Human Stem Cell Transplantation for Retinal Degenerative Diseases. Where Are We Now?

Background and Objectives: Irreversible visual impairment is mainly caused by retinal degenerative diseases such as age-related macular degeneration and retinitis pigmentosa. Stem cell research has experienced rapid progress in recent years, and researchers and clinical ophthalmologists are trying to implement this promising technology to treat retinal degeneration. The objective of this systematic review is to analyze currently available data from clinical trials applying stem cells to treat human retinal diseases. Materials and Methods: We performed a systematic literature search in PubMed to identify articles related with stem cell therapies to retinal diseases published prior to September 2021. Furthermore, a systematic search in ClinicalTrials (NIH U.S. National Library of Medicine) was performed to identify clinical trials using stem cells to treat retinal diseases. A descriptive analysis of status, conditions, phases, interventions, and outcomes is presented here. Conclusions: To date, no available therapy based on stem cell transplantation is approved for use with patients. However, numerous clinical trials are currently finishing their initial phases and, in general, the outcomes related to implantation techniques and their long-term safety seem promising. In the next few years, we expect to see quantifiable results pertaining to visual function improvement.

The interplay of autophagy and oxidative stress in the pathogenesis and therapy of retinal degenerative diseases

Oxidative stress is mainly caused by intracellular reactive oxygen species (ROS) production, which is highly associated with normal physiological homeostasis and the pathogenesis of diseases, particularly ocular diseases. Autophagy is a self-clearance pathway that removes oxidized cellular components and regulates cellular ROS levels. ROS can modulate autophagy activity through transcriptional and posttranslational mechanisms. Autophagy further triggers transcription factor activation and degrades impaired organelles and proteins to eliminate excessive ROS in cells. Thus, autophagy may play an antioxidant role in protecting ocular cells from oxidative stress. Nevertheless, excessive autophagy may cause autophagic cell death. In this review, we summarize the mechanisms of interaction between ROS and autophagy and their roles in the pathogenesis of several ocular diseases, including glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and optic nerve atrophy, which are major causes of blindness. The autophagy modulators used to treat ocular diseases are further discussed. The findings of the studies reviewed here might shed light on the development and use of autophagy modulators for the future treatment of ocular diseases.

Renormalization of metabolic coupling treats age-related degenerative disorders: an oxidative RPE niche fuels the more glycolytic photoreceptors

Retinitis pigmentosa is characterized by a dysregulation within the metabolic coupling of the retina, particularly between the glycolytic photoreceptors and the oxidative retina pigment epithelium. This phenomenon of metabolic uncoupling is seen in both aging and retinal degenerative diseases, as well as across a variety of cell types in human biology. Given its crucial role in the health and maintenance of these cell types, the metabolic pathways involved present a suitable area for therapeutic intervention. Herein, this review covers the scope of this delicate metabolic interplay, its dysregulation, how it relates to the retina as well other cell types, and finally concludes with a summary of various strategies aimed at reinstating normal metabolic coupling within the retina, and future directions within the field.

The Role of Inflammation in Retinal Neurodegeneration and Degenerative Diseases

Retinal neurodegeneration is predominantly reported as the apoptosis or impaired function of the photoreceptors. Retinal degeneration is a major causative factor of irreversible vision loss leading to blindness. In recent years, retinal degenerative diseases have been investigated and many genes and genetic defects have been elucidated by many of the causative factors. An enormous amount of research has been performed to determine the pathogenesis of retinal degenerative conditions and to formulate the treatment modalities that are the critical requirements in this current scenario. Encouraging results have been obtained using gene therapy. We provide a narrative review of the various studies performed to date on the role of inflammation in human retinal degenerative diseases such as age-related macular degeneration, inherited retinal dystrophies, retinitis pigmentosa, Stargardt macular dystrophy, and Leber congenital amaurosis. In addition, we have highlighted the pivotal role of various inflammatory mechanisms in the progress of retinal degeneration. This review also offers an assessment of various therapeutic approaches, including gene-therapies and stem-cell-based therapies, for degenerative retinal diseases.

Shaping the Microglia in Retinal Degenerative Diseases Using Stem Cell Therapy: Practice and Prospects

Retinal degenerative disease (RDD) refers to a group of diseases with retinal degeneration that cause vision loss and affect people’s daily lives. Various therapies have been proposed, among which stem cell therapy (SCT) holds great promise for the treatment of RDDs. Microglia are immune cells in the retina that have two activation phenotypes, namely, pro-inflammatory M1 and anti-inflammatory M2 phenotypes. These cells play an important role in the pathological progression of RDDs, especially in terms of retinal inflammation. Recent studies have extensively investigated the therapeutic potential of stem cell therapy in treating RDDs, including the immunomodulatory effects targeting microglia. In this review, we substantially summarized the characteristics of RDDs and microglia, discussed the microglial changes and phenotypic transformation of M1 microglia to M2 microglia after SCT, and proposed future directions for SCT in treating RDDs.

Retinal degeneration: molecular mechanisms and therapeutic strategies

: 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.

Human-in-the-loop optimization of visual prosthetic stimulation

Retinal prostheses are a promising strategy to restore sight to patients with retinal degenerative diseases. These devices compensate for the loss of photoreceptors by electrically stimulating neurons in the retina. Currently, the visual function that can be recovered with such devices is very limited. This is due, in part, to current spread, unintended axonal activation, and the limited resolution of existing devices. Here we show, using a recent model of prosthetic vision, that optimizing how visual stimuli are encoded by the device can help overcome some of these limitations, leading to dramatic improvements in visual perception. We propose a strategy to do this in practice, using patients' feedback in a visual task. The main challenge of our approach comes from the fact that, typically, one only has access to a limited number of noisy responses from patients. We propose two ways to deal with this: first, we use a model of prosthetic vision to constrain and simplify the optimisation; second, we use preferential Bayesian optimisation to efficiently learn the encoder using minimal trials. As a proof-of concept, we presented healthy subjects with visual stimuli generated by a recent model of prosthetic vision, to replicate the perceptual experience of patients fitted with an implant. Our optimisation procedure led to significant and robust improvements in perceived image quality, that transferred to increased performance in other tasks. Importantly, our strategy is agnostic to the type of prosthesis and thus could readily be implemented in existing implants.

Therapeutic effects of mesenchymal stem cells-derived extracellular vesicles’ miRNAs on retinal regeneration: a review

Extracellular vesicles (EVs), which consist of microvesicles and exosomes, are secreted from all cells to transform vital information in the form of lipids, proteins, mRNAs and small RNAs such as microRNAs (miRNAs). Many studies demonstrated that EVs’ miRNAs have effects on target cells. Numerous people suffer from the blindness caused by retinal degenerations. The death of retinal neurons is irreversible and creates permanent damage to the retina. In the absence of acceptable cures for retinal degenerative diseases, stem cells and their paracrine agents including EVs have become a promising therapeutic approach. Several studies showed that the therapeutic effects of stem cells are due to the miRNAs of their EVs. Considering the effects of microRNAs in retinal cells development and function and studies which provide the possible roles of mesenchymal stem cells-derived EVs miRNA content on retinal diseases, we focused on the similarities between these two groups of miRNAs that could be helpful for promoting new therapeutic techniques for retinal degenerative diseases.

Monitoring Visual Cortical Activities During Progressive Retinal Degeneration Using Functional Bioluminescence Imaging

Mouse models of inherited retinal degenerative diseases such as retinitis pigmentosa are characterized by degeneration of photoreceptors, which hinders the generation of signal to be transmitted to the visual cortex. By monitoring Ca2+-bioluminescence neural activity, we quantified changes in visual cortical activities in response to visual stimuli in RD10 mice during progression of retinal degeneration, which correlated with progressive deteriorations of electro-retinography signal from the eyes. The number of active neurons in the visual cortex, the intensity of Ca2+-bioluminescence response, and neural activation parameter showed progressive deterioration during aging. Further, we correlated the thinning of retina as measured by Optical Coherence Tomography with the decrease in visual cortical activities as retinal degeneration progressed. The present study establishes Ca2+-bioluminescence monitoring as a longitudinal imaging modality to characterize activities in visual cortex of retinal degenerative disease models and therapeutic interventions.