Retinoschisin Gene Therapy and Natural History in theRs1h-KO Mouse: Long-term Rescue from Retinal Degeneration

Optogenetic strategies to restore vision in patients who are blind from end-stage retinal degenerations aim to render remaining retinal cells light sensitive once photoreceptors are lost. Here, we assessed long-term functional outcomes following subretinal delivery of the human melanopsin gene (OPN4) in the rd1 mouse model of retinal degeneration using an adeno-associated viral vector. Ectopic expression of OPN4 using a ubiquitous promoter resulted in cellular depolarization and ganglion cell action potential firing. Restoration of the pupil light reflex, behavioral light avoidance, and the ability to perform a task requiring basic image recognition were restored up to 13 mo following injection. These data suggest that melanopsin gene therapy via a subretinal route may be a viable and stable therapeutic option for the treatment of end-stage retinal degeneration in humans.

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Limited time window for retinal gene therapy in a preclinical model of ciliopathy

Human Molecular Genetics ◽

10.1093/hmg/ddaa124 ◽

2020 ◽

Vol 29 (14) ◽

pp. 2337-2352

Author(s):

Poppy Datta ◽

Avri Ruffcorn ◽

Seongjin Seo

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Retinal Degeneration ◽

Time Window ◽

Therapeutic Effects ◽

Limited Time ◽

Term Efficacy ◽

Disease Stages ◽

Retinal Gene Therapy

Abstract Retinal degeneration is a common clinical feature of ciliopathies, a group of genetic diseases linked to ciliary dysfunction, and gene therapy is an attractive treatment option to prevent vision loss. Although the efficacy of retinal gene therapy is well established by multiple proof-of-concept preclinical studies, its long-term effect, particularly when treatments are given at advanced disease stages, is controversial. Incomplete treatment and intrinsic variability of gene delivery methods may contribute to the variable outcomes. Here, we used a genetic rescue approach to ‘optimally’ treat retinal degeneration at various disease stages and examined the long-term efficacy of gene therapy in a mouse model of ciliopathy. We used a Bardet–Biedl syndrome type 17 (BBS17) mouse model, in which the gene-trap that suppresses Bbs17 (also known as Lztfl1) expression can be removed by tamoxifen administration, restoring normal gene expression systemically. Our data indicate that therapeutic effects of retinal gene therapy decrease gradually as treatments are given at later stages. These results suggest the presence of limited time window for successful gene therapy in certain retinal degenerations. Our study also implies that the long-term efficacy of retinal gene therapy may depend on not only the timing of treatment but also other factors such as the function of mutated genes and residual activities of mutant alleles.

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Reply to Townes-Anderson: RPE65 gene therapy does not alter the natural history of retinal degeneration

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1304296110 ◽

2013 ◽

Vol 110 (19) ◽

pp. E1706-E1706 ◽

Cited By ~ 2

Author(s):

A. V. Cideciyan ◽

S. G. Jacobson ◽

W. A. Beltran ◽

W. W. Hauswirth ◽

G. D. Aguirre

Keyword(s):

Gene Therapy ◽

Natural History ◽

Retinal Degeneration ◽

History Of

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Limited time window for retinal gene therapy in a preclinical model of ciliopathy

10.1101/2020.05.05.072793 ◽

2020 ◽

Author(s):

Poppy Datta ◽

Avri Ruffcorn ◽

Seongjin Seo

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Retinal Degeneration ◽

Time Window ◽

Therapeutic Effects ◽

Limited Time ◽

Term Efficacy ◽

Disease Stages ◽

Retinal Gene Therapy

ABSTRACTRetinal degeneration is a common clinical feature of ciliopathies, a group of genetic diseases linked to ciliary dysfunction, and gene therapy is an attractive treatment option to prevent vision loss. Although the efficacy of retinal gene therapy is well established by multiple proof-of-concept preclinical studies, its long-term effect, particularly when treatments are given at advanced disease stages, is controversial. Incomplete treatment and intrinsic variability of gene delivery methods may contribute to the variable outcomes. Here, we used a genetic rescue approach to “optimally” treat retinal degeneration at various disease stages and examined the long-term efficacy of gene therapy in a mouse model of ciliopathy. We used a Bardet-Biedl syndrome type 17 (BBS17) mouse model, in which the gene-trap that suppresses Bbs17 (also known as Lztfl1) expression can be removed by tamoxifen administration, restoring normal gene expression systemically. Our data indicate that therapeutic effects of retinal gene therapy decrease gradually as treatments are given at later stages. These results suggest the presence of limited time window for successful gene therapy in certain retinal degenerations. Our study also implies that the long-term efficacy of retinal gene therapy may depend on not only the timing of treatment but also other factors such as the function of mutated genes and residual activities of mutant alleles.

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Reduction of major amputations in the diabetic ischaemic foot: A strategy to "take control" with conservative care as well as revascularisation

VASA ◽

10.1024/0301-1526.30.s58.6 ◽

2001 ◽

Vol 30 (Supplement 58) ◽

pp. 6-14 ◽

Cited By ~ 13

Author(s):

Edmonds ◽

Foster

Keyword(s):

Natural History ◽

Treatment Plan ◽

Staging System ◽

Vascular Control ◽

New Approach ◽

Conservative Care ◽

Arterial Bypass ◽

Therapeutic Footwear ◽

Frequent Problem

The diabetic ischaemic foot has become an increasingly frequent problem over the last decade. However, we report a new approach consisting of a basic classification, a simple staging system of the natural history and a treatment plan for each stage, within a multi-disciplinary framework. This approach of "taking control" consists of two parts: 1. long-term conservative care including debridement of ulcers (to obtain wound control), eradication of sepsis (micribiological control), and provision of therapeutic footwear (mechanical control), and 2. revascularisation by angioplasty and arterial bypass (vascular control). This approach has led to a 50% reduction in the rate of major amputations in patients attending with ischaemic ulceration and absent foot pulses from 1989 to 1999 (from 4.6% to 2.3% per year). Patients who underwent angioplasty increased from 6% to 13%. Arterial bypass similarly increased from 3% to 7% of cases. However, even with an increased rate of revascularisation, 80% of patients responded to conservative care alone. This,we conclude, is an essential part of the management of all patients with ischaemic feet.

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