Persistent expression of FLAG-tagged micro dystrophin in nonhuman primates following intramuscular and vascular delivery

Mol Ther. 2010 Jan;18(1):109-17. doi: 10.1038/mt.2009.254. Epub 2009 Nov 10.

Abstract

Animal models for Duchenne muscular dystrophy (DMD) have species limitations related to assessing function, immune response, and distribution of micro- or mini-dystrophins. Nonhuman primates (NHPs) provide the ideal model to optimize vector delivery across a vascular barrier and provide accurate dose estimates for widespread transduction. To address vascular delivery and dosing in rhesus macaques, we have generated a fusion construct that encodes an eight amino-acid FLAG epitope at the C-terminus of micro-dystrophin to facilitate translational studies targeting DMD. Intramuscular (IM) injection of AAV8.MCK.micro-dys.FLAG in the tibialis anterior (TA) of macaques demonstrated robust gene expression, with muscle transduction (50-79%) persisting for up to 5 months. Success by IM injection was followed by targeted vascular delivery studies using a fluoroscopy-guided catheter threaded through the femoral artery. Three months after gene transfer, >80% of muscle fibers showed gene expression in the targeted muscle. No cellular immune response to AAV8 capsid, micro-dystrophin, or the FLAG tag was detected by interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot (ELISpot) at any time point with either route. In summary, an epitope-tagged micro-dystrophin cassette enhances the ability to evaluate site-specific localization and distribution of gene expression in the NHP in preparation for vascular delivery clinical trials.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Dependovirus / genetics
  • Dystrophin / genetics
  • Dystrophin / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Genetic Therapy
  • Genetic Vectors / genetics
  • Humans
  • Injections, Intra-Arterial / methods*
  • Injections, Intramuscular / methods*
  • Macaca mulatta
  • Mice
  • Mice, Inbred C57BL
  • Muscular Dystrophy, Animal / metabolism*
  • Muscular Dystrophy, Animal / therapy*
  • Oligopeptides
  • Peptides / genetics
  • Peptides / metabolism*

Substances

  • Dystrophin
  • Oligopeptides
  • Peptides
  • FLAG peptide