Retinal degeneration: molecular mechanisms and therapeutic strategies

2021 ◽  
Vol 28 ◽  
Author(s):  
Xue Wu ◽  
Naihong Yan ◽  
Ming Zhang
Keyword(s):  
Stem Cells ◽  
Gene Therapy ◽  
Diabetic Retinopathy ◽  
Gut Microbiota ◽  
Molecular Mechanisms ◽  
Retinal Pigment ◽  
Therapeutic Strategies ◽  
Retinal Layer ◽  
Degenerative Diseases ◽  
Retinal Degenerative Diseases

: Retinal degenerative diseases are the main retinal diseases that threatens vision. Most retinal degenerative diseases are inherited diseases, including autosomal recessive inheritance, autosomal dominant inheritance, X-linked inheritance and mitochondrial inheritance, so emerging gene therapy strategies may provide an alternative method of treatment. Currently, three viral vectors are usually used in gene therapy studies: adenovirus, lentivirus and adeno-associated virus. Other gene therapies have their own advantages, such as DNA nanoparticles, antisense oligonucleotides and gene editing therapies. In addition, retinal degenerative diseases are often accompanied by abnormalities of retinal cells, including photoreceptor and retinal pigment epithelial cells. At present, stem cell transplantation is a promising new treatment for retinal degenerative diseases. Common sources of stem cells include retinal progenitor cells, induced pluripotent stem cells, embryonic stem cells and mesenchymal stem cells. In addition, retina explant cultures in vitro can be used as an effective platform for screening new therapies for retinal degenerative diseases. Drugs that actually reaches the retinal layer are more controlled, more consistent, and less invasive when using retinal explants. Furthermore, studies have shown that the imbalance of the gut microbiota is closely related to the occurrence and development of diabetic retinopathy. Therefore, the progression of diabetic retinopathy may be restrained by adjusting the imbalance of the gut microbiota. The purpose of this review is to discuss and summarize the molecular mechanisms and potential therapeutic strategies of retinal degenerative diseases.

Stem Cell Based Treatment Strategies for Degenerative Diseases of the Retina

2021 ◽  
Vol 16 ◽  
Author(s):  
Deepthi Rajendran Nair ◽  
Biju Thomas
Keyword(s):  
Stem Cells ◽  
Clinical Trials ◽  
Stem Cell ◽  
Pluripotent Stem Cells ◽  
Retinal Pigment Epithelial ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelial Cells ◽  
Degenerative Diseases ◽  
Retinal Degenerative Diseases ◽  
Pigment Epithelial Cells

Background: The main cause of progressive vision impairment in retinal degenerative diseases is the dysfunction of photoreceptors and the underlying retinal pigment epithelial cells. The inadequate regenerative capacity of the neural retina and lack of established therapeutic options demand the development of clinical grade protocols to halt degenerative process in the eye or to replace the damaged cells by using stem cell derived products. Recently, stem cell-based regenerative therapies are at the forefront of clinical investigations for retinal dystrophies. Objective: This article will review different stem cell-based therapies currently employed for retinal degenerative diseases, recent clinical trials, and major challenges in the translation of these therapies from bench to bedside. Methodology: A systematic literature review was carried out to identify potentially relevant articles published in MEDLINE/PubMed, Embase, ClinicalTrials.gov, Drugs@FDA, European Medicines Agency, World Health Organization International Clinical Trials Registry Platform and CENTRAL Result: Transplantation of healthy cells to replace the damaged cells in the outer retina is a clinically relevant concept because the inner retina that communicates with the visual areas of the brain remains functional even after the photoreceptors are completely lost. Different methods have been established for the differentiation of pluripotent stem cells into different retinal cell types that can be used for therapies. Factors released from transplanted somatic stem cells showed trophic support and photoreceptor rescue during early stages of the disease. Several preclinical and phase I/II clinical studies using terminally differentiated photoreceptor/ retinal pigment epithelial cells derived from pluripotent stem cells have shown proof of concept for visual restoration in Age-related macular degeneration (AMD), Stargardt disease and Retinitis pigmentosa (RP). Conclusion: Cell replacement therapy has great potential for vision restoration. The results obtained from the initial clinical trials are encouraging and indicates its therapeutic benefits. The current status of the therapies suggests that there is a long way to go before these results can be applied to routine clinical practice. Input from the ongoing multicentre clinical trials will give a more refined idea for the future design of clinical- grade protocols to transplant GMP level HLA matched cells.

scholarly journals Advancement in Nanostructure-Based Tissue-Engineered Biomaterials for Retinal Degenerative Diseases

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1005
Author(s):  
Sonali Suresh Rohiwal ◽  
Zdenka Ellederová ◽  
Taras Ardan ◽  
Jiri Klima
Keyword(s):  
Stem Cells ◽  
Retinal Degeneration ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Subretinal Space ◽  
Retinal Diseases ◽  
Degenerative Diseases ◽  
Retinal Cells ◽  
Wide Range ◽  
Retinal Degenerative Diseases

The review intends to overview a wide range of nanostructured natural, synthetic and biological membrane implants for tissue engineering to help in retinal degenerative diseases. Herein, we discuss the transplantation strategies and the new development of material in combination with cells such as induced pluripotent stem cells (iPSC), mature retinal cells, adult stem cells, retinal progenitors, fetal retinal cells, or retinal pigment epithelial (RPE) sheets, etc. to be delivered into the subretinal space. Retinitis pigmentosa and age-related macular degeneration (AMD) are the most common retinal diseases resulting in vision impairment or blindness by permanent loss in photoreceptor cells. Currently, there are no therapies that can repair permanent vision loss, and the available treatments can only delay the advancement of retinal degeneration. The delivery of cell-based nanostructure scaffolds has been presented to enrich cell survival and direct cell differentiation in a range of retinal degenerative models. In this review, we sum up the research findings on different types of nanostructure scaffolds/substrate or material-based implants, with or without cells, used to deliver into the subretinal space for retinal diseases. Though, clinical and pre-clinical trials are still needed for these transplants to be used as a clinical treatment method for retinal degeneration.

scholarly journals Association of Thiol–disulfide Homeostasis with Retinal Layer Thickness in Patients with Diabetes Mellitus

2021 ◽  
Author(s):  
Muhammet Cuneyt Bilginer ◽  
Abbas Ali Tam ◽  
Berna Evranos Ogmen ◽  
Bagdagul Yuksel Guler ◽  
Nagihan Ugurlu ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Diabetic Retinopathy ◽  
Layer Thickness ◽  
Disease Duration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Control Group ◽  
Retinal Layer ◽  
Healthy Controls ◽  
Total Thiol

Abstract Background: This study aimed to investigate the relationship between early changes in retinal layer thickness and thiol–disulfide homeostasis in patients with type II diabetes mellitus (T2DM).Materials-Methods: There were 69 patients with T2DM (61 patients without retinopathy, 8 patients with retinopathy) and 21 healthy controls. In patients without retinopathy, 31 of the patients had a disease duration under 10 years, 30 of the patients had a disease duration over 10 years. Retinal layer thickness of the right eye was measured using Spectral Domain Optical Coherence Tomography. Results: Patients with T2DM and healthy controls had mean ages of 48.40 ± 8.25 years and 45.94 ± 7.32 years, respectively. The ganglion cell layer and retinal pigment epithelium thicknesses were significantly lesser in patients without diabetic retinopathy than those in the control group. In patients without diabetic retinopathy and with a disease duration of under 10 years, there was a negative correlation between the retinal nerve fiber layer thickness (µm) and disulphide/total thiol ratio, between the inner nuclear layer thickness (µm) and disulphide/native thiol ratio as well as disulphide/total thiol ratio (r= −0.376, p= 0.037; r= −0.356, p= 0.050; r= −0.380, p= 0.035, respectively) and positive correlation between the INL thickness (µm) and native thiol/total thiol ratio (r= 0.359, p= 0.047).Conclusion: Early changes in retinal layers in patients with DM were associated with thiol–disulfide homeostasis. Administration of therapeutic supplements may aid in the management of low thiol concentrations; this increases the importance of the study findings.

scholarly journals Non-medical treatment for late age-related macular degeneration

2021 ◽  
Vol 21 (4) ◽  
pp. 215-219
Author(s):  
A.K. Drakon ◽  
◽  
A.G. Kurguzova ◽  
V.M. Sheludchenko ◽  
N.B. Korchazhkina ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Therapy ◽  
Medical Treatment ◽  
Macular Degeneration ◽  
Retinal Pigment ◽  
Embryonic Stem ◽  
Age Related Macular Degeneration ◽  
Target Cells ◽  
Specific Gene ◽  
Age Related

Age-related macular degeneration (AMD) is the leading cause of blindness in people over 55 in developed countries. Moreover, the number of these patients will increase growth as life expectancy increases. It is estimated that late AMD accounts for half of blindness and low vision cases in European countries. A myriad of studies is currently underway to discover cutting-edge, effective therapeutic modalities. Gene therapy is a novel alternative to regular intravitreal injections of anti-VEGF agents for late wet AMD. This technique’s heart is a specific gene delivery to target cells to generate natural VEGF inhibitors. Gene therapy affecting the complement system to deactivate its end product, the membrane attack complex, is reasonable in late atrophic AMD. Studies on stem cell therapy for late atrophic AMD undergo as well. It was demonstrated that retinal pigment epithelium (RPE) cells derived from human embryonic stem cells or induced pluripotent stem cells express typical RPE markers that can phagocytize photoreceptor segments. Electrical stimulation and magnet therapy are already introduced into clinical practice to rehabilitate patients with late AMD. Magnetic and electrical fields improve impulse transmitting, activate intracellular and tissue regeneration of the retina. Recent findings are promising but require further in-depth studies. Keywords: age-related macular degeneration, retinal scar, gene therapy, stem cells, physiotherapy, rehabilitative medicine. For citation: Drakon A.K., Kurguzova A.G., Sheludchenko V.M., Korchazhkina N.B. Non-medical treatment for late age-related macular degeneration. Russian Journal of Clinical Ophthalmology. 2021;21(4):215–219 (in Russ.). DOI: 10.32364/2311-7729-2021-21-4-215-219.

scholarly journals Resveratrol Modulates SIRT1 and DNMT Functions and Restores LINE-1 Methylation Levels in ARPE-19 Cells under Oxidative Stress and Inflammation

2018 ◽  
Vol 19 (7) ◽  
pp. 2118 ◽  
Author(s):  
Andrea Maugeri ◽  
Martina Barchitta ◽  
Maria Mazzone ◽  
Francesco Giuliano ◽  
Guido Basile ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Retinal Pigment ◽  
Sirtuin 1 ◽  
Age Related Macular Degeneration ◽  
Degenerative Diseases ◽  
P Values ◽  
Sirt1 Expression ◽  
Inflammatory Conditions ◽  
Age Related ◽  
Retinal Degenerative Diseases

The role of epigenetic alterations in the pathogenesis of retinal degenerative diseases, including age-related macular degeneration (AMD), has been pending so far. Our study investigated the effect of oxidative stress and inflammation on DNA methyltransferases (DNMTs) and Sirtuin 1 (SIRT1) functions, as well as on long interspersed nuclear element-1 (LINE-1) methylation, in human retinal pigment epithelial (ARPE-19) cells. Therefore, we evaluated whether treatment with resveratrol may modulate DNMT and SIRT1 functions and restore changes in LINE-1 methylation. Cells were treated with 25 mU/mL glucose oxidase (GOx) or 10 µg/mL lipopolysaccharide (LPS) to mimic oxidative or inflammatory conditions, respectively. Oxidative stress decreased DNMT1, DNMT3a, DNMT3b, and SIRT1 expression (p-values < 0.05), as well as total DNMTs (−28.5%; p < 0.0001) and SIRT1 (−29.0%; p < 0.0001) activities. Similarly, inflammatory condition decreased DNMT1 and SIRT1 expression (p-values < 0.05), as well as total DNMTs (−14.9%; p = 0.007) and SIRT1 (−20.1%; p < 0.002) activities. Interestingly, GOx- and LPS-treated cells exhibited lower LINE-1 methylation compared to controls (p-values < 0.001). We also demonstrated that treatment with 10 μM resveratrol for 24 h counteracted the detrimental effect on DNMT and SIRT1 functions, and LINE-1 methylation, in cells under oxidative and inflammatory conditions. However, further studies should explore the perspectives of resveratrol as a suitable strategy for the prevention and/or treatment of retinal degenerative diseases.

scholarly journals Autophagy activated via GRP78 to alleviate endoplasmic reticulum stress for cell survival in blue light-mediated damage of A2E-laden RPEs

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Jingyang Feng ◽  
Yuhong Chen ◽  
Bing Lu ◽  
Xiangjun Sun ◽  
Hong Zhu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Signaling Pathway ◽  
Blue Light ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Degenerative Diseases ◽  
Caspase 12 ◽  
Age Related ◽  
Retinal Degenerative Diseases

Abstract Background Retinal pigment epithelium cells (RPEs) are critical for maintaining retinal homeostasis. Accumulation of age-related lipofuscin, N-retinylidene-N-retinylethanolamine (A2E), makes RPEs vulnerable to blue light-mediated damage, which represents an initial cause of some retinal degenerative diseases. This study investigated the activation of autophagy and the signaling pathway involved in glucose-related protein 78 (GRP78) induced autophagy in blue light-mediated damage of A2E-laden RPEs. In addition, we explored whether autophagy could play a protective role by alleviating endoplasmic reticulum (ER) stress to promote RPEs survival. Methods RPEs were incubated with 25 μM A2E for 2 h and exposed to blue light for 20 min. The expression of ER stress-related apoptotic proteins, CHOP and caspase-12, as well as autophagy marker LC3 were measured by western blot analysis. Autophagosomes were observed by both transmission electron microscopy and immunofluorescence assays. GRP78 interference performed by short hairpin RNA (shRNA) was used to identify the signaling pathway involved in GRP78 induced autophagy. Cell death was assessed using TUNEL analysis. Results Treatment with A2E and blue light markedly increased the expression of ER stress-related apoptotic molecules CHOP and caspase-12. The activation of autophagy was recognized by observing autophagosomes at ultrastructural level. Additionally, punctate distributions of LC3 immunofluorescence and enhanced conversions of LC3-I to LC3-II were found in A2E and blue light-treated RPEs. Moreover, GRP78 interference reduced AMPK phosphorylation and promoted mTOR activity, thereby downregulating autophagy. In addition, the inhibition of autophagy made RPEs vulnerable to A2E and blue light damage. In contrast, the autophagy inducer rapamycin alleviated ER stress to promote RPEs survival. Conclusions GRP78 activates autophagy via AMPK/mTOR in blue light-mediated damage of A2E-laden RPEs in vitro. Autophagy may be a vital endogenous cytoprotective process to alleviate stress for RPEs survival in retinal degenerative diseases.

scholarly journals Transplanted embryonic retinal stem cells have the potential to repair the injured retina in mice

2021 ◽  
Author(s):  
Xia Feng ◽  
Peng Chen ◽  
Xin Zhao ◽  
Jing Wang ◽  
Hong Wang
Keyword(s):  
Stem Cells ◽  
Optic Nerve ◽  
Intravitreal Injection ◽  
Brdu Incorporation ◽  
Positive Staining ◽  
Degenerative Diseases ◽  
Nerve Crush ◽  
Body Tissues ◽  
Retinal Degenerative Diseases

Abstract Background: Stem cell transplantation has been reported as one of the promising strategies to treat retinal degenerative diseases. But, the application and the role of retina stem cells (RSCs) in the treatment of patients with retinal degenerative diseases have not been fully revealed. This study aimed to investigate the potential role of transplantation of the embryo-derived RSCs into the vitreous cavity in repairing the damaged retina in mice.Methods: RSCs were isolated from Kunming mice E17 embryonic retina and ciliary body tissues, and labeled with 5-bromo-2’-deoxyuridin (BrdU). Retinal optic nerve crush injury was induced in left eyes in male Kunming mice by ring clamping the optic nerve. The 6th-generation of BrdU-labeled RSCs were transplanted into the damaged retina by the intravitreal injection, and saline injected eyes were used as the control. Hematoxylin and eosin histological staining, and BrdU, Nestin and Pax6 immunostaining were performed. Electroretinogram (ERG) was used for assessing the electrical activity of the retina.Results: Embryo-derived RSCs were identified by the positive stains of Pax6 and Nestin. BrdU incorporation was detected in the majority of RSCs. The damaged retina showed cellular nuclear disintegration and fragmentation in the retinal tissue which progressed over the periods of clamping time, and decreased amplitudes of a and b waves in ERG. In the damaged retina with RSCs transplantation, the positive staining for BrdU, Pax6 and Nestin were revealed on the retinal surface. Notably, RSCs migrated into the retinal ganglion cell layer and inner nuclear. Transplanted RSCs significantly elevated the amplitudes of a waves in retina injured eyes.Conclusions: Embryonic RSCs have similar characteristics to neural stem cells. Transplantation of RSCs by intravitreal injection would be able to repair the damaged retina.

Gene therapy in inherited retinal degenerative diseases, a review

2018 ◽  
Vol 39 (5) ◽  
pp. 560-568 ◽  
Author(s):  
Vitor K. L. Takahashi ◽  
Júlia T. Takiuti ◽  
Ruben Jauregui ◽  
Stephen H. Tsang
Keyword(s):  
Gene Therapy ◽  
Degenerative Diseases ◽  
Retinal Degenerative Diseases
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