Systemic and persistent muscle gene expression in rhesus monkeys with a liver de-targeted adeno-associated virus vector

Alice F Tarantal, Charles C Lee, Michele L. Martinez, Aravind Asokan, R. Jude Samulski

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

The liver is a major off-target organ in gene therapy approaches for cardiac and musculoskeletal disorders. Intravenous administration of most of the naturally occurring adeno-associated virus (AAV) strains invariably results in vector genome sequestration within the liver. In the current study, we compared the muscle tropism and transduction efficiency of a liver de-targeted AAV variant to AAV9 following systemic administration in newborn rhesus monkeys. In vivo bioluminescence imaging was performed to monitor transgene expression (firefly luciferase) post administration. Results indicated comparable and sustained levels of systemic firefly luciferase gene expression in skeletal muscle over a period of two years. Quantitation of vector biodistribution in harvested tissues post-administration revealed widespread recovery of vector genomes delivered by AAV9 but markedly decreased levels in major systemic organs from the AAV variant. These studies validate the translational potential and safety of liver de-targeted AAV strains for gene therapy of muscle-related diseases.

Original languageEnglish (US)
Pages (from-to)385-391
Number of pages7
JournalHuman Gene Therapy
Volume28
Issue number5
DOIs
StatePublished - May 1 2017

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Keywords

  • AAV9
  • chimeric AAV
  • liver de-targeting
  • Rhesus monkey

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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