June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Gene Therapy for LHON Suppresses Neurodegeneration
Author Affiliations & Notes
  • John Guy
    Bascom Palmer Eye Institute, MIAMI, Florida, United States
  • Rajeshwari D Koilkonda
    Bascom Palmer Eye Institute, MIAMI, Florida, United States
  • William J Feuer
    Bascom Palmer Eye Institute, MIAMI, Florida, United States
  • Janet L Davis
    Bascom Palmer Eye Institute, MIAMI, Florida, United States
  • Vittorio Porciatti
    Bascom Palmer Eye Institute, MIAMI, Florida, United States
  • Phillip Gonzalez
    Bascom Palmer Eye Institute, MIAMI, Florida, United States
  • Huijan Yuan
    Bascom Palmer Eye Institute, MIAMI, Florida, United States
  • Byron L Lam
    Bascom Palmer Eye Institute, MIAMI, Florida, United States
  • Footnotes
    Commercial Relationships   John Guy, U.S. Patent No.: 8,278,428 (P), U.S. Patent No. 7,405, 284 (P); Rajeshwari Koilkonda, None; William Feuer, None; Janet Davis, None; Vittorio Porciatti, None; Phillip Gonzalez, None; Huijan Yuan, None; Byron Lam, None
  • Footnotes
    Support  Funding/Support: Supported by the National Eye Institute, National Institutes of Health, Department of Health and Human Services. Grant numbers: 1U10EY023558-01A1 (Guy), 1U10EY024247-01 (Feuer) and P30EY014801 (Porciatti).
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4492. doi:
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    • Get Citation

      John Guy, Rajeshwari D Koilkonda, William J Feuer, Janet L Davis, Vittorio Porciatti, Phillip Gonzalez, Huijan Yuan, Byron L Lam; Gene Therapy for LHON Suppresses Neurodegeneration. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4492.

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

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Purpose : Contradicting our initial preclinical studies, Oca-Cossio and coworkers showed that allotopic expression by delivering a mitochondrial targeting sequence appended to a nuclear-encoded ND4 gene killed cells suggesting it was harmful. Here we show that the retinal nerve fiber layer (RNFL) of patients with LHON caused by the G11778A is not damaged by allotopic ND4 gene therapy.

Methods : 14 patients with mutated G11778A mtDNA were injected with gene therapy vector AAV-P1ND4v2. As of 11/2016, they returned for 5 or more post-injection visits (3 to 18 months). Eyes with the worse visual acuity were treated except two with unilateral visual loss injected into the good eye before losing vision. Testing included ETDRS acuity, visual fields, OCT, PERG and neuro-ophthalmic examinations.Protocol post-injection OCTs were not collected between 2 and 12 months follow up.

Results : Nine treated patients had at least 12 months of follow-up. In eyes selected for treatment average temporal RNFL thickness at the baseline2 was 54 µm and at month12, it was 55 µm and average overall RNFL thickness was 71 µm at baseline2 and 58.8 µm at month12. Month 12 average acuity improvements with treatment relative to baseline2 were 0.24 logMAR. Fellow eyes had a 0.1 logMAR improvement with the temporal RNFL being 55.8 µm at baseline2 and dropping to 50.1 at month12. Average temporal RNFL was thicker in treated than in fellow eyes at month12,p = 0.013. Average overall RNFL thickness in fellow eyes was 82.2 µm at baseline2 and 59.6 µm at month12. Although average RNFL thickness of injected eyes at baseline2 was thinner than fellow eyes (p=0.043), no significant differences of average overall RNFL thickness were detected at month12. Eight patients were treated before 24 months of visual loss. Four patients improved by ~0.3 logMAR or more and four did not. The average temporal RNFL at the first baseline examination was 65 µm in four patients whose vision improved, but lower in the 4 patients who did not improve with an average of 51.75 µm (not statistically significant). On the day prior to injection, measurements were 55.2 µm in the eyes selected for injection vs 60 µm in fellow eyes. Twelve months after treatment, average temporal RNFL thickness was 56 µm in treated eyes relative to 48 µm in the fellow eyes, p = 0.026.

Conclusions : OCT suggests that allotopic ND4 does not damage the temporal RNFL subserving macular fibers targeted by an intravitreal AAV2 injection.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.


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