September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Towards a clinical trial to treat GUCY2D Leber congenital amaurosis (LCA1)
Author Affiliations & Notes
  • Shannon Elizabeth Boye
    Department of Ophthalmology, University of Florida, Gainesville, Florida, United States
  • Sanford L. Boye
    Department of Ophthalmology, University of Florida, Gainesville, Florida, United States
  • William Hauswirth
    Department of Ophthalmology, University of Florida, Gainesville, Florida, United States
  • James Peterson
    Department of Ophthalmology, University of Florida, Gainesville, Florida, United States
  • Seok-Hong Min
    Department of Ophthalmology, University of Florida, Gainesville, Florida, United States
  • Qing Ruan
    Department of Ophthalmology, University of Florida, Gainesville, Florida, United States
  • Catherine O'Riordan
    Genzyme, Framingham, Massachusetts, United States
  • Michael Lukason
    Genzyme, Framingham, Massachusetts, United States
  • Rena Baek
    Genzyme, Framingham, Massachusetts, United States
  • Abraham Scaria
    Genzyme, Framingham, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Shannon Boye, Genzyme (F), University of Florida (P); Sanford Boye, University of Florida (P); William Hauswirth, University of Florida (P); James Peterson, None; Seok-Hong Min, None; Qing Ruan, None; Catherine O'Riordan, Genzyme (E); Michael Lukason, Genzyme (E); Rena Baek, Genzyme (E); Abraham Scaria, Genzyme (E)
  • Footnotes
    Support  Genzyme/Sanofi, Foundation Fighting Blindness
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      Shannon Elizabeth Boye, Sanford L. Boye, William Hauswirth, James Peterson, Seok-Hong Min, Qing Ruan, Catherine O'Riordan, Michael Lukason, Rena Baek, Abraham Scaria; Towards a clinical trial to treat GUCY2D Leber congenital amaurosis (LCA1). Invest. Ophthalmol. Vis. Sci. 201657(12):.

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      © 2017 Association for Research in Vision and Ophthalmology.

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Abstract

Purpose : Mutations in GUCY2D are a leading cause of the most severe form of early-onset retinal dystrophy, Leber congenital amaurosis (LCA1). GUCY2D encodes retinal guanylate cyclase-1 (retGC1), a protein expressed in photoreceptor outer segments that plays a role in the recovery phase of phototransduction. Proof of concept for gene replacement has been established in mouse models of LCA1 using AAV vectors. Despite a high degree of visual disturbance stemming predominantly from severe cone dysfunction, LCA1 patients largely retain normal photoreceptor laminar architecture. Together, these results suggest LCA1 is a worthy target for gene replacement therapy and prompted initiation of additional IND-enabling preclinical studies. First we asked whether the AAV capsid of our choice, containing a human photoreceptor-specific promoter, was capable of driving murine Gucy2e or human GUCY2D in photoreceptors of GCDKO mice and restoring retinal function to this mouse model. Second, using this AAV vector/promoter combination, we evaluated transduction efficiency using GFP as the transgene in photoreceptors of the non-human primate (NHP).

Methods : All AAV vectors were titered and characterized by analytical ultracentrifugation prior to injection. GCDKO mice were subretinally injected between P21-P35 in one eye with either AAV-Gucy2e or AAV-GUCY2D at varying doses. Photopic and scoptopic electroretinogram was performed at 1, 2 or 3 months post-injection. Cynomolgous NHPs were subretinally injected with AAV-GFP at varying doses. Spectralis imaging and immunohistochemistry of retinal sections were used to document GFP expression in life and post mortem, respectively.

Results : Both AAV-Gucy2e and AAV-GUCY2D restored significant cone and rod function to retinas of GCDKO mice. In NHP, transduction of ~75% of photoreceptors was achieved following subretinal injection of AAV-GFP vector.

Conclusions : These results expand on our knowledge of GUCY2D gene replacement in mouse models of LCA1 and transduction efficiency for AAV delivered transgene under the control of a photoreceptor-specific promoter in NHP. These studies also confirm biological potency of the clinical candidate vector for human clinical trials.

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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