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Restoration of visual function by transplantation of optogenetically engineered photoreceptors.

ABSTRACT: A major challenge in the treatment of retinal degenerative diseases, with the transplantation of replacement photoreceptors, is the difficulty in inducing the grafted cells to grow and maintain light sensitive outer segments in the host retina, which depends on proper interaction with the underlying retinal pigment epithelium (RPE). Here, for an RPE-independent treatment approach, we introduce a hyperpolarizing microbial opsin into photoreceptor precursors from newborn mice, and transplant them into blind mice lacking the photoreceptor layer. These optogenetically-transformed photoreceptors are light responsive and their transplantation leads to the recovery of visual function, as shown by ganglion cell recordings and behavioral tests. Subsequently, we generate cone photoreceptors from human induced pluripotent stem cells, expressing the chloride pump Jaws. After transplantation into blind mice, we observe light-driven responses at the photoreceptor and ganglion cell levels. These results demonstrate that structural and functional retinal repair is possible by combining stem cell therapy and optogenetics.

SUBMITTER: Garita-Hernandez M

PROVIDER: S-EPMC6778196 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Restoration of visual function by transplantation of optogenetically engineered photoreceptors.

Garita-Hernandez Marcela M Lampič Maruša M Chaffiol Antoine A Guibbal Laure L Routet Fiona F Santos-Ferreira Tiago T Gasparini Sylvia S Borsch Oliver O Gagliardi Giuliana G Reichman Sacha S Picaud Serge S Sahel José-Alain JA Goureau Olivier O Ader Marius M Dalkara Deniz D Duebel Jens J

Nature communications 20191004 1

A major challenge in the treatment of retinal degenerative diseases, with the transplantation of replacement photoreceptors, is the difficulty in inducing the grafted cells to grow and maintain light sensitive outer segments in the host retina, which depends on proper interaction with the underlying retinal pigment epithelium (RPE). Here, for an RPE-independent treatment approach, we introduce a hyperpolarizing microbial opsin into photoreceptor precursors from newborn mice, and transplant them ...[more]

PMID: 31586094

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Project description:BackgroundAge-related macular degeneration (AMD) is a result of degeneration/damage of the retinal pigment epithelium (RPE) while retinitis pigmentosa (RP), an inherited early-onset disease, results from premature loss of photoreceptors. A promising therapeutic approach for both is the replacement of lost/damaged cells with human induced pluripotent stem cell (hiPSC)-derived retinal cells.MethodsThe aim of this study was to investigate the in vivo functionality of RPE and photoreceptor progenitor (PRP) cells derived from a clinical-grade hiPSC line through a unified protocol. De novo-generated RPE and PRP were characterized extensively to validate their identity, purity, and potency.ResultsRPE expressed tight junction proteins, showed pigmentation and ciliation, and secreted polarization-related factors vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). PRP expressed neural retina proteins and cone and rod markers, and responded to KCl-induced polarization. Transcriptomic analysis demonstrated an increase in the expression of mature retinal tissue-specific genes coupled with concomitant downregulation of genes from undesired lineages. RPE transplantation rescued visual function in RCS rats shown via optokinetic tracking and photoreceptor rescue. PRP transplantation improved light perception in NOD.SCID-rd1 mice, and positive electroretinography signals indicated functional photoreceptor activity in the host's outer nuclear layer. Graft survival and integration were confirmed using immunohistochemistry, and no animals showed teratoma formation or any kind of ectopic growth in the eye.ConclusionsTo our knowledge, this is the first demonstration of a unified, scalable, and GMP-adaptable protocol indicating strong animal efficacy and safety data with hiPSC-derived RPE and PRP cells. These findings provide robust proof-of-principle results for IND-enabling studies to test these potential regenerative cell therapies in patients.

Project description:ObjectiveTo investigate the effects of mirror neuron theory-based visual feedback therapy (VFT) on restoration of upper limb function of stroke patients and motor-related cortical function using functional magnetic resonance imaging (fMRI).MethodsHemiplegic stroke patients were randomly divided into two groups: a VFT group and a control (CTL) group. Sixteen patients in the VFT group received conventional rehabilitation (CR) and VFT for 8 weeks, while 15 patients in the CTL group received only CR. The Barthel Index (BI) was used to assess the activities of daily living at baseline and the 8th week of the recovery training period. The Fugl-Meyer assessment (FMA) scale, somatosensory evoked potential (SEP), and fMRI were used to evaluate the recovery effect of the training therapies. The latencies and amplitudes of N9 and N20 were measured. Before recovery training, fMRI was performed for all patients in the VFT and CTL groups. In addition, 17 patients (9 in the VFT group and 8 in the CTL group) underwent fMRI for follow-up 2 months after treatment. Qualitative data were analyzed using the χ 2 test. The independent sample t-test was used to compare normally distributed data among different groups, the paired sample t-test was used to compare data between groups, and the non-parametric test was used to comparing data without normal distribution among groups.ResultsThere were no significant differences between the VFT and CTL group in all indexes. However, after 8 weeks of recovery training, these indexes were all significantly improved (P < 0.05). As compared with the CTL group, the FMA scores, BI, and N9/N20 latencies and amplitudes of SEP in the VFT group were significantly improved (P < 0.05). Two months after recovery training, fMRI showed that the degree of activation of the bilateral central anterior gyrus, parietal lobe, and auxiliary motor areas was significantly higher in the VFT group than the CTL group (P < 0.05).ConclusionsVFT based on mirror neuron theory is an effective approach to improve upper extremity motor function and daily activity performance of stroke patients. The therapeutic mechanism promotes motor relearning by activating the mirror neuron system and motor cortex. SEP amplitudes increased only for patients who participated in visual feedback. VFT promotes sensory-motor plasticity and behavioral changes in both the motor and sensory domains.

Dataset Information

Restoration of visual function by transplantation of optogenetically engineered photoreceptors.

Publications

Restoration of visual function by transplantation of optogenetically engineered photoreceptors.

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