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AAV2-Mediated Gene Therapy for Choroideremia: 5-Year Results and Alternate Anti-sense Oligonucleotide Therapy
Yi Zhai1, Manlong Xu1, Alina Radziwon2
1From the Department of Ophthalmology and Visual Sciences (Y.Z., M.X., A.R., R.S., M.T.T., I.M.M.), University of Alberta, Edmonton, Alberta, Canada.
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.
Insights
Long-term AAV2-REP1 gene therapy for choroideremia (CHM) showed limited efficacy and caused intraretinal inflammation. Antisense oligonucleotide (ASO) therapy demonstrated potential for treating CHM in a subset of patients.
Area of Science:
- Ophthalmology
- Genetics
- Retinal Diseases
Background:
- Choroideremia (CHM) is an X-linked genetic disorder causing progressive vision loss.
- Current treatments for CHM are limited, necessitating the development of novel therapeutic strategies.
Purpose of the Study:
- To evaluate the long-term safety and efficacy of AAV2-REP1 gene therapy in CHM patients.
- To investigate the potential of antisense oligonucleotide (ASO) therapy for CHM.
Main Methods:
- A prospective phase 1/2 clinical trial involving five CHM patients receiving AAV2-REP1 subretinal injections.
- Long-term safety assessment via ophthalmic examinations, OCT, and FAF for up to 5 years.
- Development and in vitro testing of four ASOs targeting the CHM c.1245-521A>G mutation.
Main Results:
- One patient experienced localized intraretinal inflammation with RPE loss; another had worsening retinoschisis.
- Variable visual acuity gains were observed, with treated eyes showing faster decline in preserved FAF areas compared to untreated eyes.
- ASO therapy in patient fibroblasts recovered significant levels of normal RNA and protein.
Conclusions:
- AAV2-REP1 gene therapy demonstrated limited long-term efficacy and caused permanent retinal damage in CHM patients.
- The study suggests that ASO therapy may offer a therapeutic benefit for a specific subgroup of CHM patients.
- Further research into ASO therapy is warranted for CHM treatment.
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