June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Leber Hereditary Optic Neuropathy Gene Therapy: Longitudinal Relationships Among Visual Function and Anatomical Measures
Author Affiliations & Notes
  • Byron L Lam
    University of Miami Health System Bascom Palmer Eye Institute, Miami, Florida, United States
  • Vittorio Porciatti
    University of Miami Health System Bascom Palmer Eye Institute, Miami, Florida, United States
  • Janet L Davis
    University of Miami Health System Bascom Palmer Eye Institute, Miami, Florida, United States
  • D. Diane Zheng
    University of Miami Health System Bascom Palmer Eye Institute, Miami, Florida, United States
  • Elizabeth Vanner
    University of Miami Health System Bascom Palmer Eye Institute, Miami, Florida, United States
  • Eleonore J. Savatovsky
    University of Miami Health System Bascom Palmer Eye Institute, Miami, Florida, United States
  • Diego Alba
    University of Miami Health System Bascom Palmer Eye Institute, Miami, Florida, United States
  • Footnotes
    Commercial Relationships   Byron Lam Biogen, Code C (Consultant/Contractor), Editas, Code C (Consultant/Contractor), Janssen, Code C (Consultant/Contractor), ProQR, Code C (Consultant/Contractor), AGTC, Code F (Financial Support), Biogen, Code F (Financial Support), Editas, Code F (Financial Support), Endogena, Code F (Financial Support); Vittorio Porciatti None; Janet Davis None; D. Zheng None; Elizabeth Vanner None; Eleonore Savatovsky None; Diego Alba None
  • Footnotes
    Support  NH Grant 1U10EY023558-01A1, UG1EY023558-01A1, 1U10EY024247-01
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1957. doi:
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      Byron L Lam, Vittorio Porciatti, Janet L Davis, D. Diane Zheng, Elizabeth Vanner, Eleonore J. Savatovsky, Diego Alba; Leber Hereditary Optic Neuropathy Gene Therapy: Longitudinal Relationships Among Visual Function and Anatomical Measures. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1957.

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

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Abstract

Purpose : Leber hereditary optic neuropathy (LHON) is a mitochondrial DNA disease causing severe visual loss and no approved treatment is available. We report longitudinal relationships among visual function and anatomical measures over the 36-month study period from a phase 1 LHON G11778A gene therapy clinical trial (NCT02161380) that utilizes AAV2(Y444,500,730F)-P1ND4v2.

Methods : The phase 1 open-label clinical trial was designed as a 3+3 dose escalation of unilateral intravitreal gene therapy injection for each group of G11778A LHON patients with visual loss. Setting: single institution. Participants: 28 adult patients (5 females) with G11778A LHON and chronic bilateral visual loss >12 months (Group 1, n=11), acute bilateral visual loss <12 months (Group 2, n=9), or unilateral visual loss (Group 3, n=8). Intervention: unilateral intravitreal AAV2(Y444,500,730F)-P1ND4v2 injection with low (5.0 x 108 vg), medium (2.5 x 109 vg), high (2.4 x 109 vg), or higher (1.0 x 1010 vg) dose to worse eye (20/200 or worse) for Groups 1 and 2 and better eye (20/40 or better) for Group 3. Outcome Measures: visual field mean deviation (VF MD), steady-state pattern electroretinogram (SS-PERG), optical coherence tomography retinal nerve fiber layer (RNFL) thickness and ganglion cell + inner plexiform layer (GCIPL) thickness, and National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). Mean follow-up was 33.6 months (range 18-36). Longitudinal analysis was performed with generalized estimating equation analysis.

Results : Baseline SS-PERG amplitude was much reduced in both eyes of all groups including asymptomatic eyes of Group 3 and showed no appreciable changes irrespective of disease stage and treatment. Significant and progressive GCIPL and RNFL thinning occurred in all eyes; BCVA and VF MD fluctuated in treated and fellow eyes with some eyes having modest improvement that may be related to LHON natural history or gene therapy.

Conclusions : Asymptomatic eyes in LHON patients with unilateral visual loss may be beyond the window of opportunity for effective neuroprotection given reduced GCL and SS-PERG. Randomization of patients to a concurrent untreated control group would help to assess treatment effect by accounting for confounders of subclinical disease and variable natural history.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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