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Retinitis pigmentosa

Yuanyuan Chen, Yu Chen, Beata Jastrzebska, Marcin Golczak, Sahil Gulati, Hong Tang, William Seibel, Xiaoyu Li, Hui Jin, Yong Han, Songqi Gao, Jianye Zhang, Xujie Liu, Hossein Heidari-Torkabadi, Phoebe L Stewart, William E Harte, Gregory P Tochtrop, Krzysztof Palczewski
Rhodopsin homeostasis is tightly coupled to rod photoreceptor cell survival and vision. Mutations resulting in the misfolding of rhodopsin can lead to autosomal dominant retinitis pigmentosa (adRP), a progressive retinal degeneration that currently is untreatable. Using a cell-based high-throughput screen (HTS) to identify small molecules that can stabilize the P23H-opsin mutant, which causes most cases of adRP, we identified a novel pharmacological chaperone of rod photoreceptor opsin, YC-001. As a non-retinoid molecule, YC-001 demonstrates micromolar potency and efficacy greater than 9-cis-retinal with lower cytotoxicity...
May 17, 2018: Nature Communications
Yi-Ting Tsai, Wen-Hsuan Wu, Ting-Ting Lee, Wei-Pu Wu, Christine L Xu, Karen S Park, Xuan Cui, Sally Justus, Chyuan-Sheng Lin, Ruben Jauregui, Pei-Yin Su, Stephen H Tsang
PURPOSE: To develop a universal gene therapy to overcome the genetic heterogeneity in retinitis pigmentosa (RP) resulting from mutations in rhodopsin (RHO). DESIGN: Experimental study for a combination gene therapy that uses both gene ablation and gene replacement. PARTICIPANTS: This study included 2 kinds of human RHO mutation knock-in mouse models: RhoP23H and RhoD190N . In total, 23 RhoP23H/P23H , 43 RhoP23H/+ , and 31 RhoD190N/+ mice were used for analysis...
May 5, 2018: Ophthalmology
Min Chen, Jiancong Wang, Ipek Oguz, Brian L VanderBeek, James C Gee
The choroid plays a critical role in maintaining the portions of the eye responsible for vision. Specific alterations in the choroid have been associated with several disease states, including age-related macular degeneration (AMD), central serous choroiretinopathy, retinitis pigmentosa and diabetes. In addition, choroid thickness measures have been shown as a predictive biomarker for treatment response and visual function. Where several approaches currently exist for segmenting the choroid in optical coherence tomography (OCT) images of healthy retina, very few are capable of addressing images with retinal pathology...
September 2017: Fetal, infant and ophthalmic medical image analysis: International Workshop, FIFI 2017, and 4th International Workshop, OMIA 2017, held in conjunction with MICCAI 2017, Québec City, QC, Canada, September 14, Proceedings
Ana M Moreno, Xin Fu, Jie Zhu, Dhruva Katrekar, Yu-Ru V Shih, John Marlett, Jessica Cabotaje, Jasmine Tat, John Naughton, Leszek Lisowski, Shyni Varghese, Kang Zhang, Prashant Mali
Development of efficacious in vivo delivery platforms for CRISPR-Cas9-based epigenome engineering will be critical to enable the ability to target human diseases without permanent modification of the genome. Toward this, we utilized split-Cas9 systems to develop a modular adeno-associated viral (AAV) vector platform for CRISPR-Cas9 delivery to enable the full spectrum of targeted in situ gene regulation functionalities, demonstrating robust transcriptional repression (up to 80%) and activation (up to 6-fold) of target genes in cell culture and mice...
April 25, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Xiao Zhang, Dan Zhang, Shang-Chih Chen, Tina Lamey, Jennifer A Thompson, Terri McLaren, John N De Roach, Fred K Chen, Samuel McLenachan
We report the generation of the human iPSC line LEIi004-A from a patient with late-onset non-syndromic retinitis pigmentosa caused by compound heterozygous mutations in the CLN3 gene. Reprogramming of primary dermal fibroblasts was performed using episomal plasmids containing OCT4, SOX2, KLF4, L-MYC, LIN28, shRNA for p53 and mir302/367 microRNA. To create a coisogenic control line, one CLN3 variant was corrected in the patient-iPSC using CRISPR/Cas9 gene editing to generate the iPSC line LEIi004-A-1.
May 1, 2018: Stem Cell Research
Farhad Nejat, Hossein Aghamollaei, Shiva Pirhadi, Khosrow Jadidi, Mohammad Amin Nejat
Macular corneal dystrophy (MCD) is an autosomal recessive hereditary disease. In most cases, various mutations in carbohydrate sulfotransferase 6 (CHST6) gene are the main cause of MCD. These mutations lead to a defect in keratan sulfate synthesis. Retinitis pigmentosa (RP) is another eye disorder with nyctalopia as its common symptom. It has been shown that more than 65 genes have been implicated in different forms of RP. Herein, we report on a 9-member family with 2 girls and 5 boys. Both parents, one of the girls and one of the boys had normal eye vision and another boy had keratoconus...
March 2018: Iranian Journal of Medical Sciences
Leila Azizzadeh Pormehr, Narsis Daftarian, Shahin Ahmadian, Mozhgan Rezaei Kanavi, Hamid Ahmadieh, Mahshid Shafiezadeh
The splicing factor PRPF31 is the most commonly mutated general splicing factor in the retinitis pigmentosa. We used a rapid, convenient and cost effective transfection method with an efficient PRPF31 knockdown in HORFC in order to study the effect of PRPF31 downregulation on retinal gene expressions in an ex vivo model. Modified calcium phosphate method was used to transfect HORFC by PRPF31 siRNA. Different times and doses of siRNA for transfection were assayed and optimum condition was obtained. PRPF31 mRNA and protein downregulation were assessed by qRTPCR and Western blot...
May 10, 2018: Journal of Cellular Biochemistry
Hwa Sun Kim, Andrew Vargas, Yun Sung Eom, Justin Li, Kyra L Yamamoto, Cheryl Mae Craft, Eun-Jin Lee
Retinitis pigmentosa (RP), an inherited retinal degenerative disease, is characterized by a progressive loss of rod photoreceptors followed by loss of cone photoreceptors. Previously, when tissue inhibitor of metalloproteinase 1 (TIMP1), a key extracellular matrix (ECM) regulator that binds to and inhibits activation of Matrix metallopeptidase 9 (MMP9) was intravitreal injected into eyes of a transgenic rhodopsin rat model of RP, S334ter-line3, we discovered cone outer segments are partially protected. In parallel, we reported that a specific MMP9 and MMP2 inhibitor, SB-3CT, interferes with mechanisms leading to rod photoreceptor cell death in an MMP9 dependent manner...
2018: PloS One
O Sjaastad, N Blau, S L Rydning, V Peters, O Rødningen, A Stray-Pedersen, B Krossnes, C Tallaksen, J Koht
OBJECTIVES: A family with homocarnosinosis was reported in the literature in 1976. Three affected siblings had spastic paraplegia, retinitis pigmentosa, mental retardation, and cerebrospinal fluid (CSF) homocarnosine concentrations 20 times higher than in controls. Based on the clinical findings and new genetic techniques, we have been able to establish a precise genetic diagnosis. METHOD: The medical records were re-evaluated, and genetic analyses were performed post-mortem in this original family...
May 6, 2018: Acta Neurologica Scandinavica
Yu Zhou, Shijin Li, Lulin Huang, Yeming Yang, Lin Zhang, Mu Yang, Wenjing Liu, Kim Ramasamy, Zhilin Jiang, Periasamy Sundaresan, Xianjun Zhu, Zhenglin Yang
Retinitis pigmentosa (RP) refers to a group of retinal degenerative diseases, which often lead to vision loss. Although 70 genes have been identified in RP patients, the genetic cause of approximately 30% of RP cases remains unknown. We aimed to identify the cause of the disease in a cohort of RP families by whole exome sequencing. A rare homozygous splicing variant, c.1160 + 1G>A, which introduced skipping of exon 9 of the aryl hydrocarbon receptor (AHR), was identified in family RD-134. This variant is very rare in several exome databases and leads to skipping of exon 9 in the transcript...
May 2, 2018: Human Molecular Genetics
Maryam Alavi, Petr Baranov
Traumatic, inherited, and age-related degenerative diseases of the retina, such as retinal detachment, glaucoma, retinitis pigmentosa, and age-related macular degeneration, are characterized by the irreversible loss of retinal neurons. Several growth factors, including glial cell-derived neurotrophic factor and pigment epithelium-derived factor, have been shown to rescue retinal neurons in animal models of retinal disease. Here we describe a scalable and robust system to study the growth factor induction in the retina: retinal organoids derived from the induced pluripotent stem cells...
2018: Advances in Experimental Medicine and Biology
Hemant Khanna
This article summarizes the recent advances in our understanding of a major retinal disease gene RPGR (retinitis pigmentosa GTPase regulator), mutations in which are associated with majority of X-linked forms of retinal degenerations. A great deal of work has been done to uncover the ciliary localization of RPGR and its interacting proteins in the retina. However, the molecular mechanisms of action of RPGR in the photoreceptors are still unclear. Recent studies have begun to shed light on the intracellular pathways in which RPGR is likely involved...
2018: Advances in Experimental Medicine and Biology
Ammaji Rajala, Yuhong Wang, Raju V S Rajala
Studies form our laboratory and others show that the oncogenic tyrosine kinase and serine threonine kinase signaling pathways are essential for cone photoreceptor survival. These pathways are downregulated in mouse models of retinal degenerative diseases. In the present study, we found that activation mutants of mTOR delayed the death of cones in a mouse model of retinal degeneration. These studies suggest that oncogenic protein kinases may be useful as therapeutic agents to treat retinal degenerations that affect cones...
2018: Advances in Experimental Medicine and Biology
Xiu-Feng Huang
Retinitis pigmentosa (RP) encompasses a heterogeneous group of inherited retinal disorders characterized by progressive photoreceptor and/or retinal pigment epithelial (RPE) degenerations with a prevalence approximately 1 in 4000 in the general population. Over 70 causative genes have been defined in RP families, and a number of animal models have been identified so far. However there have been no widely recognized treatments able to recover or reverse the degenerating retina, to prevent the disease deterioration, ultimately to restore the remaining vision...
2018: Advances in Experimental Medicine and Biology
Martial K Mbefo, Yvan Arsenijevic
Retinitis Pigmentosa (RP) is a class of hereditary retinal dystrophy associated with gradual visual failure and a subsequent loss of light-sensitive cells in the retina, leading to blindness. Many mutated genes were found to be causative of this disease. Despite a number of compiling efforts, the process of cell death in photoreceptors remains to be clearly elucidated. We recently reported an abnormal cell cycle reentry in photoreceptors undergoing degeneration in Rd1 mice, a model of RP, and identified the polycomb repressive complex 1 (PRC1) core component BMI1 as a critical molecular factor orchestrating the cell death mechanism...
2018: Advances in Experimental Medicine and Biology
Byung-Jin Kim, Donald J Zack
c-Jun N-terminal kinase (JNK), a member of stress-induced mitogen-activated protein (MAP) kinase family, has been shown to modulate a variety of biological processes associated with neurodegenerative pathology of the retina. In particular, various retinal cell culture and animal models related to glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa indicate that JNK signaling may contribute to disease pathogenesis. This mini-review discusses the impact of JNK signaling in retinal disease, with a focus on retinal ganglion cells (RGCs), photoreceptor cells, retinal pigment epithelial (RPE) cells, and animal studies, with particular attention to modulation of JNK signaling as a potential therapeutic target for the treatment of retinal disease...
2018: Advances in Experimental Medicine and Biology
Maria Iribarne, Ichiro Masai
Humans with mutations in the phototransduction pathway develop forms of retinal degeneration, such as retinitis pigmentosa, cone dystrophy, or Leber congenital amaurosis. Similarly, numerous phototransduction mutant animal models resemble retinal degeneration. In our lab, using a zebrafish model, we study cone-specific phototransduction mutants. cGMP is the second messenger in the phototransduction pathway, and abnormal cGMP levels are associated with photoreceptor death. Rd1, a rod-specific phosphodiesterase 6 (Pde6) subunit mutant in mice, is one of the most widely used animal models for retinal degeneration...
2018: Advances in Experimental Medicine and Biology
Ayako Furukawa, Kayo Sugitani, Yoshiki Koriyama
Retinal degenerative diseases, such as retinitis pigmentosa, are characterized by night blindness and peripheral vision loss caused by the slowly progressive loss of photoreceptor cells. A comprehensive molecular mechanism of the photoreceptor cell death remains unclear. We previously reported that heat shock protein 70 (HSP70), which has a protective effect on neuronal cells, was cleaved by a calcium-dependent protease, calpain, in N-methyl-N-nitrosourea (MNU)-treated mice retina. Carbonylated HSP70 is much more vulnerable than noncarbonylated HSP70 to calpain cleavage...
2018: Advances in Experimental Medicine and Biology
Stephen P Daiger, Sara J Bowne, Lori S Sullivan, Kari Branham, Dianna K Wheaton, Kaylie D Jones, Cheryl E Avery, Elizabeth D Cadena, John R Heckenlively, David G Birch
Genetic testing of probands in families with an initial diagnosis of autosomal dominant retinitis pigmentosa (adRP) usually confirms the diagnosis, but there are exceptions. We report results of genetic testing in a large cohort of adRP families with an emphasis on exceptional cases including X-linked RP with affected females; homozygous affected individuals in families with heterozygous, dominant disease; and independently segregating mutations in the same family. Genetic testing was conducted in more than 700 families with a provisional or probable diagnosis of adRP...
2018: Advances in Experimental Medicine and Biology
Kari Branham, Aditya A Guru, Igor Kozak, Pooja Biswas, Mohammad Othman, Kameron Kishaba, Hassan Mansoor, Sheikh Riazuddin, John R Heckenlively, S Amer Riazuddin, J Fielding Hejtmancik, Paul A Sieving, Radha Ayyagari
Retinal dystrophies are a phenotypically and genetically complex group of conditions. Because of this complexity, it can be challenging in many families to determine the inheritance based on pedigree analysis alone. Clinical examinations were performed and blood samples were collected from a North American (M1186) and a consanguineous Pakistani (PKRD168) pedigree affected with two different retinal dystrophies (RD). Based on the structure of the pedigrees, inheritance patterns in the families were difficult to determine...
2018: Advances in Experimental Medicine and Biology
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