June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
AAV2-hCHM Subretinal Delivery to the Macula in Choroideremia: Preliminary Six Month Safety Results of an Ongoing Phase I/II Gene Therapy Trial
Author Affiliations & Notes
  • Tomas S Aleman
    Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
    Center for Advanced Retinal and Ophthalmic Therapeutics, Department of Ophthalmoilogy, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Leona Serrano
    Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Grace K. Han
    Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Denise J Pearson
    Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Sarah McCague
    Center for Advanced Retinal and Ophthalmic Therapeutics, Department of Ophthalmoilogy, University of Pennsylvania, Philadelphia, Pennsylvania, United States
    The Children's Hospital of Philadelphia , Philadelphia, Pennsylvania, United States
  • Kathleen A Marshall
    Center for Advanced Retinal and Ophthalmic Therapeutics, Department of Ophthalmoilogy, University of Pennsylvania, Philadelphia, Pennsylvania, United States
    The Children's Hospital of Philadelphia , Philadelphia, Pennsylvania, United States
  • Daniel C Chung
    Spark Therapeutics, Philadelphia, Pennsylvania, United States
  • Emily Liu
    Spark Therapeutics, Philadelphia, Pennsylvania, United States
  • Jessica Ijams Wolfing Morgan
    Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Jean Bennett
    Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
    Center for Advanced Retinal and Ophthalmic Therapeutics, Department of Ophthalmoilogy, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Albert M Maguire
    Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
    Center for Advanced Retinal and Ophthalmic Therapeutics, Department of Ophthalmoilogy, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Tomas Aleman, None; Leona Serrano, None; Grace Han, None; Denise Pearson, None; Sarah McCague, None; Kathleen Marshall, None; Daniel Chung, Spark Therapeutics (I), Spark Therapeutics (E); Emily Liu, Spark Therapeutics (E), Spark Therapeutics (I); Jessica Morgan, AGTC (F), Canon (F), US Patent 8226236 (P); Jean Bennett, Biogen (F), Gensight Biologics (S), Limelight (F), Sanofi (C), Spark Therapeutics (P), Spark Therapeutics (S); Albert Maguire, Spark Therapeutics (F)
  • Footnotes
    Support  Spark Therapeutics Clinical Trials Agreement, National Institutes of Health (NEI-K12EY015398-10, U01EY025477, UL1TR000003), Research to Prevent Blindness, Foundation Fighting Blindness, Hope for Vision, Macula Vision Research, the Paul and Evanina Bell Mackall Foundation Trust and The Pennsylvania Lions Sight Conservation
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4485. doi:
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    • Get Citation

      Tomas S Aleman, Leona Serrano, Grace K. Han, Denise J Pearson, Sarah McCague, Kathleen A Marshall, Daniel C Chung, Emily Liu, Jessica Ijams Wolfing Morgan, Jean Bennett, Albert M Maguire; AAV2-hCHM Subretinal Delivery to the Macula in Choroideremia: Preliminary Six Month Safety Results of an Ongoing Phase I/II Gene Therapy Trial. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4485.

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

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Abstract

Purpose : To assess preliminary safety data of the investigational subretinal delivery of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human REP-1-encoding cDNA in choroideremia (CHM).

Methods : Nine subjects with CHM (ages 26-57 years), 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=4) AAV2-hCHM. Patients were evaluated pre- and post-operatively for 6 months with follow-up ongoing. Ocular safety was assessed by ophthalmic examination, perimetry, spectral domain optical coherence tomography (SD-OCT) and short-wavelength autofluorescence (SW-FAF).

Results : There were no surgery-related complications or unexpected adverse events. Visual acuity (VA) returned to baseline in all but one patient who slowly recovered to within 20 letters of baseline by 6 months. This subject had foveal thinning (to ~80% of baseline) and foveal sensitivity loss. All other patients showed no obvious changes in foveal structure post-injection. Mean sensitivity by light-adapted perimetry (10-2 protocol) was unchanged in treated and control eyes. Fundus perimetry showed non-significant (<3SD of the intervisit variability) increases in light sensitivity in some locations and subjects in the operated eye. Cone-mediated sensitivities by two-color dark-adapted perimetry showed non-significant increases in sensitivity above mean baseline for some locations in the operated eye of three subjects. Residual islands of retinal pigment epithelium preservation by SW-FAF showed trace reduction in area that was not significantly different in the injected eye compared to the control. There were no obvious dose-dependent relationships.

Conclusions : VA returned to baseline in most subjects after subfoveal injections of AAV2-hCHM. Foveal thinning and slow recovery of VA with unchanged perifoveal function in one patient raises the possibility of non-vector related individual vulnerability to the subfoveal injection. Not unexpectedly, short-term increases in sensitivity in the operated eyes of a subset of patients did not exceed the intervisit or inter-ocular variability estimates. Longer observation intervals are required to better evaluate the significance of the preliminary changes.

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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