September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Allotopic Gene Therapy for ND4 Leber Hereditary Optic Neuropathy with rAAV2/2-ND4 (GS010): From Pre-Clinical Development to Phase III
Author Affiliations & Notes
  • Scott Uretsky
    Ophthalmology, GenSight Biologics, Paris, France
  • Footnotes
    Commercial Relationships   Scott Uretsky, GenSight Biologics (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      Scott Uretsky; Allotopic Gene Therapy for ND4 Leber Hereditary Optic Neuropathy with rAAV2/2-ND4 (GS010): From Pre-Clinical Development to Phase III. Invest. Ophthalmol. Vis. Sci. 201657(12):.

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

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Presentation Description : Gene therapy has come of age. Treatment of hereditary causes of vision loss is now feasible. The anatomy and physiology of the eye is conducive for the delivery of gene therapy treatments to the neural cells of the retina. Allotopic expression utilizes the nuclear machinery for expression of mitochondrial encoded proteins. Adeno-associated viral vectors have been shown to be safe for use in the eye. Drug development in rare disease includes unique challenges requiring global strategic development and interaction with regulatory agencies is vital and should begin at early stages.
Leber Hereditary Optic Neuropathy (LHON) is a rare mitochondrial genetic disorder primarily affecting young males. Affected patients experience bilateral severe central vision loss. Currently no therapy is approved in the United States to prevent, halt or reverse vision loss due to LHON.
GS010 is a recombinant adeno-associated viral vector, serotype 2, carrying the wild-type ND4 gene (rAAV2/2-ND4) and is an experimental gene therapy for the treatment of LHON due to the G11778A ND4 mitochondrial mutation. GS010 has received orphan drug designation in EU & USA. GS010 contains a Mitochondrial Targeting Sequence (MTS) that allows localization of the wild-type protein to the mitochondrion, enabling restoration of mitochondrial function.
A Phase I/IIa safety and tolerability study of GS010 has completed recruitment. Systemic safety is excellent. No unexpected adverse events occurred. Local (ocular) tolerability is good with side effects that are responsive to and resolve with standard therapy. Trends of efficacy in improving vision have been detected in the safety study despite the relative chronicity of disease in a majority of the included patients.
Regulatory approval to initiate Phase III efficacy studies have been received. The RESCUE and REVERSE Phase III studies of GS010 will be conducted in the United States and some European Union countries. RESCUE and REVERSE are randomized, double-masked, sham-controlled trials and will collectively include patients up to one year after the onset of vision loss.

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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