Gene Therapy for Retinitis Pigmentosa Caused by <i>MFRP</i> Mutations: Human Phenotype and Preliminary Proof of Concept

Dinculescu, Astra; Estreicher, Jackie; Zenteno, Juan Carlos; Alemán, Tomás S.; Schwartz, Sharon; Huang, Wei; Román, Alejandro J.; Sumaroka, Alexander; Li, Qiuhong; Deng, Wen‐Tao; Min, Seok-Hong; Chiodo, Vince A.; Neeley, Andy W.; Li, Xuan; Shu, Xinhua; Matías-Florentino, Margarita; Buentello-Volante, Beatríz; Boye, Sanford L.; Cideciyan, Artur V.; Hauswirth, William W.; Jacobson, Samuel G.

doi:10.1089/hum.2011.169

Cited by 35 publications

(31 citation statements)

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“…These results demonstrate that injection of an rAAV8(Y733F) vector does not, per se, have any apparent effect on Tg(RHO P347S) PRs, and that the injection wound itself does not enhance PR survival. These findings also support the use of an uninjected eye as an appropriate control, as has been demonstrated by others (38)(39)(40).…”

Section: Pr Expression Of the Raav8(y733f)-hgrk1-stat3-flag Vector Insupporting

confidence: 88%

STAT3 promotes survival of mutant photoreceptors in inherited photoreceptor degeneration models

Jiang

Wright

Zhu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Inherited photoreceptor degenerations (IPDs), a group of incurable progressive blinding diseases, are caused by mutations in more than 200 genes, but little is known about the molecular pathogenesis of photoreceptor (PR) death. Increased retinal expression of STAT3 has been observed in response to many retinal insults, including IPDs, but the role of this increase in PR death is unknown. Here, we show that the expression of Stat3 is increased in PRs of the Tg(RHO P347S) and Prph2 rds/+ mouse models of IPD and is activated by tyrosine phosphorylation. PR-specific deletion of Stat3 substantially accelerated PR degeneration in both mutant strains. In contrast, increased PR-specific expression of ROSA26 (R26) alleles encoding either WT STAT3 (Stat3 C allele demonstrated increased a-wave amplitude of the scotopic electroretinogram. Phosphorylation of STAT3 at tyrosine 705 was required for the prosurvival effect because an R26-Stat3 Y705F allele was not protective. The prosurvival role of enhanced Stat3 activity was validated using recombinant adenoassociated virus (rAAV) vector-mediated PR Stat3 expression in Tg(RHO P347S) mice. Our findings (i) establish that the increase in endogenous PR Stat3 expression is a protective response in IPDs, (ii) suggest that therapeutic augmentation of PR Stat3 expression has potential as a common neuroprotective therapy for these disorders, and (iii) indicate that prosurvival molecules whose expression is increased in mutant PRs may have promise as novel therapies for IPDs.inherited photoreceptor degeneration | Stat3 | neuroprotection I nherited photoreceptor degenerations (IPDs) are associated with striking genetic heterogeneity, resulting from mutations in more than 200 genes (RetNet Retinal Information Network, sph.uth.edu/retnet/). At least 20 different classes of proteins are affected, and a broad range of biological processes are disrupted (1, 2). Despite this diversity of genetic etiology, disease progression may be regulated by shared pathways that either promote or resist photoreceptor (PR) death (3). The identification of responses to a PR mutation that are common to many if not most IPDs include the increased expression of endothelin 2 (3, 4), accumulation of reactive oxygen species (ROS) (1, 5), increased expression of GFAP (3, 6, 7), and exponential death kinetics (8,9). Some of these common events may have no influence on PR death, but others may represent general pathogenetic or survival responses that influence the rate of PR death, or even dictate it. The inhibition of common pathogenetic responses or the enhancement of shared prosurvival responses may constitute novel and potentially commonly applicable therapies for this largely untreatable group of inherited disorders.To identify common prosurvival or pathogenetic responses in IPDs, we first examined changes in retinal gene expression in two well-characterized IPD models, Tg(RHO P347S) and Prph2 rds/+ mice. We chose these two models because they are well-characterized, have substantially different rates of PR deat...

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Section: Pr Expression Of the Raav8(y733f)-hgrk1-stat3-flag Vector Insupporting

confidence: 88%

STAT3 promotes survival of mutant photoreceptors in inherited photoreceptor degeneration models

Jiang

Wright

Zhu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…A recent report by Dinculescu et al. (2012) suggested that the retinal dystrophy in MFRP mutations might be a target for gene‐based therapy.…”

Section: Discussionmentioning

confidence: 99%

Novel membrane frizzled‐related protein gene mutation as cause of posterior microphthalmia resulting in high hyperopia with macular folds

Wasmann

Wassink-Ruiter

Sundin

et al. 2013

Acta Ophthalmologica

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Purpose We present a genetic and clinical analysis of two sisters, 3 and 4 years of age, with nanophthalmos and macular folds. Methods Ophthalmological examination, general pediatric examination and molecular genetic analysis of the MFRP gene were performed in both affected siblings. Results Clinical analysis showed high hyperopia (+11 and +12 D), short axial lengths (15 mm), and the presence of macular folds and optic nerve head drusen. Autofluorescence of the retina was generally normal with subtle macular abnormalities. Sequence analysis showed compound heterozygosity for severe MFRP mutations in both sisters: a previously reported p.Asn167fs (c.498dupC) and a novel stop codon mutation p.Gln91X (c.271C>T). Conclusion These are the youngest nanophthalmos patients in the literature identified with severe loss of MFRP function, showing already the known structural abnormalities for this disease. Adult patients affected by homozygous or compound heterozygous MFRP mutations generally show signs of retinal dystrophy, with ERG disturbances and RPE abnormalities on autofluorescence imaging. ERG examination could not be performed in these children, but extensensive RPE abnormalities were not seen at this young age.

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“…Furthermore, funduscopic analysis and postmortem retinal morphology of vector-injected eyes were normal as compared to the controls (Conlon et al, 2013). Subretinal administration of AAV expressing the wild-type mouse Mfrp (membrane-type frizzledrelated protein) gene prevented retinal degeneration in the Rd6 Mfrp mutant mouse model of autosomal recessive RP (Dinculescu et al, 2012). CNGB1a (subunit of rod cyclic nucleotide-gated (CNG) channel) gene replacement via subretinal space AAV delivery restored the rod CNG channel expression and localization, improving retinal function and vision-guided behavior, and delaying retinal degeneration in autosomal recessive RP mouse model CNGB1 À/À (Koch et al, 2012).…”

Section: Viral-mediated Therapiesmentioning

confidence: 94%

Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases

Cuenca

Fernández‐Sánchez

Campello

et al. 2014

Progress in Retinal and Eye Research

344

394

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Gene Therapy for Retinitis Pigmentosa Caused by MFRP Mutations: Human Phenotype and Preliminary Proof of Concept

Cited by 35 publications

References 50 publications

STAT3 promotes survival of mutant photoreceptors in inherited photoreceptor degeneration models

STAT3 promotes survival of mutant photoreceptors in inherited photoreceptor degeneration models

Novel membrane frizzled‐related protein gene mutation as cause of posterior microphthalmia resulting in high hyperopia with macular folds

Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases

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