Gene Therapy for Dominantly Inherited Retinal Degeneration

Farrar, G. Jane; Millington‐Ward, Sophia; Palfi, Arpad; Chadderton, Naomi; Kenna, Paul F.

doi:10.1007/978-3-662-45188-5_4

Cited by 2 publications

(4 citation statements)

References 125 publications

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“…Retinal degenerative diseases are the most common cause of blindness in industrial countries, substantially impacting both quality of life and healthcare costs [ 1 ]. Indeed, in the US alone, age-related visual impairment has a financial burden of over $5.5 billion per year [ 2 , 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world, affecting up to 20% of people over 65 years old [ 5 , 6 , 7 , 8 ]. Dry AMD is characterized by the irreversible loss of retinal pigment epithelium (RPE) cells, followed by a gradual loss of photoreceptors in later stages of the disease [ 1 , 9 ]. Unfortunately, there is currently no curative clinical treatment for AMD patients, and most current clinical interventions aim only slow progression of the disease [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Scaffold-Free Retinal Pigment Epithelium Microtissues Exhibit Increased Release of PEDF

Al-Ani

Toms

Sunba

et al. 2021

IJMS

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The retinal pigmented epithelium (RPE) plays a critical role in photoreceptor survival and function. RPE deficits are implicated in a wide range of diseases that result in vision loss, including age-related macular degeneration (AMD) and Stargardt disease, affecting millions worldwide. Subretinal delivery of RPE cells is considered a promising avenue for treatment, and encouraging results from animal trials have supported recent progression into the clinic. However, the limited survival and engraftment of transplanted RPE cells delivered as a suspension continues to be a major challenge. While RPE delivery as epithelial sheets exhibits improved outcomes, this comes at the price of increased complexity at both the production and transplant stages. In order to combine the benefits of both approaches, we have developed size-controlled, scaffold-free RPE microtissues (RPE-µTs) that are suitable for scalable production and delivery via injection. RPE-µTs retain key RPE molecular markers, and interestingly, in comparison to conventional monolayer cultures, they show significant increases in the transcription and secretion of pigment-epithelium-derived factor (PEDF), which is a key trophic factor known to enhance the survival and function of photoreceptors. Furthermore, these microtissues readily spread in vitro on a substrate analogous to Bruch’s membrane, suggesting that RPE-µTs may collapse into a sheet upon transplantation. We anticipate that this approach may provide an alternative cell delivery system to improve the survival and integration of RPE transplants, while also retaining the benefits of low complexity in production and delivery.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Scaffold-Free Retinal Pigment Epithelium Microtissues Exhibit Increased Release of PEDF

Al-Ani

Toms

Sunba

et al. 2021

IJMS

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“…When looking at age-related macular degeneration (AMD) specifically, the most common cause of visual dysfunction in industrialized countries, incidence increases to 20% of people over 65 years of age (Mitchell et al, 1995;Vingerling et al, 1995;Huang et al, 2003;Kashani et al, 2018). Absent injury or infection of the retina, most visual dysfunction qualifies as inherited retinal degeneration, a genetically heterogeneous group of disorders affecting the viability and function of rod and cone photoreceptors that can have autosomal, X-linked, and mitochondrial patterns of inheritance (Farrar et al, 2015;Thompson et al, 2015). Over 200 causative genes have been identified that affect multiple pathways and mechanisms associated with vision dysfunctions (Thompson et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Over 200 causative genes have been identified that affect multiple pathways and mechanisms associated with vision dysfunctions (Thompson et al, 2015). Retinal degenerative diseases can also be a consequence of genetic dysfunction in the underlying retinal pigment epithelium (RPE) or vasculature that support the retina (Bhutto and Lutty, 2012;Alexander et al, 2015;Farrar et al, 2015). Given the complexity and scope of the underlying causes, curative treatments are not currently available, with most clinical interventions aiming to slow the progression of the disorders (Rolling, 2004).…”

Section: Introductionmentioning

confidence: 99%

Automated Hypothesis Generation to Identify Signals Relevant in the Development of Mammalian Cell and Tissue Bioprocesses, With Validation in a Retinal Culture System

Toms

Al-Ani

Sunba

et al. 2020

Front. Bioeng. Biotechnol.

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We have developed an accessible software tool (receptoR) to predict potentially active signaling pathways in one or more cell type(s) of interest from publicly available transcriptome data. As proof-of-concept, we applied it to mouse photoreceptors, yielding the previously untested hypothesis that activin signaling pathways are active in these cells. Expression of the type 2 activin receptor (Acvr2a) was experimentally confirmed by both RT-qPCR and immunochemistry, and activation of this signaling pathway with recombinant activin A significantly enhanced the survival of magnetically sorted photoreceptors in culture. Taken together, we demonstrate that our approach can be easily used to mine publicly available transcriptome data and generate hypotheses around receptor expression that can be used to identify novel signaling pathways in specific cell types of interest. We anticipate that receptoR (available at https://www.ucalgary.ca/ungrinlab/receptoR) will enable more efficient use of limited research resources.

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Gene Therapy for Dominantly Inherited Retinal Degeneration

Cited by 2 publications

References 125 publications

Scaffold-Free Retinal Pigment Epithelium Microtissues Exhibit Increased Release of PEDF

Scaffold-Free Retinal Pigment Epithelium Microtissues Exhibit Increased Release of PEDF

Automated Hypothesis Generation to Identify Signals Relevant in the Development of Mammalian Cell and Tissue Bioprocesses, With Validation in a Retinal Culture System

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