scholarly journals Antioxidant and Biological Properties of Mesenchymal Cells Used for Therapy in Retinitis Pigmentosa

Antioxidants ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 983
Author(s):  
Paolo Giuseppe Limoli ◽  
Enzo Maria Vingolo ◽  
Celeste Limoli ◽  
Marcella Nebbioso
Keyword(s):  
Retinitis Pigmentosa ◽  
Tissue Repair ◽  
Therapeutic Option ◽  
Retinal Dystrophy ◽  
Retinal Disease ◽  
Biological Properties ◽  
Mesenchymal Cells ◽  
Cell Therapies ◽  
Tissue Repair And Regeneration ◽  
Inherited Retinal Dystrophy

Both tissue repair and regeneration are a priority in regenerative medicine. Retinitis pigmentosa (RP), a complex retinal disease characterized by the progressive loss of impaired photoreceptors, is currently lacking effective therapies: this represents one of the greatest challenges in the field of ophthalmological research. Although this inherited retinal dystrophy is still an incurable genetic disease, the oxidative damage is an important pathogenetic element that may represent a viable target of therapy. In this review, we summarize the current neuroscientific evidence regarding the effectiveness of cell therapies in RP, especially those based on mesenchymal cells, and we focus on their therapeutic action: limitation of both oxidative stress and apoptotic processes triggered by the disease and promotion of cell survival. Cell therapy could therefore represent a feasible therapeutic option in RP.

scholarly journals Targeting of the NRL Pathway as a Therapeutic Strategy to Treat Retinitis Pigmentosa

2020 ◽  
Vol 9 (7) ◽  
pp. 2224 ◽  
Author(s):  
Spencer M. Moore ◽  
Dorota Skowronska-Krawczyk ◽  
Daniel L. Chao
Keyword(s):  
Retinitis Pigmentosa ◽  
Autosomal Recessive ◽  
Therapeutic Strategy ◽  
Leucine Zipper ◽  
Retinal Dystrophy ◽  
Rod Photoreceptor ◽  
Cone Photoreceptor ◽  
Future Directions ◽  
Inherited Retinal Dystrophy ◽  
Visual Acuity Loss

Retinitis pigmentosa (RP) is an inherited retinal dystrophy (IRD) with a prevalence of 1:4000, characterized by initial rod photoreceptor loss and subsequent cone photoreceptor loss with accompanying nyctalopia, visual field deficits, and visual acuity loss. A diversity of causative mutations have been described with autosomal dominant, autosomal recessive, and X-linked inheritance and sporadic mutations. The diversity of mutations makes gene therapy challenging, highlighting the need for mutation-agnostic treatments. Neural leucine zipper (NRL) and NR2E3 are factors important for rod photoreceptor cell differentiation and homeostasis. Germline mutations in NRL or NR2E3 leads to a loss of rods and an increased number of cones with short wavelength opsin in both rodents and humans. Multiple groups have demonstrated that inhibition of NRL or NR2E3 activity in the mature retina could endow rods with certain properties of cones, which prevents cell death in multiple rodent RP models with diverse mutations. In this review, we summarize the literature on NRL and NR2E3, therapeutic strategies of NRL/NR2E3 modulation in preclinical RP models, as well as future directions of research. In summary, inhibition of the NRL/NR2E3 pathway represents an intriguing mutation agnostic and disease-modifying target for the treatment of RP.

scholarly journals Basic Roles of Sex Steroid Hormones in Wound Repair with Focus on Estrogens (A Review)

2016 ◽  
Vol 60 (1) ◽  
pp. 41-46
Author(s):  
Z. Čriepoková ◽  
L’. Lenhardt ◽  
P. Gál
Keyword(s):  
Postmenopausal Women ◽  
Steroid Hormones ◽  
Tissue Repair ◽  
Wound Repair ◽  
Review Paper ◽  
Therapeutic Option ◽  
Hormone Replacement ◽  
Sex Steroid ◽  
Biological Processes ◽  
Tissue Repair And Regeneration

Abstract Previously, it has been shown that sex hormones, in particular estrogens, play an important role in the regulation of biological processes involved in tissue repair and regeneration. Accordingly, several studies have supported the beneficial properties of hormone replacement therapies (HRT) in postmenopausal models. The present review paper explores the potential for targeted sex steroid HRT as a new therapeutic option for the surgical management of wounds in postmenopausal women and animals.

scholarly journals Loss of RPGR glutamylation underlies the pathogenic mechanism of retinal dystrophy caused by TTLL5 mutations

2016 ◽  
Vol 113 (21) ◽  
pp. E2925-E2934 ◽  
Author(s):  
Xun Sun ◽  
James H. Park ◽  
Jessica Gumerson ◽  
Zhijian Wu ◽  
Anand Swaroop ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Tandem Repeats ◽  
Mutant Mouse ◽  
Retinal Dystrophy ◽  
Retinal Disease ◽  
Pathogenic Mechanism ◽  
Common Disease ◽  
Photoreceptor Degeneration ◽  
Interaction Domain ◽  
Basic Domain

Mutations in the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene are a major cause of retinitis pigmentosa, a blinding retinal disease resulting from photoreceptor degeneration. A photoreceptor specific ORF15 variant of RPGR (RPGRORF15), carrying multiple Glu-Gly tandem repeats and a C-terminal basic domain of unknown function, localizes to the connecting cilium where it is thought to regulate cargo trafficking. Here we show that tubulin tyrosine ligase like-5 (TTLL5) glutamylates RPGRORF15 in its Glu-Gly–rich repetitive region containing motifs homologous to the α-tubulin C-terminal tail. The RPGRORF15 C-terminal basic domain binds to the noncatalytic cofactor interaction domain unique to TTLL5 among TTLL family glutamylases and targets TTLL5 to glutamylate RPGR. Only TTLL5 and not other TTLL family glutamylases interacts with RPGRORF15 when expressed transiently in cells. Consistent with this, a Ttll5 mutant mouse displays a complete loss of RPGR glutamylation without marked changes in tubulin glutamylation levels. The Ttll5 mutant mouse develops slow photoreceptor degeneration with early mislocalization of cone opsins, features resembling those of Rpgr-null mice. Moreover TTLL5 disease mutants that cause human retinal dystrophy show impaired glutamylation of RPGRORF15. Thus, RPGRORF15 is a novel glutamylation substrate, and this posttranslational modification is critical for its function in photoreceptors. Our study uncovers the pathogenic mechanism whereby absence of RPGRORF15 glutamylation leads to retinal pathology in patients with TTLL5 gene mutations and connects these two genes into a common disease pathway.

scholarly journals Allele-Specific Knockout by CRISPR/Cas to Treat Autosomal Dominant Retinitis Pigmentosa Caused by the G56R Mutation in NR2E3

2021 ◽  
Vol 22 (5) ◽  
pp. 2607
Author(s):  
Michalitsa Diakatou ◽  
Gregor Dubois ◽  
Nejla Erkilic ◽  
Carla Sanjurjo-Soriano ◽  
Isabelle Meunier ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Autosomal Dominant ◽  
Vision Loss ◽  
Retinal Dystrophy ◽  
Common Mutation ◽  
Wild Type ◽  
Inherited Retinal Dystrophy ◽  
Allele Specific ◽  
Induced Pluripotent ◽  
Overexpression System

Retinitis pigmentosa (RP) is an inherited retinal dystrophy that causes progressive vision loss. The G56R mutation in NR2E3 is the second most common mutation causing autosomal dominant (ad) RP, a transcription factor that is essential for photoreceptor development and maintenance. The G56R variant is exclusively responsible for all cases of NR2E3-associated adRP. Currently, there is no treatment for NR2E3-related or, other, adRP, but genome editing holds promise. A pertinent approach would be to specifically knockout the dominant mutant allele, so that the wild type allele can perform unhindered. In this study, we developed a CRISPR/Cas strategy to specifically knockout the mutant G56R allele of NR2E3 and performed a proof-of-concept study in induced pluripotent stem cells (iPSCs) of an adRP patient. We demonstrate allele-specific knockout of the mutant G56R allele in the absence of off-target events. Furthermore, we validated this knockout strategy in an exogenous overexpression system. Accordingly, the mutant G56R-CRISPR protein was truncated and mis-localized to the cytosol in contrast to the (peri)nuclear localizations of wild type or G56R NR2E3 proteins. Finally, we show, for the first time, that G56R iPSCs, as well as G56R-CRISPR iPSCs, can differentiate into NR2E3-expressing retinal organoids. Overall, we demonstrate that G56R allele-specific knockout by CRISPR/Cas could be a clinically relevant approach to treat NR2E3-associated adRP.

scholarly journals Cell-derived extracellular vesicles and membranes for tissue repair

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yuan Ding ◽  
Yanjie Li ◽  
Zhongquan Sun ◽  
Xin Han ◽  
Yining Chen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Membrane ◽  
Tissue Repair ◽  
Extracellular Vesicle ◽  
Stem Cell Therapies ◽  
Differentiation Potential ◽  
Cell Therapies ◽  
Tissue Repair And Regeneration ◽  
Unmet Demand ◽  
Multipotent Differentiation

AbstractHumans have a limited postinjury regenerative ability. Therefore, cell-derived biomaterials have long been utilized for tissue repair. Cells with multipotent differentiation potential, such as stem cells, have been administered to patients for the treatment of various diseases. Researchers expected that these cells would mediate tissue repair and regeneration through their multipotency. However, increasing evidence has suggested that in most stem cell therapies, the paracrine effect but not cell differentiation or regeneration is the major driving force of tissue repair. Additionally, ethical and safety problems have limited the application of stem cell therapies. Therefore, nonliving cell-derived techniques such as extracellular vesicle (EV) therapy and cell membrane-based therapy to fulfil the unmet demand for tissue repair are important. Nonliving cell-derived biomaterials are safer and more controllable, and their efficacy is easier to enhance through bioengineering approaches. Here, we described the development and evolution from cell therapy to EV therapy and cell membrane-based therapy for tissue repair. Furthermore, the latest advances in nonliving cell-derived therapies empowered by advanced engineering techniques are emphatically reviewed, and their potential and challenges in the future are discussed. Graphical Abstract

scholarly journals Genetic and Phenotypic Landscape of PRPH2-Associated Retinal Dystrophy in Japan

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1817
Author(s):  
Akio Oishi ◽  
Kaoru Fujinami ◽  
Go Mawatari ◽  
Nobuhisa Naoi ◽  
Yasuhiro Ikeda ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Age Of Onset ◽  
Phenotypic Variability ◽  
Retinal Dystrophy ◽  
Japanese Patients ◽  
Macular Dystrophy ◽  
Hand Motion ◽  
Pathogenic Variants ◽  
Inherited Retinal Dystrophy ◽  
Asian Cohort

Peripherin-2 (PRPH2) is one of the causative genes of inherited retinal dystrophy. While the gene is relatively common in Caucasians, reports from Asian ethnicities are limited. In the present study, we report 40 Japanese patients from 30 families with PRPH2-associated retinal dystrophy. We identified 17 distinct pathogenic or likely pathogenic variants using next-generation sequencing. Variants p.R142W and p.V200E were relatively common in the cohort. The age of onset was generally in the 40’s; however, some patients had earlier onset (age: 5 years). Visual acuity of the patients ranged from hand motion to 1.5 (Snellen equivalent 20/13). The patients showed variable phenotypes such as retinitis pigmentosa, cone-rod dystrophy, and macular dystrophy. Additionally, intrafamilial phenotypic variability was observed. Choroidal neovascularization was observed in three eyes of two patients with retinitis pigmentosa. The results demonstrate the genotypic and phenotypic variations of the disease in the Asian cohort.

scholarly journals A family with spinocerebellar ataxia and retinitis pigmentosa attributed to an ELOVL4 mutation

2019 ◽  
Vol 5 (5) ◽  
pp. e357 ◽  
Author(s):  
Changrui Xiao ◽  
Elaine M. Binkley ◽  
Jessica Rexach ◽  
Amy Knight-Johnson ◽  
Pravin Khemani ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Spinocerebellar Ataxia ◽  
Extended Family ◽  
Age At Onset ◽  
Retinal Dystrophy ◽  
Cerebellar Atrophy ◽  
Retinal Disease ◽  
Heterozygous Mutation ◽  
Incomplete Penetrance ◽  
Progressive Cerebellar Ataxia

ObjectiveTo identify the genetic cause of autosomal dominant spinocerebellar ataxia and retinitis pigmentosa in a large extended pedigree.MethodsClinical studies were done at 4 referral centers. Ten individuals in the same extended family participated in at least a portion of the study. Records were obtained from an 11th, deceased, individual. Neurologic and dermatological examinations were performed. Ophthalmologic evaluation including funduscopic examination and in some cases ocular coherence tomography were used to identify the presence of retinal disease. Whole exome sequencing (WES), in conjunction with Sanger sequencing and segregation analysis, was used to identify potential genetic mutation.ResultsAffected individuals reported slowly progressive cerebellar ataxia with age at onset between 38 and 57. Imaging demonstrated cerebellar atrophy (3/3). WES identified a novel heterozygous mutation in the elongation of very long chain fatty acids 4 (ELOVL4) gene (c.512T>C, p.Ile171Thr) that segregated with ataxia in 7 members tested. Four of 8 members who underwent ophthalmologic evaluation were found to have retinitis pigmentosa. No skin findings were identified or reported. Ocular movement abnormalities and pyramidal tract signs were also present with incomplete penetrance.ConclusionsWe report a family with both spinocerebellar ataxia and retinal dystrophy associated with an ELOVL4 mutation. In addition, to supporting prior reports that ELOVL4 mutations can cause spinocerebellar ataxia, our findings further broaden the spectrum of clinical presentations associated with spinocerebellar ataxia 34.

Current Status of Stem Cell Therapies in Tissue Repair and Regeneration

2019 ◽  
Vol 14 (2) ◽  
pp. 117-126 ◽  
Author(s):  
Tapan Kumar Giri ◽  
Amit Alexander ◽  
Mukta Agrawal ◽  
Swarnalata Saraf ◽  
Shailendra Saraf ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Stem Cell ◽  
Tissue Repair ◽  
Good Reason ◽  
Current Status ◽  
Stem Cell Therapies ◽  
Cell Therapies ◽  
Tissue Repair And Regeneration ◽  
Disciplinary Field ◽  
Repair Techniques

Tissue engineering is a multi-disciplinary field such as material science, life science, and bioengineering that are necessary to make artificial tissue or rejuvenate damaged tissue. Numerous tissue repair techniques and substitute now exist even though it has several shortcomings; these shortcomings give a good reason for the continuous research for more acceptable tissue-engineered substitutes. The search for and use of a suitable stem cell in tissue engineering is a promising concept. Stem cells have a distinctive capability to differentiate and self-renew that make more suitable for cell-based therapies in tissue repair and regeneration. This review article focuses on stem cell for tissue engineering and their methods of manufacture with their application in nerve, bone, skin, cartilage, bladder, cardiac, liver tissue repair and regeneration.

scholarly journals Retinitis Pigmentosa withEYSMutations Is the Most Prevalent Inherited Retinal Dystrophy in Japanese Populations

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Yuuki Arai ◽  
Akiko Maeda ◽  
Yasuhiko Hirami ◽  
Chie Ishigami ◽  
Shinji Kosugi ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Direct Sequencing ◽  
Retinal Dystrophy ◽  
In Silico Analysis ◽  
Japanese Patients ◽  
Sequence Variants ◽  
Stargardt Disease ◽  
Identification Rate ◽  
Inherited Retinal Dystrophies ◽  
Inherited Retinal Dystrophy

The aim of this study was to gain information about disease prevalence and to identify the responsible genes for inherited retinal dystrophies (IRD) in Japanese populations. Clinical and molecular evaluations were performed on 349 patients with IRD. For segregation analyses, 63 of their family members were employed. Bioinformatics data from 1,208 Japanese individuals were used as controls. Molecular diagnosis was obtained by direct sequencing in a stepwise fashion utilizing one or two panels of 15 and 27 genes for retinitis pigmentosa patients. If a specific clinical diagnosis was suspected, direct sequencing of disease-specific genes, that is,ABCA4for Stargardt disease, was conducted. Limited availability of intrafamily information and decreasing family size hampered identifying inherited patterns. Differential disease profiles with lower prevalence of Stargardt disease from European and North American populations were obtained. We found 205 sequence variants in 159 of 349 probands with an identification rate of 45.6%. This study found 43 novel sequence variants. In silico analysis suggests that 20 of 25 novel missense variants are pathogenic.EYSmutations had the highest prevalence at 23.5%. c.4957_4958insA and c.8868C>A were the two majorEYSmutations identified in this cohort.EYSmutations are the most prevalent among Japanese patients with IRD.

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