AAV2-Mediated Gene Therapy for Choroideremia: 5-Year Results and Alternate Anti-sense Oligonucleotide Therapy

Am J Ophthalmol. 2023 Apr:248:145-156. doi: 10.1016/j.ajo.2022.12.022. Epub 2022 Dec 26.

Abstract

Purpose: To assess the long-term safety and efficacy of AAV2-REP1 in choroideremia (CHM) patients, and to test a potential antisense oligonucleotide therapy for CHM.

Design: Extended, prospective phase 1/2 clinical trial and laboratory investigation.

Methods: Five patients who received a single subfoveal injection of AAV2-REP1 were studied. The long-term safety was evaluated by ophthalmic examination, spectral domain optical coherence tomography, and fundus autofluorescence (FAF) for up to 5 years. Functional and structural changes were determined by different test modalities. Four antisense oligonucleotides (ASOs) were designed to treat the CHM c.1245-521A>G mutation, which was present in 2 patients within this trial.

Results: Subject P3 experienced a localized intraretinal immune response that resulted in a significant loss of preserved retinal pigment epithelium (RPE). P4 experienced an exacerbation of peripheral retinoschisis. P2 had a constant ≥15-letter best-corrected visual acuity (BCVA) gain in the treated eye, whereas P5 had ≥15-letter BCVA improvement once in the untreated eye. The preserved FAF areas declined more rapidly in the treated eyes compared to the untreated eyes (P = .043). A customized 25-mer ASO recovered 83.2% to 95.0% of the normal RNA and 57.5% of the normal protein in fibroblasts from 2 trial patients.

Conclusions: Intraretinal inflammation triggered by AAV2-REP1 subretinal injection stabilized after 2 years but resulted in permanent damage to the retinal structure. Long-term progression of the disease was seen in both treated and untreated eyes, casting doubt as to the effectiveness of this approach in late-stage CHM. Alternative approaches such as ASO may have a therapeutic effect in a subgroup of CHM patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Choroideremia* / diagnosis
  • Choroideremia* / genetics
  • Choroideremia* / therapy
  • Genetic Therapy / methods
  • Humans
  • Oligonucleotides, Antisense / therapeutic use
  • Prospective Studies
  • Retina
  • Retinal Pigment Epithelium / metabolism
  • Tomography, Optical Coherence / methods

Substances

  • Oligonucleotides, Antisense

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