Advancements in small molecule drug design: A structural perspective

Drug Discovery Today, Год журнала: 2023, Номер 28(10), С. 103730 - 103730

Опубликована: Авг. 1, 2023

Язык: Английский

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Pluripotent stem cell-derived models of retinal disease: Elucidating pathogenesis, evaluating novel treatments, and estimating toxicity

Progress in Retinal and Eye Research, Год журнала: 2024, Номер 100, С. 101248 - 101248

Опубликована: Фев. 16, 2024

Blindness poses a growing global challenge, with approximately 26% of cases attributed to degenerative retinal diseases. While gene therapy, optogenetic tools, photosensitive switches, and prostheses offer hope for vision restoration, these high-cost therapies will benefit few patients. Understanding diseases is therefore key advance effective treatments, requiring in vitro models replicating pathology allowing quantitative assessments drug discovery. Pluripotent stem cells (PSCs) provide unique solution given their limitless supply ability differentiate into light-responsive tissues encompassing all cell types. This review focuses on the history current state photoreceptor pigment epithelium (RPE) generation from PSCs. We explore applications this technology disease modelling, experimental therapy testing, biomarker identification, toxicity studies. consider challenges scalability, standardisation, reproducibility, stress importance incorporating vasculature immune organoids. advocate high-throughput automation data acquisition analyses underscore value advanced micro-physiological systems that fully capture interactions between neural retina, RPE, choriocapillaris.

Язык: Английский

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Resilience to diabetic retinopathy

Progress in Retinal and Eye Research, Год журнала: 2024, Номер 101, С. 101271 - 101271

Опубликована: Май 11, 2024

Chronic elevation of blood glucose at first causes relatively minor changes to the neural and vascular components retina. As duration hyperglycemia persists, nature extent damage increases becomes readily detectable. While this second, overt manifestation diabetic retinopathy (DR) has been studied extensively, what prevents maximal from very start remains largely unexplored. Recent studies indicate that diabetes (DM) engages mitochondria-based defense during retinopathy-resistant phase, thereby enables retina remain healthy in face hyperglycemia. Such resilience is transient, its deterioration results progressive accumulation retinal damage. The concepts co-emerge with these discoveries set stage for novel intellectual therapeutic opportunities within DR field. Identification biomarkers mediators protection DM-mediated will enable development resilience-based therapies indefinitely delay onset DR.

Язык: Английский

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Retinal Ciliopathies and Potential Gene Therapies: A Focus on Human iPSC-Derived Organoid Models

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(5), С. 2887 - 2887

Опубликована: Март 1, 2024

The human photoreceptor function is dependent on a highly specialised cilium. Perturbation of cilial can often lead to death the and loss vision. Retinal ciliopathies are genetically diverse range inherited retinal disorders affecting aspects Despite advances in understanding utilising animal disease models, they lack ability accurately mimic observed patient phenotype, possibly due structural functional deviations from retina. Human-induced pluripotent stem cells (hiPSCs) be utilised generate an alternative model, 3D organoid, which contains all major cell types including photoreceptors complete with structures. These organoids facilitate study mechanisms potential therapies human-derived system. Three-dimensional still developing technology, despite impressive progress, several limitations remain. This review will discuss state hiPSC-derived organoid technology for modelling prominent related genes, RPGR, CEP290, MYO7A, USH2A. Additionally, we development novel gene therapy approaches targeting ciliopathies, delivery large genes gene-editing techniques.

Язык: Английский

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Application of patient-derived induced pluripotent stem cells and organoids in inherited retinal diseases

Stem Cell Research & Therapy, Год журнала: 2023, Номер 14(1)

Опубликована: Ноя. 27, 2023

Abstract Inherited retinal diseases (IRDs) can induce severe sight-threatening degeneration and impose a considerable economic burden on patients society, making efforts to cure blindness imperative. Transgenic animals mimicking human genetic have long been used as primary research tool decipher the underlying pathogenesis, but there are still some obvious limitations. As an alternative strategy, patient-derived induced pluripotent stem cells (iPSCs), particularly three-dimensional (3D) organoid technology, considered promising platform for modeling different forms of IRDs, including retinitis pigmentosa, Leber congenital amaurosis, X-linked recessive retinoschisis, Batten disease, achromatopsia, best vitelliform macular dystrophy. Here, this paper focuses status iPSCs organoids in IRDs recent years concerning disease therapeutic exploration, along with potential challenges translating laboratory clinical application. Finally, importance combination emerging technologies such multi-omics integration analysis, 3D bioprinting, or microfluidic chip highlighted. Patient-derived may be preferred choice more accurately uncovering mechanisms will contribute practice.

Язык: Английский

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Cell-cell interaction in the pathogenesis of inherited retinal diseases

Frontiers in Cell and Developmental Biology, Год журнала: 2024, Номер 12

Опубликована: Март 4, 2024

The retina is part of the central nervous system specialized for vision. Inherited retinal diseases (IRD) are a group clinically and genetically heterogenous disorders that lead to progressive vision impairment or blindness. Although each disorder rare, IRD accumulatively cause blindness in up 5.5 million individuals worldwide. Currently, pathophysiological mechanisms not fully understood there limited treatment options available. Most caused by degeneration light-sensitive photoreceptors. Genetic mutations abrogate structure and/or function photoreceptors visual followed loss In healthy retina, structurally functionally interact with pigment epithelium (RPE) Müller glia (MG) maintain homeostasis. Multiple photoreceptor as major phenotype RPE- MG-associated genes. Recent studies also reveal compromised MG RPE ubiquitously expressed ciliary Therefore, could be direct consequence gene secondary dysfunction their interaction partners retina. This review summarizes photoreceptor-RPE/MG supporting functions discusses how disruption these processes degeneration, an aim provide unique perspective pathogenesis paradigm. We will first describe biology then discuss between MG/RPE well implications disease pathogenesis. Finally, we summarize recent advances therapeutics targeting RPE.

Язык: Английский

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The New Frontiers of Gene Therapy and Gene Editing in Inflammatory Diseases

Human Gene Therapy, Год журнала: 2024, Номер 35(7-8), С. 219 - 231

Опубликована: Фев. 7, 2024

Inflammatory diseases are conditions characterized by abnormal and often excessive immune responses, leading to tissue organ inflammation. The complexity of these disorders arises from the intricate interplay genetic factors which challenges conventional therapeutic approaches. However, field manipulation has sparked unprecedented optimism in addressing complex disorders. This review aims comprehensively explore application gene therapy editing context inflammatory diseases, offering solutions that range correcting defects precise modulation. These therapies have exhibited remarkable potential ameliorating symptoms, improving quality life, even achieving disease remission. As we delve into recent breakthroughs applications, illustrate how advancements offer novel transformative for traditionally eluded treatments. By examining successful case studies preclinical research, emphasize favorable results substantial impacts gene-based interventions demonstrated patients animal models such as chronic granulomatous disease, cryopyrin-associated syndromes, adenosine deaminase 2 deficiency, well those multifactorial origins arthropathies (osteoarthritis, rheumatoid arthritis) bowel disease. In conclusion, opportunities address underlying causes ushering a new era precision medicine providing hope personalized, targeted

Язык: Английский

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Retinal primary cilia and their dysfunction in retinal neurodegenerative diseases: beyond ciliopathies

Molecular Medicine, Год журнала: 2024, Номер 30(1)

Опубликована: Июль 26, 2024

Primary cilia are sensory organelles that extend from the cellular membrane and found in a wide range of cell types. Cilia possess plethora vital components enable detection transmission several signaling pathways, including Wnt Shh. In turn, regulation ciliogenesis cilium length is influenced by various factors, autophagy, organization actin cytoskeleton, inside cilium. Irregularities development, maintenance, function this component lead to clinical manifestations known as ciliopathies. The majority people with ciliopathies have high prevalence retinal degeneration. most common theory degeneration primarily caused functional developmental problems within photoreceptors. contribution other ciliated types has not been explored date. review, we examine occurrence primary their significance pathology. Additionally, explore potential therapeutic approaches targeting By engaging endeavor, present new ideas elucidate innovative concepts for future investigation treatment

Язык: Английский

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Sex-specific attenuation of photoreceptor degeneration by reserpine in a rhodopsin P23H rat model of autosomal dominant retinitis pigmentosa

Опубликована: Янв. 21, 2025

Inherited retinal degenerations (IRDs) constitute a group of clinically and genetically diverse vision-impairing disorders. Retinitis pigmentosa (RP), the most common form IRD, is characterized by gradual dysfunction degeneration rod photoreceptors, followed loss cone photoreceptors. Recently, we identified reserpine as lead molecule for maintaining survival in mouse human organoids well rd16 mouse, which phenocopy Leber congenital amaurosis caused mutations cilia-centrosomal gene CEP290 (Chen et al. eLife 2023;12:e83205. DOI: https://doi.org/10.7554/eLife.83205). Here, show therapeutic potential rhodopsin P23H rat model autosomal dominant RP. At postnatal day (P) 68, when males females are analyzed together, reserpine-treated rats exhibit higher rod-derived scotopic b-wave amplitudes compared to controls with little or no change a-wave cone-derived photopic b-wave. Interestingly, female display enhanced a- b-waves responses at P68, along better contrast threshold increased outer nuclear layer thickness. The demonstrate preservation both photoreceptors following treatment. Retinal transcriptome analysis reveals sex-specific reserpine, significant upregulation phototransduction genes proteostasis-related pathways, notably, associated stress response. This study builds upon our previously reported results reaffirming gene-agnostic treatment IRDs emphasizes importance biological sex disease research therapy development.

Язык: Английский

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Sex-specific attenuation of photoreceptor degeneration by reserpine in a rhodopsin P23H rat model of autosomal dominant retinitis pigmentosa

Опубликована: Янв. 21, 2025

Inherited retinal degenerations (IRDs) constitute a group of clinically and genetically diverse vision-impairing disorders. Retinitis pigmentosa (RP), the most common form IRD, is characterized by gradual dysfunction degeneration rod photoreceptors, followed loss cone photoreceptors. Recently, we identified reserpine as lead molecule for maintaining survival in mouse human organoids well rd16 mouse, which phenocopy Leber congenital amaurosis caused mutations cilia-centrosomal gene CEP290 (Chen et al., 2023). Here, show therapeutic potential rhodopsin P23H rat model autosomal dominant RP. At postnatal day (P) 68, when males females are analyzed together, reserpine-treated rats exhibit higher rod-derived scotopic b-wave amplitudes compared to controls with little or no change a-wave cone-derived photopic b-wave. Interestingly, female display enhanced a- b-waves responses at P68, along better contrast threshold increased outer nuclear layer thickness. The demonstrate preservation both photoreceptors following treatment. Retinal transcriptome analysis reveals sex-specific reserpine, significant upregulation phototransduction genes proteostasis-related pathways, notably, associated stress response. This study builds upon our previously reported results reaffirming gene-agnostic treatment IRDs emphasizes importance biological sex disease research therapy development.

Язык: Английский

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