun 17, 2020·Gene Therapy·Sławomir AndrzejewskiChristopher J Layton
Oct 20, 2020·Trends in Molecular Medicine·Bijay P DhungelJohn E J Rasko

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electrophoresis

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Ingenuity Pathway

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