The Resveratrol Prodrug JC19 Delays Retinal Degeneration in rd10 Mice.

It has been reported that resveratrol (RES) has a therapeutic effect in different neurodegenerative and ocular diseases. However, RES is rapidly eliminated from the organism, and high doses need to be administered resulting in potential toxic side effects. We hypothesized that a RES prodrug such as 3,4'-diglucosyl resveratrol (JC19) would reduce RES metabolism to produce a neuroprotective effect. Here, we have examined the protective effect of JC19 in an experimental mouse model of autosomal recessive RP. Rd10 mice at postnatal day 13 (P13) were subretinally injected with vehicle and two different doses of JC19. Electroretinogram (ERG) and histological evaluation were performed 15 days after injections. The amplitude of a- and b-waves was quantified in ERG recordings, and the number of photoreceptor nuclei in the outer nuclear layer was counted. In addition, the mouse retinas were immunostained with anti-rhodopsin antibodies. JC19 treatment delayed the loss of rod photoreceptor in rd10 mice, maintaining the expression of rhodopsin and preserving their electrical responses to light stimuli. The exact mechanism by which RES delays retinal degeneration in rd10 mice remains to be elucidated, but Sirtuin 1 activation could be one of the key molecular pathways involved in its neuroprotective effect.

Subretinal Transplant of Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium on Nanostructured Fibrin-Agarose.

IMPACT STATEMENT: In the promising field of cellular therapy for retinal degenerative diseases, a new biomaterial is proposed as a scaffold to grow and surgically introduce a monolayer of retinal pigment epithelial cells into the subretinal space, keeping the orientation of the cells for a proper functional integration of the transplant. The use of induced pluripotent stem cells as the starting material for retinal pigment epithelial cells is intended to advance toward a personalized medicine approach.

Generation and characterization of the human iPSC line CABi001-A from a patient with retinitis pigmentosa caused by a novel mutation in PRPF31 gene.

PRPF31 gene codes for a ubiquitously expressed splicing factor but mutations affect exclusively the retina, producing the progressive death of photoreceptor cells. We have identified a novel PRPF31 mutation in a patient with autosomal dominant retinitis pigmentosa. A blood sample was obtained and mononuclear cells were reprogrammed using the non-integrative Sendai virus to generate the cell line CABi001-A. The iPSC line has been characterized for pluripotency and differentiation capacity and will be differentiated toward photoreceptors and retinal pigment epithelium cells to study the molecular mechanism of the disease and test possible therapeutic strategies.

Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins.

BACKGROUND: Mutations in pre-mRNA splicing factor PRPF31 can lead to retinitis pigmentosa (RP). Although the exact disease mechanism remains unknown, it has been hypothesized that haploinsufficiency might be involved in the pathophysiology of the disease. METHODS: In this study, we have analyzed a mouse model containing the p.A216P mutation in Prpf31 gene. RESULTS: We found that mutant Prpf31 protein produces cytoplasmic aggregates in the retinal pigment epithelium and decreasing the protein levels of this splicing factor in the nucleus. Additionally, normal protein was recruited in insoluble aggregates when the mutant protein was overexpressed in vitro. In response to protein aggregation, Hspa4l is overexpressed. This member of the HSP70 family of chaperones might contribute to the correct folding and solubilization of the mutant protein, allowing its translocation to the nucleus. CONCLUSIONS: Our data suggests that a mechanism haploinsufficiency and dominant-negative is involved in retinal degeneration due to mutations in PRPF31. HSP70 over-expression might be a new therapeutic target for the treatment of retinal degeneration due to PRPF31 mutations.

Generation of a human iPS cell line from a patient with retinitis pigmentosa due to EYS mutation.

Retinitis pigmentosa (RP) is an inherited retinal degenerative disease. Mutations in EYS have been associated with autosomal recessive RP. The human iPS cell line, CABi002-A, derived from peripheral blood mononuclear cells from a patient carrying a heterozygous double mutation in EYS gene was generated by non-integrative reprogramming technology, using hOCT3/4, hSOX2, hc-MYC and hKLF4 reprogramming factors. Pluripotency and differentiation capacity were assessed by immunocytochemistry and RT-PCR. This iPSC line can be further differentiated towards the affected cells to understand the pathophysiology of the disease and test new therapeutic strategies.

Rasagiline delays retinal degeneration in a mouse model of retinitis pigmentosa via modulation of Bax/Bcl-2 expression.

AIMS: Retinitis pigmentosa (RP) is an inherited disease characterized by a progressive degeneration of rod photoreceptors. An imbalance between pro- and antiapoptotic factors, such as Bax/Bcl-2, has been involved in retinal degeneration. To date, no cure or effective treatments are available for RP. Rasagiline is an antiparkinsonian drug that has shown neuroprotective effects in part attributed to a modulation of Bax/Bcl-2 expression. In this study, we have evaluated the use of rasagiline as a potential treatment for RP. METHODS: Newborn rd10 mice, a RP model, were treated with oral rasagiline during 30 days followed by a functional and morphological characterization of their mouse retinas. RESULTS: Treated animals showed a significant improvement in visual acuity and in the electrical responses of photoreceptors to light stimuli. Rasagiline delayed photoreceptor degeneration, which was confirmed not only by a high photoreceptor nuclei counting, but also by a sustained expression of photoreceptor-specific markers. In addition, the expression of proapoptotic Bax decreased, whereas the antiapoptotic factor Bcl-2 increased after rasagiline treatment. CONCLUSION: This study provides new evidences regarding the neuroprotective effect of rasagiline in the retina, and it brings new insight into the development of future clinical trials using this well-established antiparkinsonian drug to treat RP.