Long-Term Structural Outcomes of Late-Stage RPE65 Gene Therapy

Gardiner, Kristin L.; Cideciyan, Artur V.; Świder, Małgorzata; Dufour, Valérie; Sumaroka, Alexander; Komàromy, András M.; Hauswirth, William W.; Iwabe, Simone; Jacobson, Samuel G.; Beltran, William A.; Aguirre, Gustavo D.

doi:10.1016/j.ymthe.2019.08.013

Cited by 62 publications

(61 citation statements)

References 49 publications

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“…With the relevant cell type identified, we tested the therapeutic potential of AAV-mediated gene replacement, an FDA-approved approach for LCA2 and an area of intense interest in the retinal degeneration field [33][34][35][36] . Using a variant of AAV8 37,38 , we found that gene replacement of NMNAT1 in photoreceptors ameliorates the retinal degeneration and visual impairment caused by loss of NMNAT1.…”

Section: Nmnat1 Plays Important Roles In Diverse Retinal Functions Omentioning

confidence: 99%

SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration

Sasaki

Kakita

Kubota

et al. 2020

Preprint

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Leber congenital amaurosis type 9 (LCA9) is an autosomal recessive, early onset retinal neurodegenerative disease caused by mutations in the gene encoding the nuclear NAD + synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1 and its role in NAD + homeostasis, LCA9 patients do not manifest pathologies other than retinal degeneration.To investigate the mechanism of degeneration, we examined retinas of developing and adult mice with conditional or tissue-specific NMNAT1 loss. Widespread NMNAT1 depletion in adult mice resulted in loss of photoreceptors, indicating these cells are exquisitely vulnerable to NMNAT1 loss. NMNAT1 is required within the photoreceptor, as conditional deletion of NMNAT1 in photoreceptors but not retinal pigment epithelial cells is sufficient to cause photoreceptor neurodegeneration and vision loss. Moreover, delivery of NMNAT1 into eyes of adult mice lacking NMNAT1 using a modified AAV8 vector containing a photoreceptor-specific promoter rescued the retinal degeneration phenotype and partially restored vision. Finally, we defined the molecular mechanism driving photoreceptor cell death. Loss of NMNAT1 activates SARM1, an inducible NADase best known as the central executioner of axon degeneration. SARM1 is required for the photoreceptor death and vision loss that occurs following NMNAT1 deletion. This surprising finding demonstrates that the essential function of NMNAT1 in photoreceptors is to inhibit SARM1, and establishes a commonality of mechanism between axonal degeneration and photoreceptor neurodegeneration. These results define a novel SARM1-dependent photoreceptor cell death pathway that is active in the setting of dysregulated NAD + metabolism and identifies SARM1 as a therapeutic candidate for the treatment of retinal degeneration.

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Section: Nmnat1 Plays Important Roles In Diverse Retinal Functions Omentioning

confidence: 99%

SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration

Sasaki

Kakita

Kubota

et al. 2020

Preprint

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“…In contrast, some other studies found that gene therapies after the onset of degeneration stopped further progression of degeneration (18)(19)(20)(21)(22). A recent study conducted in an RPE65 dog model found that the long-term outcome of gene therapy was dependent on the health of the photoreceptor cell layer; gene therapy arrested retinal degeneration in areas where more than 63% of photoreceptors were remaining at the time of intervention, but retinal degeneration continued in areas with fewer retained photoreceptors (23).…”

Section: Introductionmentioning

confidence: 95%

“…Although the efficacy of retinal gene therapies is well established when the treatment is given before the onset or at early stages of a disease, long-term effects of mid-to-late stage gene therapies are controversial (15)(16)(17)(18)(19)(20)(21)(22)(23). In most proof-of-concept preclinical studies, therapeutic genes were delivered before degeneration became evident.…”

Section: Introductionmentioning

confidence: 99%

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

Datta

Ruffcorn

Seo

2020

Preprint

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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 longterm 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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“…It was found that, in retinal regions with a lower proportion of normal photoreceptors (< 63%), degeneration progresses similarly to untreated regions. It is therefore expected that gene therapy may not stop the progressive degeneration of the entire retina (Gardiner et al 2020). Successful gene therapy has also been reported for canine X-linked retinitis pigmentosa (XLRP), which is caused by a mutation of the retinitis pigmentosa GTPase regulator (RPGR) gene (Beltran et al 2012).…”

Section: Eye Diseasesmentioning

confidence: 99%

Impact of gene therapy for canine monogenic diseases on the progress of preclinical studies

Świtoński

2020

J Appl Genetics

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Rapid progress in knowledge of the organization of the dog genome has facilitated the identification of the mutations responsible for numerous monogenic diseases, which usually present a breed-specific distribution. The majority of these diseases have clinical and molecular counterparts in humans. The affected dogs have thus become valuable models for preclinical studies of gene therapy for problems such as eye diseases, immunodeficiency, lysosomal storage diseases, hemophilia, and muscular dystrophy. Successful gene therapies in dogs have significantly contributed to decisions to run clinical trials for several human diseases, such as Leber's congenital amaurosis 2-LCA2 (caused by a mutation of RPE65), X-linked retinitis pigmentosa-XLRP (caused by mutation RPGR), and achromatopsia (caused by mutation of CNGB3). Promising results were also obtained for canine as follows: hemophilia (A and B), mucopolysaccharidoses (MPS I, MPS IIIB, MPS VII), leukocyte adhesion deficiency (CLAD), and muscular dystrophy (a counterpart of human Duchenne dystrophy). Present knowledge on molecular background of canine monogenic diseases and their successful gene therapies prove that dogs have an important contribution to preclinical studies.

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Long-Term Structural Outcomes of Late-Stage RPE65 Gene Therapy

Cited by 62 publications

References 49 publications

SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration

SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration

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

Impact of gene therapy for canine monogenic diseases on the progress of preclinical studies

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