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Precision Medicine: Genetic Repair of Retinitis Pigmentosa in Patient-Derived Stem Cells.

ABSTRACT: Induced pluripotent stem cells (iPSCs) generated from patient fibroblasts could potentially be used as a source of autologous cells for transplantation in retinal disease. Patient-derived iPSCs, however, would still harbor disease-causing mutations. To generate healthy patient-derived cells, mutations might be repaired with new gene-editing technology based on the bacterial system of clustered regularly interspersed short palindromic repeats (CRISPR)/Cas9, thereby yielding grafts that require no patient immunosuppression. We tested whether CRISPR/Cas9 could be used in patient-specific iPSCs to precisely repair an RPGR point mutation that causes X-linked retinitis pigmentosa (XLRP). Fibroblasts cultured from a skin-punch biopsy of an XLRP patient were transduced to produce iPSCs carrying the patient's c.3070G?>?T mutation. The iPSCs were transduced with CRISPR guide RNAs, Cas9 endonuclease, and a donor homology template. Despite the gene's repetitive and GC-rich sequences, 13% of RPGR gene copies showed mutation correction and conversion to the wild-type allele. This is the first report using CRISPR to correct a pathogenic mutation in iPSCs derived from a patient with photoreceptor degeneration. This important proof-of-concept finding supports the development of personalized iPSC-based transplantation therapies for retinal disease.

SUBMITTER: Bassuk AG

PROVIDER: S-EPMC4728485 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Precision Medicine: Genetic Repair of Retinitis Pigmentosa in Patient-Derived Stem Cells.

Bassuk Alexander G AG Zheng Andrew A Li Yao Y Tsang Stephen H SH Mahajan Vinit B VB

Scientific reports 20160127

Induced pluripotent stem cells (iPSCs) generated from patient fibroblasts could potentially be used as a source of autologous cells for transplantation in retinal disease. Patient-derived iPSCs, however, would still harbor disease-causing mutations. To generate healthy patient-derived cells, mutations might be repaired with new gene-editing technology based on the bacterial system of clustered regularly interspersed short palindromic repeats (CRISPR)/Cas9, thereby yielding grafts that require no ...[more]

PMID: 26814166

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Project description:PURPOSE:The aim of this study is to determine if umbilical cord Wharton's jelly derived mesenchymal stem cells implanted in sub-tenon space have beneficial effects on visual functions in retinitis pigmentosa patients by reactivating the degenerated photoreceptors in dormant phase. MATERIAL AND METHODS:This prospective, open-label, phase-3 clinical trial was conducted between April of 2019 and October of 2019 at Ankara University Faculty of Medicine, Department of Ophthalmology. 32 RP patients (34 eyes) were included in the study. The patients were followed for 6?months after the Wharton's jelly derived mesenchymal stem cell administration, and evaluated with consecutive examinations. All patients underwent a complete routine ophthalmic examination, and best corrected visual acuity, optical coherens tomography angiography, visual field, multifocal and full-field electroretinography were performed. The quantitative results were obtained from a comparison of the pre-injection and final examination (6th month) values. RESULTS:The mean best corrected visual acuity was 70.5 letters prior to Wharton's jelly derived mesenchymal stem cell application and 80.6 letters at the 6th month (p?=?0.01). The mean visual field median deviation value was 27.3?dB before the treatment and 24.7?dB at the 6th month (p?=?0.01). The mean outer retinal thickness was 100.3??m before the treatment and 119.1??m at 6th month (p?=?0.01). In the multifocal electroretinography results, P1 amplitudes improved in ring1 from 24.8 to 39.8 nv/deg2 (p?=?0.01), in ring2 from 6.8 to 13.6 nv/deg2 (p?=?0.01), and in ring3 from 3.1 to 5.7 nv/deg2 (p?=?0.02). P1 implicit times improved in ring1 from 44.2 to 32.4?ms (p?=?0.01), in ring2 from 45.2 to 33.2?ms (p?=?0.02), and in ring3 from 41.9 to 32.4?ms (p?=?0.01). The mean amplitude improved in 16 Tds from 2.4 to 5.0 nv/deg2 (p?=?0.01) and in 32 Tds from 2.4 to 4.8 nv/deg2 (p?=?0.01) in the full-field flicker electroretinography results. Full field flicker electroretinography mean implicit time also improved in 16 Tds from 43.3 to 37.9?ms (p?=?0.01). No ocular or systemic adverse events related to the two types of surgical methods and/or Wharton's jelly derived mesenchymal stem cells itself were observed during the follow-up period. CONCLUSION:RP is a genetic disorder that can result in blindness with outer retinal degeneration. Regardless of the type of genetic mutation, sub-tenon Wharton's jelly derived mesenchymal stem cell administration appears to be an effective and safe option. There are no serious adverse events or ophthalmic / systemic side effects for 6?months follow-up. Although the long-term adverse effects are still unknown, as an extraocular approach, subtenon implantation of the stem cells seems to be a reasonable way to avoid the devastating side effects of intravitreal/submacular injection. Further studies that include long-term follow-up are needed to determine the duration of efficacy and the frequency of application. TRIAL REGISTRATION:SHGM56733164. Redistered 28 January 2019 https://shgm.saglik.gov.tr/organ-ve-doku-nakli-koordinatorlugu/56733164/203 E.507.

Project description:PurposeThe aim of the study was to investigate annual structural and functional results, and their correlation with inheritance pattern of retinitis pigmentosa (RP) patients who were treated with Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs).Material and methodsThis prospective, sequential, open-label phase-3 clinical study was conducted at Ankara University Faculty of Medicine, Department of Ophthalmology, between April 2019 and May 2020. The study included 34 eyes from 32 retinitis pigmentosa patients of various genotypes who were enrolled in the stem cells clinical trial. The patients were followed for 12 months after the WJ-MSCs transplantation into subtenon space and evaluated with consecutive examinations. Genetic mutations were investigated using a retinitis pigmentosa panel sequencing method consisting of 90 genes. All patients underwent a complete routine ophthalmic examination with best corrected visual acuity, optical coherence tomography angiography, visual field, and full-field electroretinography. Quantitative data obtained from baseline (T0), 6th month (T1), and 12th month (T2) examinations were compared.ResultsAccording to timepoints at T0, T1, and T2: The mean outer retinal thickness was 100.3 μm, 119.1 μm, and 118.0 μm, respectively (p = 0.01; T0 < T1, T2). The mean horizontal ellipsoid zone width were 2.65 mm, 2.70 mm, and 2.69 mm respectively (p = 0.01; T0 < T1, T2). The mean best corrected visual acuity (BCVA) were 70.5 letters, 80.6 letters, and 79.9 letters, respectively (p = 0.01; T0 < T1, T2). The mean fundus perimetry deviation index (FPDI) was 8.0%, 11.4%, and 11.6%, respectively (p = 0.01; T0 < T1, T2). The mean full-field flicker ERG parameters at T0, T1, and T2: amplitudes were 2.4 mV, 5.0 mV, and 4.6 mV, respectively (p = 0.01; T0 < T1, T2). Implicit time were 43.3 ms, 37.9 ms, and 38.6 ms, respectively (p = 0.01; T0 > T1, T2). According to inheritance pattern, BCVA, FPDI, ERG amplitude, and implicit time data improved significantly in autosomal dominant (AD) and in autosomal recessive (AR) RP at 1 year follow-up (pAD = 0.01, pAR = 0.01; pAD = pAR > pX-linked). No ocular or systemic adverse events related to the surgical methods and/or WJ-MSCs were observed during the 1 year follow-up period.ConclusionSubtenon transplantation of WJ-MSCs was found to be effective and safe in the treatment of RP during the first year, similar to the sixth month's results. In autosomal dominant and autosomal recessive inheritance of RP, regardless of the genetic mutations, subtenon administration of WJ-MSCs can be considered an effective and safe option without any adverse effect for slowing or stopping the disease progression.Trial registrationClinicalTrials.gov, NCT04224207 . Registered 8 January 2020.

Dataset Information

Precision Medicine: Genetic Repair of Retinitis Pigmentosa in Patient-Derived Stem Cells.

Publications

Precision Medicine: Genetic Repair of Retinitis Pigmentosa in Patient-Derived Stem Cells.

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