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Tao Zhang, Jingshan Bai, Xinyi Zhang, Xiaowei Zheng, Nan Lu, Zhongyin Liang, Ling Lin, Yongsong Chen | Frontiers in Medicine Overview The small nuclear ribonucleoprotein 200 kDa (SNRNP200) gene plays a key role in the maturation of pre-message RNA (pre-mRNA) splicing with the indication for the etiology of retinitis pigmentosa (RP). Gene recognition can facilitate the diagnosis of these patients for better clinical management, treatment and counseling. This study aimed to outline the causative mutation in a Chinese family and the pathogenic mechanism of this SNRNP200 mutation in RP. Eighteen individuals from the affected family underwent a complete ophthalmic examination. Whole exome sequencing (WES) was conducted to identify the pathogenic variant in the proband, which was then confirmed by Sanger sequencing. Expression of the SNRNP200 transcript in zebrafish was identified via whole mount in situ hybridization. Morpholino oligonucleotide (MO) and SNRNP200 wild and mutant mRNA were injected into zebrafish embryos followed by analyses of the systemic changes and retinal phenotypes using immunofluorescence. Heterozygous SNRNP200c.C6088T (p.Arg2030Cys) mutation was ascertained in two members of this family: the proband and his father (II-2). Overexpression of SNRNP200Arg2030Cys, but not SNRNP200WT caused systemic deformities in the wild-type zebrafish embryos with the retina primarily injured, and significantly increased death rates in the morphant embryos, in which the orthologous zebrafish SNRNP200 gene was blocked. In conclusion, this study reports a novel heterozygous SNRNP200c.C6088T mutation, which is evidenced to cause RP via a dominant-negative effect. Introduction Retinitis pigmentosa (RP) is reported as the most regular form of inherited degenerative retinal dystrophy, with a prevalence ranging between 1/3,500 to 1/5,000 among different countries worldwide (1, 2). Nyctalopia is one of the earliest and most common symptoms of RP, followed by subsequent constricted visual fields (VFs), and eventual loss of central vision caused by the degeneration of photoreceptor and retinal pigment epithelium (RPE) (3, 4). The fundus in RP is characterized by peripheral bone-spicule pigmentary deposits, attenuation of the artery, and waxy pallor of the optic nerve head. Outer nuclear layer attenuation and the loss of outer/inner segments of RPE in the macular area of the retina are the typical characteristics. The inheritance of RP could be in three modes, autosomal dominant RP (adRP), autosomal recessive RP, and X-linked RP. Thus far, 307 genes and gene loci have been shown to be involved in retina degeneration [Retnet database; reviewed in Daiger et al. (5)]. The majority of these genes are specifically expressed in the retina. Interestingly, 6 of 22 adRP-related genes code for universally expressed pre-mRNA splicing proteins that are essential splicing factors, called the small nuclear ribonucleoprotein particles (snRNPs). These genes include PRPF6 (MIM 613979) (6), PRPF31(MIM 606419) (7), PRPF8 (MIM 607300) (8), PRPF3 (MIM 607301) (9), PIM1-associated protein [RP9 (MIM 607331)] (10), and small nuclear ribonucleoprotein 200 kDa (SNRNP200) (11, 12). For most eukaryotic genes, the primarily transcribed RNA from the gene's DNA must be edited through a process called splicing before it becomes mature, and only then can it guide the synthesis of proteins. During the process of primary RNA editing, the sequence of the introns will be removed and the sequence of the exons will be connected together, through the actions of the spliceosome, primarily comprising U1, U2, U4/U6, and U5 snRNPs. The complex of U4/U6–U5 tri-snRNP is essential for installing and the catalytic process of the spliceosome structural rearrangements. Thus, any defect in the complex could possibly contribute to the pathogenesis of RP (13). SNRNP200 encodes hBrr2, which is one of the U5 snRNP-specific proteins (NP_054733.2) (14), containing 2,136 amino acids (15) and catalyzing the U4/U6 unwinding (16). It has been reported in the literature that the mutation of SNRNP200 can compromise the U4/U6 unwinding (11) and when blocked, could cause the demorphogenesis of rod photoreceptors in a zebrafish model (17). However, the exact pathogenic mechanism of the SNRNP200 mutations has never been demonstrated. Herein, we report one naturally occurring heterozygous mutation in SNRNP200, c.C6088T (p.Arg2030Cys), which associates with adRP in a Chinese family and investigate the pathogenic mechanism of this SNRNP200 mutation. Read the original article References 1. Hu DN. Genetic aspects of retinitis pigmentosa in China. American Journal Medical Genetics. (1982) 12:51–6. 2. Chizzolini M, Galan A, Milan E, Sebastiani A, Costagliola C, Parmeggiani F. Good epidemiologic practice in retinitis pigmentosa: from phenotyping to biobanking. Curr Genomics. (2011) 12:260–6. 3. Mendes HF, Van Der Spuy J, Chapple JP, Cheetham ME. Mechanisms of cell death in rhodopsin retinitis pigmentosa: implications for therapy. Trends Mol Med. (2005) 11:177–85. 4. Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. (2006) 368:1795–809. 5. Daiger SP, Sullivan LS, Bowne SJ, Rossiter BJF. (2020). RetNet. Available online at: https://sph.uth.edu/retnet/ 6. Tanackovic G, Ransijn A, Ayuso C, Harper S, Berson EL, Rivolta C. A missense mutation in PRPF6 causes impairment of pre-mRNA splicing and autosomal-dominant retinitis pigmentosa. Am J Hum Genet. (2011) 88:643–9. 7. Vithana EN, Abu-Safieh L, Allen MJ, Carey A, Papaioannou M, Chakarova C, et al. A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4. (RP11). Mol. Cell. (2001) 8:375–81. 8. Mckie AB, Mchale JC, Keen TJ, Tarttelin EE, Goliath R, Van Lith-Verhoeven JJ, et al. Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13). Hum Mol Genet. (2001) 10:1555–62. 9. Chakarova CF, Hims MM, Bolz H, Abu-Safieh L, Patel RJ, Papaioannou MG, et al. Mutations in HPRP3, a third member of pre-mRNA splicing factor genes, implicated in autosomal dominant retinitis pigmentosa. Hum Mol Genet. (2002) 11:87–92. 10. Keen TJ, Hims MM, Mckie AB, Moore AT, Doran RM, Mackey DA, et al. Mutations in a protein target of the Pim-1 kinase associated with the RP9 form of autosomal dominant retinitis pigmentosa. Eur J Hum Genet. (2002) 10:245–9. 11. Zhao C, Bellur DL, Lu S, Zhao F, Grassi MA, Bowne SJ, et al. Autosomal-dominant retinitis pigmentosa caused by a mutation in SNRNP200, a gene required for unwinding of U4/U6 snRNAs. Am J Hum Genet. (2009) 85:617–27. 12. Li N, Mei H, Macdonald IM, Jiao X, Hejtmancik JF. Mutations in ASCC3L1 on 2q11.2 are associated with autosomal dominant retinitis pigmentosa in a Chinese family. Invest Ophthalmol Vis Sci. (2010) 51:1036–43. 13. Laggerbauer B, Liu S, Makarov E, Vornlocher HP, Makarova O, Ingelfinger D, et al. The human U5 snRNP 52K protein. (CD2BP2) interacts with U5-102K. (hPrp6), a U4/U6.U5 tri-snRNP bridging protein, but dissociates upon tri-snRNP formation. RNA. (2005) 11:598–608. 14. Liu T, Jin X, Zhang X, Yuan H, Cheng J, Lee J, et al. A novel missense SNRNP200 mutation associated with autosomal dominant retinitis pigmentosa in a Chinese family. PLoS ONE. (2012) 7:e45464. 15. Hahn D, Beggs JD. Brr2p RNA helicase with a split personality: insights into structure and function. Biochem Soc Trans. (2010) 38:1105–9. 16. Lauber J, Fabrizio P, Teigelkamp S, Lane WS, Hartmann E, Luhrmann R. The HeLa 200 kDa U5 snRNP-specific protein and its homologue in Saccharomyces cerevisiae are members of the DEXH-box protein family of putative RNA helicases. EMBO J. (1996) 15:4001–15. 17. Liu Y, Chen X, Qin B, Zhao K, Zhao Q, Staley JP, et al. Knocking down SNRNP200 initiates demorphogenesis of rod photoreceptors in zebrafish. Journal Ophthalmology. (2015) 2015:816329.

Test of drug could prove role of hyperactive retinal cells in blindness, potentially leading to better therapies Richard Kramer, Michael Goard, Michael Telias, Daniel Frozenfar, Benjamin Smith and Arjit Misra | UC Berkeley Summary: Animal and cell studies show that as retinal cells die in degenerative eye diseases, they make other cells hyperactive, creating noise that further obscures vision. Tests to prove this in humans are hard to conduct, however. Antabuse, an approved drug used to wean people off alcohol, should tamp down this hyperactivity and conclusively show whether hyperactivity plays a role in humans, potentially driving work to find better drugs to help those with progressive vision loss. Introduction Researchers at the University of California, Berkeley, have found that a drug once widely used to wean alcoholics off of drinking helps to improve sight in mice with retinal degeneration. The drug may revive sight in humans with the inherited disease retinitis pigmentosa (RP), and perhaps in other vision disorders, including age-related macular degeneration. A group of scientists led by Richard Kramer, UC Berkeley professor of molecular and cell biology, had previously shown that a chemical -- retinoic acid -- is produced when light-sensing cells in the retina, called rods and cones, gradually die off. This chemical causes hyperactivity in retinal ganglion cells, which ordinarily send visual information to the brain. The hyperactivity interferes with their encoding and transfer of information, obscuring vision. He realized, however, that the drug disulfiram -- also called Antabuse -- inhibits not only enzymes involved in the body's ability to degrade alcohol, but also enzymes that make retinoic acid. In new experiments, Kramer and collaborator Michael Goard, who directs a lab at UC Santa Barbara (UCSB), discovered that treatment with disulfiram decreased the production of retinoic acid and made nearly-blind mice much better at detecting images displayed on a computer screen. Read the article Story Source: Materials provided by University of California - Berkeley. Original written by Robert Sanders. Note: Content may be edited for style and length. Journal Reference: Michael Telias, Kevin K. Sit, Daniel Frozenfar, Benjamin Smith, Arjit Misra, Michael J. Goard and Richard H. Kramer. Retinoic acid inhibitors mitigate vision loss in a mouse model of retinal degeneration. Science Advances, 2022 DOI: 10.1126/sciadv.abm4643

Late-Breaking 12-Month Data of Investigational RPGR Gene Therapy Shows Statistically Significant and Continued Vision Improvement in Patients with X-Linked Retinitis Pigmentosa NEWS PROVIDED BY Janssen Pharmaceutical Companies of Johnson & Johnson Nov 13, 2020, 17:55 ET One-year findings support advancement into Phase 3 and include significant functional vision improvements observed in the time taken to walk through a vision-guided mobility maze at nine months RARITAN, N.J., Nov. 13, 2020 /PRNewswire/ -- The Janssen Pharmaceutical Companies of Johnson & Johnson announced today new 12-month data from the ongoing Phase 1/2 trial (NCT03252847) of its investigational gene therapy for inherited retinal disease X-linked retinitis pigmentosa (XLRP). The data showed that low and intermediate doses were well-tolerated and continued to demonstrate statistically significant sustained or increased vision improvement across multiple metrics (mean sensitivity, volumetric and pointwise) and modalities (full-field static perimetry and microperimetry). Data on the novel adeno-associated virus retinitis pigmentosa GTPase regulator (AAV-RPGR), jointly developed with MeiraGTx Holdings plc, were presented today as a late-breaking study at the American Academy of Ophthalmology (AAO) 2020 Virtual Annual Meeting. In patients with XLRP, the photoreceptors that are responsible for converting light into signals that are sent to the brain, function poorly, leading to degeneration of the retina and legal blindness in adulthood. The companies' AAV-RPGR gene therapy is being investigated for the most common and severe forms of XLRP caused by mutations in the RPGR gene by preserving and improving vision and slowing retinal degeneration. Currently, there are no available treatments. "Living with XLRP is extremely devastating for patients and their families, as there is no treatment available and they live each day knowing they will eventually go blind," said Michel Michaelides,1 B.Sc., M.B., B.S., M.D. (Res), FRCOphth, FACS, trial investigator, Consultant Ophthalmologist, Moorfields Eye Hospital, Professor of Ophthalmology, University College London. "The continuous upward trend in efficacy we've observed through one year with this gene therapy is extremely promising as a potential way to halt the progression toward blindness in these patients." Read the entire press release Media Contacts: Sarah Freeman Phone: +1 215-510-4758 sfreem21@its.jnj.com Jennifer Silvent Phone: +1 973-479-9845 jsilvent@its.jnj.com Investor Relations: Christopher DelOrefice Office: +1 732-524-2955 Jennifer McIntyre Office: +1 732-524-3922 SOURCE Janssen Pharmaceutical Companies of Johnson & Johnson

Rupak Datta, Abdul Waheed, Giuseppe Bonapace, Gul N. Shah, and William S. Sly | March 3, 2009 | Vol. 106, Issue 9 | Abstract Missense mutations in the carbonic anhydrase IV (CA4) gene have been identified in patients with an autosomal dominant form of retinitis pigmentosa (RP17). We used two transient expression systems to investigate the molecular mechanism by which the newly identified CA4 mutations, R69H and R219S, contribute to retinal pathogenesis. Although the R219S mutation drastically reduced the activity of the enzyme, the R69H mutation had a minimal effect, suggesting that loss of CA activity is not the molecular basis for their pathogenesis. Defective processing was apparent for both mutant proteins. Cell surface-labeling techniques showed that the R69H and R219S mutations both impaired the trafficking of CA4 to the cell surface, resulting in their abnormal intracellular retention. Expression of both CA4 mutants induced elevated levels of the endoplasmic reticulum (ER) stress markers, BiP and CHOP, and led to cell death by apoptosis. They also had a dominant-negative effect on the secretory function of the ER. These properties are similar to those of R14W CA4, the signal sequence variant found in the original patients with RP17. These findings suggest that toxic gain of function involving ER stress-induced apoptosis is the common mechanism for pathogenesis of this autosomal-dominant disease. Apoptosis induced by the CA4 mutants could be prevented, at least partially, by treating the cells with dorzolamide, a CA inhibitor. Thus, the use of a CA inhibitor as a chemical chaperone to reduce ER stress may delay or prevent the onset of blindness in RP17. Introduction Retinitis pigmentosa (RP) is a group of progressive eye diseases characterized by the deaths of retinal photoreceptors. Patients suffer from night blindness, gradual constriction of visual fields, and eventual loss of central vision (1). Increasing evidence points to a causative role for mutations in the carbonic anhydrase IV (CA4) gene in pathogenesis of RP17, an autosomal dominant form of RP (2–4). Three different missense mutations in the coding region of CA IV have been discovered. The first was a signal sequence mutation, changing Arg14 to Trp (R14W) (2). The other 2 mutations change amino acids in the mature portion of the protein, replacing Arg69 and Arg219 with His and Ser, respectively (R69H and R219S) (3, 4). RP associated with the R14W and R219S mutations is inherited in an autosomal-dominant fashion (2, 3). The R69H mutation was found in a sporadic case of RP (4). Because CA IV is not expressed in the retina (5), explaining the pathogenesis of RP17 presented a challenge. Understanding the pathogenesis is essential to design mechanism-based therapies for this disease for which no effective treatment is currently available. Read the article References 1.) DT Hartong, EL Berson, TP Dryja, Retinitis pigmentosa. Lancet 368, 1795–1809 (2006). 2.) G Rebello, et al., Apoptosis-inducing signal sequence mutation in carbonic anhydrase IV identified in patients with the RP17 form of retinitis pigmentosa. Proc Natl Acad Sci USA 101, 6617–6622 (2004). 3.) Z Yang, et al., Mutant carbonic anhydrase 4 impairs pH regulation and causes retinal photoreceptor degeneration. Hum Mol Genet 14, 255–265 (2005). 4.) BV Alvarez, et al., Identification and characterization of a novel mutation in the carbonic anhydrase IV gene that causes retinitis pigmentosa. Invest Ophthalmol Vis Sci 48, 3459–3468 (2007). 5.) GS Hageman, XL Zhu, A Waheed, WS Sly, Localization of carbonic anhydrase IV in a specific capillary bed of the human eye. Proc Natl Acad Sci USA 88, 2716–2720 (1991).

Zhenglin Yang, Bernardo V. Alvarez, Christina Chakarova, Li Jiang, Goutam Karan, Jeanne M. Frederick, Yu Zhao, Yves Sauvé, Xi Li, Eberhart Zrenner, Bernd Wissinger, Anneke I. Den Hollander, Bradley Katz, Wolfgang Baehr, Frans P. Cremers,Joseph R. Casey, Shomi S. Bhattacharya, Kang Zhang Human Molecular Genetics, Volume 14, Issue 2, 15 January 2005, Pages 255–265, https://doi.org/10.1093/hmg/ddi023 INTRODUCTION Retinitis pigmentosa (RP) is the most prevalent group of inherited retinal degeneration, affecting approximately 1 in 3500 persons or a total of 1.8 million people worldwide (1,2). Clinical features of RP include night blindness, constriction and progressive loss of peripheral visual field affecting rod photoreceptors, followed by eventual loss of central vision (cones). RP may be transmitted as an autosomal dominant, recessive or X-linked trait (3,4). All known RP genes are expressed either in photoreceptors or in retinal pigment epithelium (RPE), and are, to the most part, involved in photoreceptor structure, phototransduction, photoreceptor development, the retinoid cycle or RNA splicing. Retinal phototransduction is modulated by pH changes in its surrounding environment (5). It has been demonstrated that the amplitude of rod photoreceptor responses will decrease by ∼70% when the extracellular pH was decreased to 6.0 (6). Furthermore, there will also be a concomitant decrease in the Na+ conductance of rod photoreceptor outer segments (7). Despite exquisite sensitivity to the extracellular pH changes, photoreceptors paradoxically have a high rate of metabolism (8) and consequently high rate of endogenous acid production. As by-products of energy production in photoreceptors, a large amount of carbon dioxide and bicarbonate is generated from oxidative phosphorylation in mitochondria in the inner segments and lactic acid is generated from the inner and outer segments (9). Additional acid is generated from H+ release from cGMP turnover in the outer segment (10), and H+ influx due to Ca++/H+ exchanger activity in the plasma membrane of inner segment (11). The increase in acid load and lowering of intracellular pH are prevented by its removal from retina and RPE and release to blood stream in the choriocapillaris in the choroid, which is located adjacent to RPE and photoreceptors. Read more References 1.) Humphries, P., Kenna, P. and Farrar, G.J. (1992) On the molecular genetics of retinitis pigmentosa. Science, 256, 804–808. 2.) Rivolta, C., Sharon, D., DeAngelis, M.M. and Dryja, T.P. (2002) Retinitis pigmentosa and allied diseases: numerous diseases, genes, and inheritance patterns. Hum. Mol. Genet., 11, 1219–1227. 3.) Pacione, L.R., Szego, M.J., Ikeda, S., Nishina, P.M. and McInnes, R.R. (2003) Progress toward understanding the genetic and biochemical mechanisms of inherited photoreceptor degenerations. Annu. Rev. Neurosci., 26, 657–700. 4.) Rattner, A., Sun, H. and Nathans, J. (1999) Molecular genetics of human retinal disease. Annu. Rev. Genet., 33, 89–131. 5.) Donner, K., Hemilä, S., Kalamkarov, G., Koskelainen, A., Pogozheva, I. and Rebrik, T. (1990) Sulfhydryl binding reagents increase the conductivity of the light-sensitive channel and inhibit phototransduction in retinal rods. Exp. Eye Res., 51, 97–105. 6.) Liebman, P.A., Mueller, P. and Pugh, E.N., Jr (1984) Protons suppress the dark current of frog retinal rods. J. Physiol. (Lond.), 347, 85–110. 7.) Gedney, C. and Ostroy, S.E. (1978) Hydrogen ion effects of the vertebrate photoreceptor. The pK's of ionizable groups affecting cell permeability. Arch. Biochem. Biophys., 188, 105–113. 8.) Wangsa-Wirawan, N.D. and Linsenmeier, R.A. (2003) Retinal oxygen: fundamental and clinical aspects. Arch. Ophthalmol., 121, 547–557. 9.) Winkler, B.S. (1986) Buffer dependence of retinal glycolysis and ERG potentials. Exp. Eye Res., 42, 585–593. 10.) Meyertholen, E.P., Wilson, M.J. and Ostroy, S.E. (1986) The effects of HEPES, bicarbonate and calcium on the cGMP content of vertebrate rod photoreceptors and the isolated electrophysiological effects of cGMP and calcium. Vision Res., 26, 521–533. 11 Krizaj, D. and Copenhagen, D.R. (1998) Compartmentalization of calcium extrusion mechanisms in the outer and inner segments of photoreceptors. Neuron, 21, 249–256.

By: Reena Mukamal Reviewed By: Ninel Z Gregori, MD and Christine Nichols Kay, MD Hope may be on the horizon for people with retinitis pigmentosa, a rare inherited eye disease with no cure. Existing treatments only help a fraction of the estimated 100,000 Americans with this condition. But advances in gene therapy may soon help restore vision to a greater number of people. Retinitis pigmentosa causes light-detecting cells in the retina to break down over time, destroying vision. Mutations in more than 60 different genes can contribute to this condition. “If you are diagnosed with retinitis pigmentosa, it’s vital to undergo genetic testing to identify your underlying mutation," says Ninel Gregori, M.D., an Academy member and a professor of clinical ophthalmology at Bascom Palmer Eye Institute. Read more

The Usher Syndrome Coalition announces partnership with ProQR to support clinical trial enrollment for a potential therapy for USH2A mediated retinitis pigmentosa. WESTFORD, Mass., Jan. 31, 2022 /PRNewswire/ -- For more than ten years, the Usher Syndrome Coalition has been working to build its international "USH Trust" registry in anticipation of the day when researchers would launch a final-stage clinical trial for the Usher syndrome community. That time has come. The Coalition is pleased to partner with ProQR to help recruit 200+ participants worldwide for this exciting study. Clinical trials Sirius and Celeste aim to determine whether the investigational RNA therapy QR-421a is effective at stopping vision loss and is safe for people with retinitis pigmentosa and Usher syndrome due to mutations in exon 13 of the USH2A gene. These Phase 2/3 clinical trials have been planned after positive findings in a Phase 1/2 clinical trial named Stellar. More information on Stellar can be found here: www.proqr.com/community-stories-and-news/positive-results-achieved-in-our-ongoing-usher-syndrome-and-retinitis-pigmentosa-research. Read more.

NEWS PROVIDED BY Eluminex Biosciences Jan 19, 2022, 06:49 ET Purchase of Assets and Related Global Commercialization Rights for Oral 9-cis-Retinol (Zuretinol) for Rare Forms of Childhood Blindness. Clinical Stage Asset Has Potential for First Approved Oral Therapy for Leber's Congenital Amaurosis (LCA) and Retinitis Pigmentosa (RP) Caused by Mutations of the RPE65 or Lecithin:Retinol Acyltransferase (LRAT) Gene. Program Has Received FDA Rare Pediatric Disease and Fast Track Designation and is Eligible for a Rare Pediatric Disease Priority Review Voucher. Future Applications of Zuretinol Include Treatment of Impaired Dark Adaptation (Night Blindness) in Adult Patients with Early Dry Age-related Macular Degeneration (AMD). SUZHOU, China and SAN FRANCISCO, Jan. 19, 2022 /PRNewswire/ -- Eluminex Biosciences (Suzhou) Limited (Eluminex), an ophthalmology-focused biotechnology company headquartered in Suzhou, China with a US-subsidiary office in the San Francisco Bay Area, California, announced today that it has acquired certain assets and the related global development and commercialization rights for a novel oral therapy, zuretinol acetate (zuretinol), from Retinagenix Holdings, LLC (Retinagenix), a privately-held ophthalmic company based in Seattle, Washington. Zuretinol is an investigational treatment that is currently being developed to treat rare forms of childhood blindness in patients with LCA or RP caused by mutations of the RPE65 or LRAT gene. "The addition of zuretinol into our growing retinal disease pipeline further bolsters our commitment towards the development of innovative therapies for vision-threatening diseases around the world," said Charles Semba, MD, Chief Medical Officer of Eluminex. "Currently, the only approved treatment for LCA and RP due to RPE65 and LRAT mutations is gene therapy which requires the child to undergo surgery and can treat only a small portion of the retina. Zuretinol offers hope in the ability to treat the entire retina and both eyes simultaneously either as a monotherapy treatment or adjunctive to gene therapy in restoring vision to these children and young adults." Under terms of the agreement, Eluminex will make an upfront payment and earnout payments to Retinagenix for the purchase of the assets. The earnout payments to Retinagenix shall include (a) clinical, regulatory, and commercial milestone payments and (b) payments based upon worldwide net sales of products and the sale or use of priority review vouchers. The closing of this transaction is subject to certain customary conditions. Read the entire of the announcement

Rinki Ratnapriya, Samuel G. Jacobson , Artur V. Cideciyan , Milton A. English, Alejandro J. Roman, Alexander Sumaroka, Rebecca Sheplock, Anand Swaroop | Frontiers in Cell and Developmental Biology | 16 August 2021 | Volume 9 | 2021 | https://doi.org/10.3389/fcell.2021.720782 Despite major progress in the discovery of causative genes, many individuals and families with inherited retinal degenerations (IRDs) remain without a molecular diagnosis. We applied whole exome sequencing to identify the genetic cause in a family with an autosomal dominant IRD. Eye examinations were performed and affected patients were studied with electroretinography and kinetic and chromatic static perimetry. Sequence variants were analyzed in genes ( n = 271) associated with IRDs listed on the RetNet database. We applied a stepwise filtering process involving the allele frequency in the control population, in silico prediction tools for pathogenicity, and evolutionary conservation to prioritize the potential causal variant(s). Sanger sequencing and segregation analysis were performed on the proband and other family members. The IRD in this family is expressed as a widespread progressive retinal degeneration with maculopathy. A novel heterozygous variant (c.200A > T) was identified in the ARL3 gene, leading to the substitution of aspartic acid to valine at position 67. The Asp67 residue is evolutionary conserved, and the change p.Asp67Val is predicted to be pathogenic. This variant was segregated in affected members of the family and was absent from an unaffected individual. Two previous reports of a de novo missense mutation in the ARL3 gene, each describing a family with two affected generations, are the only examples to date of autosomal dominant IRD associated with this photoreceptor gene. Our results, identifying a novel pathogenic variant in ARL3 in a four-generation family with a dominant IRD, augment the evidence that the ARL3 gene is another cause of non-syndromic retinal degeneration. Introduction Emerging from the era of ungenotyped inherited retinal degenerations (IRDs), we are now aware of the heterogeneous basis of these blinding diseases ( Bramall et al., 2010 ; Wright et al., 2010 ; Ratnapriya and Swaroop, 2013 ; Verbakel et al., 2018 ; Garafalo et al., 2020 ). From the linkage mapping of disease loci to the identification of causative genes and mutations, there was a steady increase in the number of genes associated with IRDs in the three decades from 1990 onward (RetNet, the Retinal Information Network) 1 . Yet, there remain many IRD patients and families with unknown genetic diagnosis (at least 30%; Birtel et al., 2018 ; Garafalo et al., 2020 ; Hejtmancik and Daiger, 2020 ). The largest percentage of these molecularly unresolved Mendelian IRDs has been the simplex/multiplex or presumed autosomal recessively inherited diseases ( Garafalo et al., 2020 ). We have been investigating patients and families with non-syndromic retinal degeneration, and whenever a genetic cause for an autosomal dominant IRD was identified, the family was screened for known mutations. In recent years, the next-generation sequencing technologies, especially targeted and whole exome sequencing, have expedited the molecular diagnosis efforts ( Booij et al., 2011 ; O’Sullivan et al., 2012 ; Ratnapriya and Swaroop, 2013 ; Beryozkin et al., 2015 ; Roberts et al., 2016 ). In the current study, we applied whole exome sequencing to a multi-generation dominant IRD family which was initially screened for known mutations but gave negative results. We analyzed all genes associated with IRDs as reported in the RetNet database and identified a novel, rare, heterozygous variant p.Asp67Val in ARL3 as a causative mutation. ARL3 encodes ADP-ribosylation factor, (Arf)-like protein 3. This soluble small GTPase has been localized to photoreceptors, and mutations in the ARL3 gene are considered to cause retinal ciliopathy ( Frederick et al., 2020 ; Sánchez-Bellver et al., 2021 ). A missense variant in ARL3 has previously been associated with non-syndromic autosomal dominant retinitis pigmentosa (OMIM 604695; Fahim et al., 2000 ). Specifically, the c.269A > G (p.Tyr90Cys) variant was determined to be a de novo mutation in two unrelated families, each with two generations of affected members ( Strom et al., 2016 ; Holtan et al., 2019 ). ARL3 has also been implicated as an autosomal recessive cause of Joubert syndrome and non-syndromic retinal degeneration ( Alkanderi et al., 2018 ; Sheikh et al., 2019 ; Fu et al., 2021 ). The identification of causal genes underlying human diseases has clear clinical and research utility, and there has been recent progress toward therapy in dominant forms of IRD ( Sudharsan and Beltran, 2019 ; Kruczek et al., 2021 ). Further, specifically considering the ARL3 gene, there are studies in patient-derived cell lines and animal models that can be the foundation for understanding the mechanism and devising the therapeutic strategies ( Grayson et al., 2002 ; Evans et al., 2010 ; Schwarz et al., 2012 ; Hanke-Gogokhia et al., 2016 ; Kruczek and Swaroop, 2020 ). Click here to read entire article References Aleman, T. S., Soumittra, N., Cideciyan, A. V., Sumaroka, A. M., Ramprasad, V. L., Herrera, W., et al. (2009). 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The first patients have been dosed in the phase 2/3 Sirius and Celeste clinical trials investigating QR-421a in patients with USH2A mediated retinitis pigmentosa and Usher syndrome, according to a press release from ProQR Therapeutics. The double-masked, randomized, sham-controlled, 24-month, multiple-dose studies are investigating the safety and effectiveness of QR-421a. Both studies will enroll patients 12 years and older, who have vision loss attributed to mutations in exon 13 of the USH2A gene, in one of three arms. Patients in the first arm will receive a 180 µg loading dose followed by 60 µg maintenance doses, patients in the second arm will receive a 60 µg loading dose followed by 60 µg maintenance doses, and patients in the third arm will serve as a control. Read more.

Publication Suzanne de Bruijn et al, Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa, The American Journal of Human Genetics, 2020 _____________________________________________ For more than thirty years, geneticists at Radboud UMC and the Donders Institute searched for the cause of vision impairment within a large Dutch family. When that cause was identified, 21 other families with the same 'RP17' gene abnormality were located worldwide. In total, there are more than 300 people who are visually impaired or blind. The study was published in the American Journal of Human Genetics. After thirty years of research, the genetic defect that causes the eye disease retinitis pigmentosa type 17 (RP17) has finally been discovered. Molecular geneticists Susanne Roosing and Suzanne de Bruijn located the gene defect by examining the genetic material (DNA) of a large Dutch family that had been forwarded by physicians from the Department of Ophthalmology. Chromosome 17 abnormality RP17 is a form of a dominant hereditary retinal disorder (retinitis pigmentosa), which causes a gradual deterioration of vision and can lead to severe forms of vision impairment and blindness. The name RP17 derives from previous indications that the defect would be located on chromosome 17. To continue reading this article, click here or click here.

Causes | Symptoms | Diagnosis | Treatment | Research What is retinitis pigmentosa? Retinitis pigmentosa (RP) is a group of rare, genetic disorders that involve a breakdown and loss of cells in the retina — which is the light sensitive tissue that lines the back of the eye. Common symptoms include difficulty seeing at night and a loss of side (peripheral) vision. How common is RP? RP is considered a rare disorder. Although current statistics are not available, it is generally estimated that the disorder affects roughly 1 in 4,000 people, both in the United States and worldwide. What causes RP? RP is an inherited disorder that results from harmful changes in any one of more than 50 genes. These genes carry the instructions for making proteins that are needed in cells within the retina, called photoreceptors. Some of the changes, or mutations, within genes are so severe that the gene cannot make the required protein, limiting the cell's function. Other mutations produce a protein that is toxic to the cell. Still other mutations lead to an abnormal protein that doesn't function properly. In all three cases, the result is damage to the photoreceptors. To read more, click here. #whatisRP