Cone photoreceptor preservation with laser photobiomodulation in murine and human retinal dystrophy.
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ABSTRACT:
SUBMITTER: Casson RJ
PROVIDER: S-EPMC8858622 | biostudies-literature | 2022 Feb
REPOSITORIES: biostudies-literature
Publications
Cone photoreceptor preservation with laser photobiomodulation in murine and human retinal dystrophy.
Casson Robert J RJ Wood John P M JPM Ao Jack J Gilhotra Jagjit S JS Durkin Shane R SR Muecke James J Chan WengOnn W Chidlow Glyn G
Clinical and translational medicine 20220201 2
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Project description:BackgroundRetinal regenerative therapies hold great promise for the treatment of inherited retinal degenerations (IRDs). Studies in preclinical lower mammal models of IRDs have suggested visual improvement following retinal photoreceptor precursors transplantation, but there is limited evidence on the ability of these transplants to rescue retinal damage in higher mammals. The purpose of this study was to evaluate the therapeutic potential of photoreceptor precursors derived from clinically compliant induced pluripotent stem cells (iPSCs).MethodsPhotoreceptor precursors were sub-retinally transplanted into non-human primates (Macaca fascicularis). The cells were transplanted both in naïve and cobalt chloride-induced retinal degeneration models who had been receiving systemic immunosuppression for one week prior to the procedure. Optical coherence tomography, fundus autofluorescence imaging, electroretinography, ex vivo histology and immunofluorescence staining were used to evaluate retinal structure, function and survival of transplanted cells.ResultsThere were no adverse effects of iPSC-derived photoreceptor precursors on retinal structure or function in naïve NHP models, indicating good biocompatibility. In addition, photoreceptor precursors injected into cobalt chloride-induced retinal degeneration NHP models demonstrated an ability both to survive and to mature into cone photoreceptors at 3 months post-transplant. Optical coherence tomography showed restoration of retinal ellipsoid zone post-transplantation.ConclusionsThese findings demonstrate the safety and therapeutic potential of clinically compliant iPSC-derived photoreceptor precursors as a cell replacement source for future clinical trials.
| S-EPMC8375124 | biostudies-literature
Project description:Potent neuroprotective effects of photobiomodulation with 670 nm red light (RL) have been demonstrated in several models of retinal disease. RL improves mitochondrial metabolism, reduces retinal inflammation and oxidative cell stress, showing its ability to enhance visual function. However, the current knowledge is limited to the main hypothesis that the respiratory chain complex IV, cytochrome c oxidase, serves as the primary target of RL. Here, we demonstrate a comprehensive cellular, molecular, and functional characterization of neuroprotective effects of 670 nm RL and 810 nm near-infrared light (NIRL) on blue light damaged murine primary photoreceptors. We show that respiratory chain complexes I and II are additional PBM targets, besides complex IV, leading to enhanced mitochondrial energy metabolism. Accordingly, our study identified mitochondria related RL- and NIRL-triggered defense mechanisms promoting photoreceptor neuroprotection. The observed improvement of mitochondrial and extramitochondrial respiration in both inner and outer segments is linked with reduced oxidative stress including its cellular consequences and reduced mitochondria-induced apoptosis. Analysis of regulatory mechanisms using gene expression analysis identified upregulation α-crystallins that indicate enhanced production of proteins with protective functions that point to the rescued mitochondrial function. The results support the hypothesis that energy metabolism is a major target for retinal light therapy.
| S-EPMC7177783 | biostudies-literature
Project description:PurposePhotobiomodulation (PBM) refers to therapeutic irradiation of tissue with low-energy, 630- to 1000-nm wavelength light. An increasing body of evidence supports a beneficial effect of PBM in retinal disorders. To date, most studies have utilized light-emitting diode irradiation sources. Slit-lamp-mounted retinal lasers produce a coherent beam that can be delivered with precisely defined dosages and predetermined target area; however, the use of retinal lasers raises safety concerns that warrant investigation prior to clinical application. In this study, we determined safe dosages of laser-delivered PBM to the retina.MethodsA custom-designed, slit-lamp-delivered, 670-nm, red/near-infrared laser was used to administer a range of irradiances to healthy pigmented and non-pigmented rat retinas. The effects of PBM on various functional and structural parameters of the retina were evaluated utilizing a combination of electroretinography, Spectral Domain Optical Coherence (SD-OCT), fluorescein angiography, histology and immunohistochemistry.ResultsIn non-pigmented rats, no adverse events were identified at any irradiances up to 500 mW/cm2. In pigmented rats, no adverse events were identified at irradiances of 25 or 100 mW/cm2; however, approximately one-third of rats that received 500 mW/cm2 displayed very localized photoreceptor damage in the peripapillary region, typically adjacent to the optic nerve head.ConclusionsA safety threshold exists for laser-delivered PBM in pigmented retinas and was identified as 500 mW/cm2 irradiance; therefore, caution should be exercised in the dosage of laser-delivered PBM administered to pigmented retinas.Translational relevanceThis study provides important data necessary for clinical translation of laser-delivered PBM for retinal diseases.
| S-EPMC7396177 | biostudies-literature
Project description:PurposeTo characterize the progression of optical gaps and expand the known etiologies of this phenotype.DesignRetrospective cohort study.MethodsThirty-six patients were selected based on the identification of an optical gap on spectral-domain optical coherence tomography (OCT) from a large cohort of patients (N = 746) with confirmed diagnoses of inherited retinal dystrophy. The width and height of the gaps in 70 eyes of 36 patients were measured by 2 independent graders using the caliper tool on Heidelberg Explorer. Measurements of outer and central retinal thickness were also evaluated and correlated with gap dimensions.ResultsLongitudinal analysis confirmed the progressive nature of optical gaps in patients with Stargardt disease, achromatopsia, occult macular dystrophy, and cone dystrophies (P < .003). Larger changes in gap width were noted in patients with Stargardt disease (78.1 μm/year) and cone dystrophies (31.9 μm/year) compared with patients with achromatopsia (16.2 μm/year) and occult macular dystrophy (15.4 μm/year). Gap height decreased in patients with Stargardt disease (6.5 μm/year; P = .02) but increased in patients with achromatopsia (3.3 μm/year) and occult macular dystrophy (1.2 μm/year). Gap height correlated with measurements of central retinal thickness at the fovea (r = 0.782, P = .00012). Interocular discordance of the gap was observed in 7 patients. Finally, a review of all currently described etiologies of optical gap was summarized.ConclusionThe optical gap is a progressive phenotype seen in an increasing number of etiologies. This progressive nature suggests a use as a biomarker in the understanding of disease progression. Interocular discordance of the phenotype may be a feature of Stargardt disease and cone dystrophies.
| S-EPMC8291221 | biostudies-literature
Project description:Photoreceptor loss is a leading cause of blindness, but mechanisms underlying photoreceptor degeneration are not well understood. Treatment strategies would benefit from improved understanding of gene-expression patterns directing photoreceptor development, as many genes are implicated in both development and degeneration. Neural retina leucine zipper (NRL) is critical for rod photoreceptor genesis and degeneration, with NRL mutations known to cause enhanced S-cone syndrome and retinitis pigmentosa. While murine Nrl loss has been characterized, studies of human NRL can identify important insights for human retinal development and disease. We utilized iPSC organoid models of retinal development to molecularly define developmental alterations in a human model of NRL loss. Consistent with the function of NRL in rod fate specification, human retinal organoids lacking NRL develop S-opsin dominant photoreceptor populations. We report generation of two distinct S-opsin expressing populations in NRL null retinal organoids and identify MEF2C as a candidate regulator of cone development.
| S-EPMC7035245 | biostudies-literature
Project description:PurposeThe purpose of this study was to investigate the spatial distribution of human cone photoreceptors and examine cone density differences between the retinal meridians and quadrants.MethodUsing adaptive optics scanning laser ophthalmoscopy, the maculae were imaged in 17 eyes of 11 subjects with normal chorioretinal health aged 54 to 72 years. We measured cone density at 325 points within the central 10 degrees radius of the retina. Cone density spatial distributions along the primary retinal meridians and in four macular quadrants (superior-nasal, superior-temporal, inferior-temporal, and inferior-nasal) were analytically modeled using the polynomial function to assess the meridional and quadrantal difference.ResultsThe mean and 95% confidence interval for the prediction of cone density along the primary retinal meridians was modeled with a 7-degree one-variable polynomial (R2 = 0.9761, root mean squared error [RMSE] = 0.0585). In the 4 retinal quadrants, cone density distribution was described by a 2-variable polynomial with X degree 3 and Y degree 4 (R² = 0.9834, RMSE = 0.0377). The models suggest no statistically significant difference between medians and between quadrants. However, cone density difference at corresponding spatial locations in different areas can be up to 25.6%. The superior-nasal region has more areas with high cone density, followed by quadrants of inferior-nasal, inferior-temporal, and superior-temporal.ConclusionsAnalytical modeling provides comprehensive knowledge of cone distribution across the entire macula. Although modeling analysis suggests no statistically significant difference between medians and between quadrants, the remarkable cone density discrepancies in certain regions should be accounted for in applications requiring sensitive detection of cone variation.
| S-EPMC11232901 | biostudies-literature
Project description:The visual (retinoid) cycle, the enzymatic pathway that regenerates chromophore after light absorption, is located primarily in the retinal pigment epithelium (RPE) and is essential for rod photoreceptor survival. Whether this pathway also is essential for cone photoreceptor survival is unknown, and there are no data from man or monkey to address this question. The visual cycle is naturally disrupted in humans with Leber congenital amaurosis (LCA), which is caused by mutations in RPE65, the gene that encodes the retinoid isomerase. We investigated such patients over a wide age range (3-52 years) for effects on the cone-rich human fovea. In vivo microscopy of the fovea showed that, even at the youngest ages, patients with RPE65-LCA exhibited cone photoreceptor loss. This loss was incomplete, however, and residual cone photoreceptor structure and function persisted for decades. Basic questions about localization of RPE65 and isomerase activity in the primate eye were addressed by examining normal macaque. RPE65 was definitively localized by immunocytochemistry to the central RPE and, by immunoblotting, appeared to concentrate in the central retina. The central retinal RPE layer also showed a 4-fold higher retinoid isomerase activity than more peripheral RPE. Early cone photoreceptor losses in RPE65-LCA suggest that robust RPE65-based visual chromophore production is important for cones; the residual retained cone structure and function support the speculation that alternative pathways are critical for cone photoreceptor survival.
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Project description:Uncovering the gene regulatory networks that control cone photoreceptor formation has been hindered because cones only make up a few percent of the retina and form asynchronously during development. To overcome these limitations, we used a γ-secretase inhibitor, DAPT, to disrupt Notch signaling and force proliferating retinal progenitor cells to rapidly adopt neuronal identity. We treated mouse retinal explants at the peak of cone genesis with DAPT and examined tissues at several time-points by histology and bulk RNA-sequencing. We found that this treatment caused supernumerary cone formation in an overwhelmingly synchronized fashion. This analysis revealed several categorical patterns of gene expression changes over time relative to DMSO treated control explants. These were placed in the temporal context of the activation of Otx2, a transcription factor that is expressed at the onset of photoreceptor development and that is required for both rod and cone formation. One group of interest had genes, such as Mybl1, Ascl1, Neurog2, and Olig2, that became upregulated by DAPT treatment before Otx2. Two other groups showed upregulated gene expression shortly after Otx2, either transiently or permanently. This included genes such as Mybl1, Meis2, and Podxl. Our data provide a developmental timeline of the gene expression events that underlie the initial steps of cone genesis and maturation. Applying this strategy to human retinal organoid cultures was also sufficient to induce a massive increase in cone genesis. Taken together, our results provide a temporal framework that can be used to elucidate the gene regulatory logic controlling cone photoreceptor development.
| S-EPMC7722777 | biostudies-literature
Project description:Photoreceptor loss is a leading cause of blindness, but mechanisms underlying photoreceptor degeneration are not well understood. Treatment strategies would benefit from an improved understanding of gene-expression patterns directing photoreceptor development, as many genes are implicated in both development and degeneration. Neural retina leucine zipper (NRL) is critical for rod photoreceptor genesis and degeneration, with NRL mutations known to cause enhanced S-cone syndrome and retinitis pigmentosa. While murine Nrl loss has been characterized, studies of human NRL can identify important insights for human retinal disease. Here we utilized human organoid models of retinal development to molecularly define developmental alterations in a human model of NRL loss. Consistent with the function of NRL in rod fate specification, human retinal organoids lacking NRL develop S-opsin dominant photoreceptor populations. We report generation of two distinct S-opsin expressing populations in NRL null retinal organoids and identify MEF2C as a candidate regulator of cone development.
2020-01-15 | GSE143669 | GEO
Project description:Variants of the TTLL5 gene, which encodes tubulin tyrosine ligase-like family member five, are a rare cause of cone dystrophy (COD) or cone-rod dystrophy (CORD). To date, only a few TTLL5 patients have been clinically and genetically described. In this study, we report five patients harbouring biallelic variants of TTLL5. Four adult patients presented either COD or CORD with onset in the late teenage years. The youngest patient had a phenotype of early onset severe retinal dystrophy (EOSRD). Genetic analysis was performed by targeted next generation sequencing of gene panels and assessment of copy number variants (CNV). We identified eight variants, of which six were novel, including two large multiexon deletions in patients with COD or CORD, while the EOSRD patient harboured the novel homozygous p.(Trp640*) variant and three distinct USH2A variants, which might explain the observed rod involvement. Our study highlights the role of TTLL5 in COD/CORD and the importance of large deletions. These findings suggest that COD or CORD patients lacking variants in known genes may harbour CNVs to be discovered in TTLL5, previously undetected by classical sequencing methods. In addition, variable phenotypes in TTLL5-associated patients might be due to the presence of additional gene defects.
| S-EPMC8232641 | biostudies-literature