Assessment of Tropism and Effectiveness of New Primate-Derived Hybrid Recombinant AAV Serotypes in the Mouse and Primate Retina

Peter Charbel Issa, Samantha R. de Silva, Daniel M. Lipinski, Mandeep Singh, Alexandre Mouravlev, Qisheng You, Alun R. Barnard, Mark W. Hankins, Matthew J. During, Robert E. MacLaren

Research output: Contribution to journalArticle

Abstract

Adeno-associated viral vectors (AAV) have been shown to be safe in the treatment of retinal degenerations in clinical trials. Thus, improving the efficiency of viral gene delivery has become increasingly important to increase the success of clinical trials. In this study, structural domains of different rAAV serotypes isolated from primate brain were combined to create novel hybrid recombinant AAV serotypes, rAAV2/rec2 and rAAV2/rec3. The efficacy of these novel serotypes were assessed in wild type mice and in two models of retinal degeneration (the Abca4-/- mouse which is a model for Stargardt disease and in the Pde6brd1/rd1 mouse) in vivo, in primate tissue ex-vivo, and in the human-derived SH-SY5Y cell line, using an identical AAV2 expression cassette. We show that these novel hybrid serotypes can transduce retinal tissue in mice and primates efficiently, although no more than AAV2/2 and rAAV2/5 serotypes. Transduction efficiency appeared lower in the Abca4-/- mouse compared to wild type with all vectors tested, suggesting an effect of specific retinal diseases on the efficiency of gene delivery. Shuffling of AAV capsid domains may have clinical applications for patients who develop T-cell immune responses following AAV gene therapy, as specific peptide antigen sequences could be substituted using this technique prior to vector re-treatments.

Original languageEnglish (US)
Article numbere60361
JournalPLoS One
Volume8
Issue number4
DOIs
StatePublished - Apr 9 2013
Externally publishedYes

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tropisms
Tropism
retina
Primates
Retina
serotypes
mice
Retinal Degeneration
Viral Genes
gene transfer
clinical trials
Clinical Trials
retinal diseases
Genes
Retinal Diseases
capsid
gene therapy
Tissue
disease models
Capsid

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Assessment of Tropism and Effectiveness of New Primate-Derived Hybrid Recombinant AAV Serotypes in the Mouse and Primate Retina. / Charbel Issa, Peter; de Silva, Samantha R.; Lipinski, Daniel M.; Singh, Mandeep; Mouravlev, Alexandre; You, Qisheng; Barnard, Alun R.; Hankins, Mark W.; During, Matthew J.; MacLaren, Robert E.

In: PLoS One, Vol. 8, No. 4, e60361, 09.04.2013.

Research output: Contribution to journalArticle

Charbel Issa, P, de Silva, SR, Lipinski, DM, Singh, M, Mouravlev, A, You, Q, Barnard, AR, Hankins, MW, During, MJ & MacLaren, RE 2013, 'Assessment of Tropism and Effectiveness of New Primate-Derived Hybrid Recombinant AAV Serotypes in the Mouse and Primate Retina', PLoS One, vol. 8, no. 4, e60361. https://doi.org/10.1371/journal.pone.0060361
Charbel Issa, Peter ; de Silva, Samantha R. ; Lipinski, Daniel M. ; Singh, Mandeep ; Mouravlev, Alexandre ; You, Qisheng ; Barnard, Alun R. ; Hankins, Mark W. ; During, Matthew J. ; MacLaren, Robert E. / Assessment of Tropism and Effectiveness of New Primate-Derived Hybrid Recombinant AAV Serotypes in the Mouse and Primate Retina. In: PLoS One. 2013 ; Vol. 8, No. 4.
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