July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
AAV2-hCHM Subretinal Delivery to the Macula in Choroideremia: 2 year Results of an Ongoing Phase I/II Gene Therapy Trial
Author Affiliations & Notes
  • Tomas S Aleman
    Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
    Center for Advanced Retinal and Ocular Therapeutics, Department of Ophthalmology, University of Pennsylvania, Pennsylvania, United States
  • Rachel M Huckfeldt
    Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, United States
  • Leona Serrano
    Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
    Center for Advanced Retinal and Ocular Therapeutics, Department of Ophthalmology, University of Pennsylvania, Pennsylvania, United States
  • Grace Vergilio
    Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Denise J Pearson
    Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
    Center for Advanced Retinal and Ocular Therapeutics, Department of Ophthalmology, University of Pennsylvania, Pennsylvania, United States
  • Katherine E. Uyhazi
    Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Sarah McCague
    The Children’s Hospital of Philadelphia, Pennsylvania, United States
  • Kathleen Marshall
    The Children’s Hospital of Philadelphia, Pennsylvania, United States
  • Daniel C Chung
    Spark Therapeutics, Philadelphia, Pennsylvania, United States
  • Emily Liu
    Spark Therapeutics, Philadelphia, Pennsylvania, United States
  • Eric A Pierce
    Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, United States
  • Jessica Ijams Wolfing Morgan
    Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
    Center for Advanced Retinal and Ocular Therapeutics, Department of Ophthalmology, University of Pennsylvania, Pennsylvania, United States
  • Jean Bennett
    Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
    Center for Advanced Retinal and Ocular Therapeutics, Department of Ophthalmology, University of Pennsylvania, Pennsylvania, United States
  • Dean Eliott
    Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, United States
  • Jason Comander
    Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, United States
  • Albert M. Maguire
    Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
    Center for Advanced Retinal and Ocular Therapeutics, Department of Ophthalmology, University of Pennsylvania, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Tomas Aleman, None; Rachel Huckfeldt, None; Leona Serrano, None; Grace Vergilio, None; Denise Pearson, None; Katherine Uyhazi, None; Sarah McCague, None; Kathleen Marshall, None; Daniel Chung, Spark Therapeutics (E); Emily Liu, Spark Therapeutics (E); Eric Pierce, Spark (F); Jessica Morgan, AGTC (F), US Patent 8226236 (P); Jean Bennett, Biogen (F), GenSight Biologics (S), Limelight Bio (F), Spark Therapeutics (P), Spark Therapeutics (S); Dean Eliott, None; Jason Comander, Beam Therapeutics (C), Blue Cross Blue Shield (C), Editas Medicine (C), Gensight (C), Sanofi (C); Albert Maguire, Spark Therapeutics (F)
  • Footnotes
    Support  Spark Therapeutics Clinical Trials Agreement, National Institutes of Health (NEI-K12EY015398-10, NIH R01EY028601), Research to Prevent Blindness, Foundation Fighting Blindness, Hope for Vision, Macula Vision Research Foundation, the Paul and Evanina Bell Mackall Foundation Trust and The Pennsylvania Lions Sight Conservation and Eye Research Foundation.
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 5173. doi:
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    • Get Citation

      Tomas S Aleman, Rachel M Huckfeldt, Leona Serrano, Grace Vergilio, Denise J Pearson, Katherine E. Uyhazi, Sarah McCague, Kathleen Marshall, Daniel C Chung, Emily Liu, Eric A Pierce, Jessica Ijams Wolfing Morgan, Jean Bennett, Dean Eliott, Jason Comander, Albert M. Maguire; AAV2-hCHM Subretinal Delivery to the Macula in Choroideremia: 2 year Results of an Ongoing Phase I/II Gene Therapy Trial. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5173.

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

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Abstract

Purpose : To assess preliminary safety and efficacy data of the investigational subretinal delivery of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human REP1-encoding cDNA in choroideremia (CHM).

Methods : Ten subjects with CHM (ages 26-57 years at injection), received uniocular subfoveal injections of low dose (up to 5x1010 vector genome (vg) per eye, n=5) or high dose (up to 1x1011 vg per eye, n=5) AAV2-hCHM. Patients were evaluated pre- and post-operatively at study-defined follow up visits for 2 years. Ocular safety was assessed by ophthalmic examination, perimetry, spectral domain optical coherence tomography (SD-OCT) and short-wavelength autofluorescence (SW-FAF) and by conventional automated perimetry and microperimetry.

Results : There were no surgery-related complications or unexpected adverse events. By two years visual acuity (VA) returned to baseline in all but one patient who slowly recovered to -17 letters of baseline. With the exclusion of this patient, mean VA letter counts differences (2 year minus baseline) were similar in injected (-1.7 letters) compared to uninjected (-0.3 letters) eyes. Two patients showed greater VA counts (5-6 letters) in the injected eye compared to baseline and to the uninjected control. Mean sensitivity by microperimetry changed minimally in injected (mean±SD=-0.7±0.75dB) and uninjected (-0.3±0.59 dB) eyes. There were no significant differences between injected and uninjected eyes in absolute dark-adapted cone-mediated sensitivities at the fovea or within the central 30° of eccentricity. There was a slightly slower mean rate of reduction of the IS/OS band horizontal extent in injected eyes (-69±59μm/year) compared to uninjected eyes (-96±67μm/year), which corresponded in extent to the areas of SW-FAF. There were no obvious dose-dependent relationships.

Conclusions : VA in 9/10 subjects was unchanged (less than ±10 letters difference from baseline) after the subfoveal injections of AAV2-hCHM and in uninjected eyes at 2 years of follow-up. Acute (~72 hours) localized foveal thinning and slow, partial recovery of VA in one patient suggests non-vector related individual vulnerability to the subfoveal injection. Residual islands of relatively preserved retina continued to shrink in both injected and uninjected eyes. Longer observation intervals are required to better evaluate the significance of these observations.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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