September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Intraocular gene expression and functional safety evaluation following intravitreal delivery of cone specific GFP-expressing AAV vectors in nonhuman primates
Author Affiliations & Notes
  • Kathryn W Woodburn
    Avalanche Biotechnologies, Menlo Park, California, United States
  • Steven J Samuelsson
    Avalanche Biotechnologies, Menlo Park, California, United States
  • Sharmila Vijay
    Avalanche Biotechnologies, Menlo Park, California, United States
  • Thomas Walter Chalberg
    Avalanche Biotechnologies, Menlo Park, California, United States
  • Vernard Woodley
    RxGen Inc, Hamden, Connecticut, United States
  • Jordan Attwood
    RxGen Inc, Hamden, Connecticut, United States
  • Matthew S Lawrence
    RxGen Inc, Hamden, Connecticut, United States
  • Mehdi Gasmi
    Avalanche Biotechnologies, Menlo Park, California, United States
  • Footnotes
    Commercial Relationships   Kathryn Woodburn, Avalanche Biotechnologies (E); Steven Samuelsson, Avalanche Biotechnologies (E); Sharmila Vijay, None; Thomas Chalberg, Avalanche Biotechnologies (I), Avalanche Biotechnologies (C); Vernard Woodley, None; Jordan Attwood, None; Matthew Lawrence, None; Mehdi Gasmi, Avalanche Biotechnologies (E), Avalanche Biotechnologies (S)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      Kathryn W Woodburn, Steven J Samuelsson, Sharmila Vijay, Thomas Walter Chalberg, Vernard Woodley, Jordan Attwood, Matthew S Lawrence, Mehdi Gasmi; Intraocular gene expression and functional safety evaluation following intravitreal delivery of cone specific GFP-expressing AAV vectors in nonhuman primates. Invest. Ophthalmol. Vis. Sci. 201657(12):.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Gene therapy is an innovative therapeutic modality for the treatment of genetic cone photoreceptor diseases such as achromatopsia, blue cone monochromacy, Leber Congenital Amaurosis (LCA), and Stargardt macular dystrophy. To ensure successful therapeutic interventions, the vector needs to deliver the transgenes to cone photoreceptors in a safe and efficient manner. To this end, transduction efficiency, selectivity and long-term functional safety of photoreceptors from vectors containing cone-specific promoters were evaluated in nonhuman primates (NHPs).

Methods : NHPs received bilateral intravitreal (IVT, 50 mL) injections of AAV2-7m8.MNTC.GFP (n=2 animals) and AAV2-7m8.pR2.1.GFP (n=2) to yield a final dose of 5E11 vg per eye. Eyes were evaluated periodically by slit lamp exam, fundus imaging and full-field electroretinography (ERG). Following week 19 examinations, a NHP from each group was terminated and ocular tissues processed for immunofluorescence evaluation of cell-specific GFP expression. The remaining NHPs and a negative control NHP were assessed by slit-lamp, fundus imaging, OCT and multifocal ERG (mfERG) for up to 1 year to assess long-term safety and transgene expression.

Results : IVT administration of the vectors was well-tolerated as defined by clinical observations, clinical pathology, ophthalmic examinations and ERG. Both AAV2-7m8.MNTC.GFP and AAV2-7m8.pR2.1.GFP vectors resulted in robust GFP expression that are specific to L/M-opsin cone photoreceptors. Longitudinal evaluation showed no change in mfERG signal in GFP positive retina area suggesting no functional impairment associated with transgene expression.

Conclusions : IVT administration of AAV2-7m8 vectors with cone-specific promoters was well- tolerated with no functional impairment associated with transgene expression. AAV2-7m8.MNTC and AAV2-7m8.pR2.1 vectors yielded robust transgene expression in L/M cones and may therefore enable the development of therapeutic agents for certain cone-associated disorders.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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