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Abstract Inherited retinal dystrophies are an important cause of blindness, for which currently there are no effective treatments. In order to study this heterogeneous group of diseases, adequate disease models are required in order to better understand pathology and to test potential therapies. Induced pluripotent stem cells offer a new way to recapitulate patient specific diseases in vitro, providing an almost limitless amount of material to study. We used fibroblast-derived induced pluripotent stem cells to generate retinal pigment epithelium (RPE) from an individual suffering from retinitis pigmentosa associated with biallelic variants in MERTK. MERTK has an essential role in phagocytosis, one of the major functions of the RPE. The MERTK deficiency in this individual results from a nonsense variant and so the MERTK-RPE cells were subsequently treated with two translational readthrough inducing drugs (G418 & PTC124) to investigate potential restoration of expression of the affected gene and production of a full-length protein. The data show that PTC124 was able to reinstate phagocytosis of labeled photoreceptor outer segments at a reduced, but significant level. These findings represent a confirmation of the usefulness of iPSC derived disease specific models in investigating the pathogenesis and screening potential treatments for these rare blinding disorders.

Inherited retinal dystrophies are an important cause of blindness, for which currently there are no effective treatments. In order to study this heterogeneous group of diseases, adequate disease models are required in order to better understand pathology and to test potential therapies. Induced pluripotent stem cells offer a new way to recapitulate patient specific diseases in vitro, providing an almost limitless amount of material to study. We used fibroblast-derived induced pluripotent stem cells to generate retinal pigment epithelium (RPE) from an individual suffering from retinitis pigmentosa associated with biallelic variants in MERTK. MERTK has an essential role in phagocytosis, one of the major functions of the RPE. The MERTK deficiency in this individual results from a nonsense variant and so the MERTK-RPE cells were subsequently treated with two translational readthrough inducing drugs (G418 & PTC124) to investigate potential restoration of expression of the affected gene and production of a full-length protein. The data show that PTC124 was able to reinstate phagocytosis of labeled photoreceptor outer segments at a reduced, but significant level. These findings represent a confirmation of the usefulness of iPSC derived disease specific models in investigating the pathogenesis and screening potential treatments for these rare blinding disorders.

Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is a rare, early-onset retinal dystrophy characterised by distinct bands of circumferential pigmentary degeneration in the peripheral retina and developmental eye defects. ADVIRC is caused by mutations in the Bestrophin1 (BEST1) gene, which encodes a transmembrane protein thought to function as an ion channel in the basolateral membrane of retinal pigment epithelial (RPE) cells. Previous studies suggest that the distinct ADVIRC phenotype results from alternative splicing of BEST1 pre-mRNA. Here, we have used induced pluripotent stem cell (iPSC) technology to investigate the effects of an ADVIRC associated BEST1 mutation (c.704T > C, p.V235A) in patient-derived iPSC-RPE. We found no evidence of alternate splicing of the BEST1 transcript in ADVIRC iPSC-RPE, however in patient-derived iPSC-RPE, BEST1 was expressed at the basolateral membrane and the apical membrane. During human eye development we show that BEST1 is expressed more abundantly in peripheral RPE compared to central RPE and is also expressed in cells of the developing retina. These results suggest that higher levels of mislocalised BEST1 expression in the periphery, from an early developmental stage, could provide a mechanism that leads to the distinct clinical phenotype observed in ADVIRC patients.

Leber congenital amaurosis (LCA) is an inherited retinal dystrophy that causes childhood blindness. Photoreceptors are especially sensitive to an intronic mutation in the cilia-related gene CEP290, which causes missplicing and premature termination, but the basis of this sensitivity is unclear. Here, we generated differentiated photoreceptors in three-dimensional optic cups and retinal pigment epithelium (RPE) from iPSCs with this common CEP290 mutation to investigate disease mechanisms and evaluate candidate therapies. iPSCs differentiated normally into RPE and optic cups, despite abnormal CEP290 splicing and cilia defects. The highest levels of aberrant splicing and cilia defects were observed in optic cups, explaining the retinal-specific manifestation of this CEP290 mutation. Treating optic cups with an antisense morpholino effectively blocked aberrant splicing and restored expression of full-length CEP290, restoring normal cilia-based protein trafficking. These results provide a mechanistic understanding of the retina-specific phenotypes in CEP290 LCA patients and potential strategies for therapeutic intervention.

Mangroves provide numerous ecological, social, and economic benefits that include carbon sequestration, habitat for biodiversity, food, recreation and leisure, income, and coastal resilience. In this regard, mangrove-based carbon market projects (MbCMP), involving mangrove conservation, protection, and restoration, are a nature-based solution (NbS) for climate change mitigation. Despite the proliferation of blue carbon projects, a highly publicized need for local community participation by developers, and existing project implementation standards, local communities are usually left out for several reasons, such as a lack of capacity to engage in business-to-business (B2B) market agreements and communication gaps. Local communities need to be engaged and supported at all stages of the MbCMP development process to enable them to protect their ecological, economic, and social interests as custodians of such a critical ecosystem. In this paper, we provided 15 strategic considerations and recommendations to engage and secure the interests of local communities in the growing mangrove carbon market trade. The 15 considerations are grouped into four recommendation categories: (i) project development and community engagement, (ii) capacity building and educational activities, (iii) transparency in resource allocation and distribution, and (iv) partnerships with local entities and long-term monitoring. We expect our study to increase local participation and community-level ecological, social, and economic benefits from MbCMP by incorporating equitable benefit-sharing mechanisms in a B2B conservation-agreement model.

In this study five new records and two probably undescribed species of heterobranch sea slugs placed in four genera, three families, and two orders are reported from Kuwait, northwestern Arabian / Persian Gulf with details and photographs. The present study increases the heterobranch diversity in Kuwaiti waters from 35 to 40 species. The range of habitats in Kuwait provides a vital opportunity for further investigation to understand the actual faunal diversity.

Adenine phosphoribosyltransferase enzyme deficiency is a rare, autosomal recessive disorder. It is a disease limited to the renal system and usually presents with urolithiasis. Herein, we report a young female with dihydroxyadenine (DHA) crystal-induced nephropathy presenting with rapidly progressive renal failure. DHA crystals can be easily diagnosed by their pathognomic color and shape in urine and biopsy specimens. A high index of clinical suspicion helps in the early diagnosis of this potentially treatable renal disease.