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1.
Orphanet J Rare Dis ; 16(1): 222, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001227

RESUMO

Mutations in the EYS gene are one of the major causes of autosomal recessive retinitis pigmentosa. EYS-retinopathy presents a severe clinical phenotype, and patients currently have no therapeutic options. The progress in personalised medicine and gene and cell therapies hold promise for treating this degenerative disease. However, lack of understanding and incomplete comprehension of disease's mechanism and the role of EYS in the healthy retina are critical limitations for the translation of current technical advances into real therapeutic possibilities. This review recapitulates the present knowledge about EYS-retinopathies, their clinical presentations and proposed genotype-phenotype correlations. Molecular details of the gene and the protein, mainly based on animal model data, are analysed. The proposed cellular localisation and roles of this large multi-domain protein are detailed. Future therapeutic approaches for EYS-retinopathies are discussed.


Assuntos
Degeneração Retiniana , Retinose Pigmentar , Animais , Análise Mutacional de DNA , Eletrorretinografia , Proteínas do Olho/genética , Humanos , Mutação/genética , Degeneração Retiniana/genética , Degeneração Retiniana/terapia
2.
Stem Cell Res ; 53: 102301, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33773389

RESUMO

Retinal dystrophies associated to mutations in the CRB1 gene comprise a wide array of clinical presentations. A blood sample from a patient with a family history of CRB1-retinal dystrophy was used to prepare the iPSC line ESi082-A. The genotype of the donor, affected of a perifoveal-bilateral macular dystrophy includes one frameshift deletion and one hypomorphic allele. ESi082-A cell line has been characterized for pluripotency and will be used to prepare retinal cellular models to study the dysfunction leading to the disease.


Assuntos
Células-Tronco Pluripotentes Induzidas , Degeneração Macular , Distrofias Retinianas , Proteínas do Olho/genética , Humanos , Degeneração Macular/genética , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Linhagem , Fenótipo , Distrofias Retinianas/genética
3.
Adv Exp Med Biol ; 1185: 457-462, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884654

RESUMO

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.


Assuntos
Pró-Fármacos/farmacologia , Resveratrol/farmacologia , Retinose Pigmentar/tratamento farmacológico , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Neuroproteção , Retinose Pigmentar/genética , Sirtuína 1
4.
Stem Cell Res ; 38: 101473, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31176916

RESUMO

Age-related macular degeneration (AMD) is the leading cause of adult blindness in developed countries and is characterized by progressive degeneration of the macula, the central region of the retina. A human induced pluripotent stem cell (hiPSC) line was derived from peripheral blood mononuclear cells (PBMCs) from a patient with a clinical diagnosis of dry AMD carrying the CFH Y402H polymorphism. Sendai virus was using for reprogramming and the pluripotent and differentiation capacity of the cells were assessed by immunocytochemistry and RT-PCR.


Assuntos
Técnicas de Reprogramação Celular , Células-Tronco Pluripotentes Induzidas , Degeneração Macular , Polimorfismo Genético , Idoso de 80 Anos ou mais , Linhagem Celular , Fator H do Complemento/genética , Fator H do Complemento/metabolismo , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Degeneração Macular/genética , Degeneração Macular/metabolismo , Degeneração Macular/patologia
5.
Tissue Eng Part A ; 25(9-10): 799-808, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30963803

RESUMO

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.


Assuntos
Células-Tronco Pluripotentes Induzidas/metabolismo , Degeneração Macular , Monócitos/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/transplante , Animais , Técnicas de Reprogramação Celular , Modelos Animais de Doenças , Células-Tronco Pluripotentes Induzidas/patologia , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Degeneração Macular/terapia , Camundongos , Monócitos/patologia , Epitélio Pigmentado da Retina/patologia , Suínos
6.
Stem Cell Res ; 36: 101426, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30921587

RESUMO

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.


Assuntos
Linhagem Celular , Proteínas do Olho/genética , Células-Tronco Pluripotentes Induzidas , Retinose Pigmentar/genética , Idoso , Diferenciação Celular , Técnicas de Reprogramação Celular , Feminino , Heterozigoto , Humanos , Cariótipo , Leucócitos Mononucleares , Mutação Puntual
7.
Stem Cell Res ; 33: 251-254, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30471616

RESUMO

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.


Assuntos
Proteínas do Olho/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Retinose Pigmentar/genética , Adulto , Humanos , Masculino , Mutação
8.
CNS Neurosci Ther ; 24(5): 448-455, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29372592

RESUMO

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.


Assuntos
Indanos/farmacologia , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Retinose Pigmentar/tratamento farmacológico , Proteína X Associada a bcl-2/metabolismo , Administração Oral , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Progressão da Doença , Expressão Gênica/efeitos dos fármacos , Camundongos Transgênicos , Células Fotorreceptoras/efeitos dos fármacos , Células Fotorreceptoras/metabolismo , Células Fotorreceptoras/patologia , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/patologia , Retinose Pigmentar/metabolismo , Retinose Pigmentar/patologia , Visão Ocular/efeitos dos fármacos , Visão Ocular/fisiologia
9.
Nanomedicine ; 12(8): 2251-2260, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27381066

RESUMO

Retinitis pigmentosa (RP) is the most common cause of inherited blindness in adults. Mutations in the PRPF31 gene produce autosomal dominant RP (adRP). To date there are no effective treatments for this disease. The purpose of this study was to design an efficient non-viral vector for human PRPF31 gene delivery as an approach to treat this form of adRP. Span based nanoparticles were developed to mediate gene transfer in the subretinal space of a mouse model of adRP carrying a point mutation (A216P) in the Prpf31 gene. Funduscopic examination, electroretinogram, optomotor test and optical coherence tomography were conducted to further in vivo evaluate the safety and efficacy of the nanosystems developed. Span-polyarginine (SP-PA) nanoparticles were able to efficiently transfect the GFP and PRPF31 plasmid in mice retinas. Statistically significant improvement in visual acuity and retinal thickness were found in Prpf31A216P/+ mice treated with the SP-PA-PRPF31 nanomedicine.


Assuntos
Proteínas do Olho/administração & dosagem , Terapia Genética/métodos , Nanopartículas , Retinose Pigmentar/terapia , Animais , Arginina , Análise Mutacional de DNA , Genes Dominantes , Humanos , Camundongos , Mutação , Linhagem
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