Emerging Gene Therapy Approaches Under Clinical Investigation for Retinal Degenerative Diseases

2020 ◽  
pp. 257-272
Author(s):  
Benjamin Bakall ◽  
Kendra Klein ◽  
Katrina Mears
Keyword(s):  
Gene Therapy ◽  
Clinical Investigation ◽  
Degenerative Diseases ◽  
Retinal Degenerative Diseases

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

scholarly journals Extracellular vesicles and their miRNA cargo in retinal health and degeneration: mediators of homeostasis, and vehicles for targeted gene therapy

2020 ◽  
Author(s):  
Yvette Wooff ◽  
Adrian V. Cioanca ◽  
Joshua A. Chu-Tan ◽  
Riemke Aggio-Bruce ◽  
Ulrike Schumann ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Cell Death ◽  
Immune Responses ◽  
Oxidative Damage ◽  
Extracellular Vesicles ◽  
Immune Modulation ◽  
Degenerative Diseases ◽  
Retinal Degenerative Diseases ◽  
Targeted Gene Therapy ◽  
Small Rnaseq

1.1.AbstractPurposePhotoreceptor cell death and inflammation are known to occur progressively in retinal degenerative diseases, however the molecular mechanisms underlying these biological processes are largely unknown. Extracellular vesicles (EV) are essential mediators of cell-to-cell communication with emerging roles in the modulation of immune responses. EVs including exosomes encapsulate and transfer nucleic acids, including microRNA (miRNA), to recipient cells which in disease may result in dysfunctional immune responses and a loss of homeostatic regulation. In this work we investigated the role of isolated retinal small-medium sized EV (s-mEV) which includes exosomes in both the healthy and degenerating retina.MethodsIsolated s-mEV from normal retinas were characterized using dynamic light scattering, transmission electron microscopy and western blotting, and quantified across 5 days of photo-oxidative damage-induced degeneration using nanotracking analysis. Small RNAseq was used to characterize the miRNA cargo of retinal s-mEV isolated from healthy and damaged retinas. Finally, the effect of exosome inhibition on cell-to-cell miRNA transfer and immune modulation was conducted using systemic daily administration of exosome inhibitor GW4869 and in situ hybridization of s-mEV-abundant miRNA, miR-124-3p. Electroretinography and immunohistochemistry was performed to assess functional and morphological changes to the retina as a result of GW4869-induced exosome depletion.ResultsResults demonstrated an inverse correlation between s-mEV secretion and photoreceptor survivability, with a decrease in s-mEV numbers following degeneration. Small RNAseq revealed that s-mEVs contained uniquely enriched miRNAs in comparison to in whole retinal tissue however, there was no differential change in the s-mEV miRNAnome following photo-oxidative damage. Exosome inhibition via the use of GW4869 was also found to exacerbate retinal degeneration, with reduced retinal function and increased levels of inflammation and cell death demonstrated following photo-oxidative damage in exosome-inhibited mice. Further, GW4869-treated mice displayed impaired translocation of photoreceptor-derived miR-124-3p to the inner retina during damage.ConclusionsTaken together, we propose that retinal s-mEV and their miRNA cargo play an essential role in maintaining retinal homeostasis through immune-modulation, and have the potential to be used in targeted gene therapy for retinal degenerative diseases.

scholarly journals Cone Specific Promoter for Use in Gene Therapy of Retinal Degenerative Diseases

2014 ◽  
pp. 695-701 ◽  
Author(s):  
Frank M. Dyka ◽  
Sanford L. Boye ◽  
Renee C. Ryals ◽  
Vince A. Chiodo ◽  
Shannon E. Boye ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Degenerative Diseases ◽  
Retinal Degenerative Diseases

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.

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