| Autor: |
Yi Zhai, Manlong Xu, Alina Radziwon, Ioannis S. Dimopoulos, Paul Crichton, Rachel Mah, Robert E. MacLaren, Rizwan Somani, Matthew T. Tennant, Ian M. MacDonald |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
American journal of ophthalmology. |
| ISSN: |
1879-1891 |
| Popis: |
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 phase 1/2 clinical trial and laboratory investigation.Five patients who received a single subfoveal injection of AAV2-REP1.The long-term safety was evaluated by ophthalmic examination, spectral-domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) for up to five years. Functional and structural changes were determined by different test modalities. Four antisense oligonucleotides (ASOs) were designed to treat the CHM c.1245-521AG mutation which was present in two patients within this trial.Subject P3 experienced a localized intraretinal immune response that resulted in a significant loss of preserved RPE. P4 experienced an exacerbation of peripheral retinoschisis. P2 had a constant ≥ 15-letter BCVA gain in the treated eye, while 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 = 0.043). A customized 25-mer ASO recovered 83.2-95.0% of the normal RNA and 57.5% of the normal protein in fibroblasts from two trial patients.Intra-retinal inflammation triggered by AAV2-REP1 subretinal injection stabilized after two 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. Alternate approaches such as ASO may have a therapeutic effect in a subgroup of CHM patients. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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