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Gene Therapy for Leber Hereditary Optic Neuropathy: Low- and Medium-Dose Visual Results.

PURPOSE: To determine the effects of AAV2(Y444,500,730F)-P1ND4v2 in patients with Leber hereditary optic neuropathy (LHON). DESIGN: Prospective open-label, unilateral single-dose, intravitreal injection of AAV2(Y444,500,730F)-P1ND4v2 per participant. PARTICIPANTS: Fourteen patients with visual loss and mutated G11778A mitochondrial DNA. METHODS: Intravitreal injection with the gene therapy vector AAV2(Y444,500,730F)-P1ND4v2 into 1 eye. Six participants with chronic bilateral visual loss lasting more than 12 months (group 1), 6 participants with bilateral visual loss lasting less than 12 mon

Molecular biomarkers in gastric cancer.

Gastric cancer (GC) represents a serious health problem on a global scale. Despite some recent advances in the field, the prognosis in metastatic GC remains poor. Even in localized disease the adjunctive therapies improve overall survival (OS) by only approximately 10%. A better understanding of molecular biology, which would lead to improved treatment options, is needed and is the basis for this review. Many potential biomarkers of prognostic significance have been identified, including ALDH, SHH, Sox9, HER2, EGFR, VEGF, Hippo/YAP, and MET. However, inhibition of only HER2 protein has led to

An unexpected role for a Wnt-inhibitor: Dickkopf-1 triggers a novel cancer survival mechanism through modulation of aldehyde-dehydrogenase-1 activity.

It is widely accepted that canonical Wnt (cWnt) signaling is required for the differentiation of osteoprogenitors into osteoblasts. Furthermore, tumor-derived secretion of the cWnt-antagonist Dickkopf-1 (Dkk-1) is known to cause bone destruction, inhibition of repair and metastasis in many bone malignancies, but its role in osteosarcoma (OS) is still under debate. In this study, we examined the role of Dkk-1in OS by engineering its overexpression in the osteochondral sarcoma line MOS-J. Consistent with the known role of Dkk-1 in osteoblast differentiation, Dkk-1 inhibited osteogenesis by the M

Trial end points and natural history in patients with G11778A Leber hereditary optic neuropathy : preparation for gene therapy clinical trial.

IMPORTANCE Establishing the natural history of G11778A Leber hereditary optic neuropathy (LHON) is important to determine the optimal end points to assess the safety and efficacy of a planned gene therapy trial. OBJECTIVE To use the results of the present natural history study of patients with G11778A LHON to plan a gene therapy clinical trial that will use allotopic expression by delivering a normal nuclear-encoded ND4 gene into the nuclei of retinal ganglion cells via an adeno-associated virus vector injected into the vitreous. DESIGN, SETTING, AND PARTICIPANTS A prospective observational st

Phenogenon: Gene to phenotype associations for rare genetic diseases.

As high-throughput sequencing is increasingly applied to the molecular diagnosis of rare Mendelian disorders, a large number of patients with diverse phenotypes have their genetic and phenotypic data pooled together to uncover new gene-phenotype relations. We introduce Phenogenon, a statistical tool that combines, Human Phenotype Ontology (HPO) annotated patient phenotypes, gnomAD allele population frequency, and Combined Annotation Dependent Depletion (CADD) score for variant pathogenicity, in order to jointly predict the mode of inheritance and gene-phenotype associations. We ran Phenogenon

Differentially expressed genes implicated in unexplained recurrent spontaneous abortion.

Recurrent spontaneous abortion occurs in approximately 3% of women with diagnosed pregnancies. The etiology in approximately 40% of recurrent spontaneous abortion is unexplained. To elucidate unexplained recurrent spontaneous abortion at the molecular level, we systemically identified differentially expressed genes during implantation window period in unexplained recurrent spontaneous abortion and characterized their functions in a human endometrial cell line. Expression levels of implantation-related genes selected from previously reported, various microarray data were determined to identify

[The role of the HIF-1 signaling pathway in retinal ganglion cell injury caused by the OPTN (E50K) mutation].

Objective: To explore the role and mechanism of the hypoxia-inducible factor-1 (HIF-1) pathway in rat retinal precursor R28 cell injury caused by the OPTN (E50K) mutation. Methods: This experimental study was conducted from November 2023 to October 2024. The retinas of 18-month-old wild-type (WT) mice and normal tension glaucoma mice with the OPTN (E50K) mutation were extracted for proteomic analysis. In vitro models carrying the genes of green fluorescent protein (GFP), GFP-OPTN (WT) and GFP-OPTN (E50K) were constructed by transfecting R28 cells with adeno-associated viruses. Western blotting

Leber hereditary optic neuropathy gene therapy clinical trial recruitment: year 1.

OBJECTIVE: To describe the patient profiles of the Leber hereditary optic neuropathy (LHON) Gene Therapy Clinical Trial, year 1. This study aims to identify and characterize affected patients and carriers with the G11778A mutation in mitochondrial DNA for planned gene therapy that will use "allotopic expression" by delivering a normal nuclear-encoded ND4 gene into the nuclei of retinal ganglion cells via an adeno-associated virus vector injected into the vitreous. METHODS: Patients with LHON with visual loss as well as asymptomatic maternally related family members were molecularly screened f

Investigation of new candidate genes in retinoblastoma using the TruSight One "clinical exome" gene panel.

BACKGROUND: Retinoblastoma (Rb) is the most prevalent intraocular pediatric malignancy of the retina. Significant genetic factors are known to have a role in the development of Rb. METHODS: Here, we report the mutation status of 4813 clinically significant genes in six patients with noncarrier of RB1 gene mutation and having normal RB1 promoter methylation from three families having higher risk for developing Rb in the study. RESULTS: A total of 27 variants were detected in the study. Heterozygous missense variants c.1162G > A (p.Gly388Arg) in the FGFR4 gene; c.559C > T (p.Pro187Ser) in the

SOD2 gene transfer protects against optic neuropathy induced by deficiency of complex I.

Mutations in genes encoding the NADH ubiquinone oxidoreductase, complex I of the respiratory chain, cause a diverse group of diseases. They include Leber hereditary optic neuropathy, Leigh syndrome, and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. There is no effective treatment for these or any other mitochondrial disorder. Using a unique animal model of severe complex I deficiency induced by ribozymes targeted against a critical complex I subunit gene (NDUFA1), we attempted rescue of the optic nerve degeneration associated with Leber hereditary optic neuropa

От диагностики к лечению: изучение механизмов, лежащих в основе оптического неврата в множестве склерозов.

Множественный склероз (MS) — хроническое аутоиммунное заболевание, воздействующее на центральную нервную систему, которое, как правило, вызывает сенсорные расстройства, моторную слабость, слабую походку, несогласованность и оптический неуриит (ON). Согласно статистическим данным, до 50% пациентов, страдающих синдромом MS, испытывают проблемы со зрением в период болезни, страдающие от нечеткого зрения, боли, недостатка зрения и даже слепоты. Лечение перешло от кортикостероидов к лечению, ориентированному на клетки В/Т. В рамках этого обзора проводится всеобъемлющая и систематическая оценка диаг

The Hypoxia-Retinoid Axis in Idiopathic Pulmonary Fibrosis: Multifaceted Etiology and Therapeutic Potential.

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease with limited therapeutic options. This review focuses on the role of retinoids, particularly all-trans retinoic acid (atRA), and hypoxia in the pathogenesis of IPF. Despite an established understanding of genetic and environmental factors in IPF, the interplay between retinoid signaling and the response to hypoxia remains poorly explored due to its complexity. Preclinical evidence suggests that atRA could help reduce pulmonary fibrosis by modulating TGF-β signaling pathways and epithelial-to-mesenchymal transition (EM

Совпадение в полном тексте источника
… The atRAL thus produced from carotenoids could be further reduced to atROL by an intestinal retinal reductase or oxidized to atRA by a retinal dehydrogenase. Both metabolites can be directly secreted to the bloodstream bound to CRBP or albumin. … Regulation of Retinal Dehydrogenases and Retinoic Acid Synthesis by Cholesterol Metabolites EMBO J. 2006 25 3203 3213 10.1038/sj.emboj.7601181 16763553 PMC1500992 93. Jetten A.M. …

Aminoquinolines as Translational Models for Drug Repurposing: Anticancer Adjuvant Properties and Toxicokinetic-Related Features.

The indiscriminate consumption of antimalarials against coronavirus disease-2019 emphasizes the longstanding clinical weapons of medicines. In this work, we conducted a review on the antitumor mechanisms of aminoquinolines, focusing on the responses and differences of tumor histological tissues and toxicity related to pharmacokinetics. This well-defined analysis shows similar mechanistic forms triggered by aminoquinolines in different histological tumor tissues and under coexposure conditions, although different pharmacological potencies also occur. These molecules are lysosomotropic amines th

Ранняя потеря "Macular Ganglion Cell" в Leber Hereditary Optic Neurophy — биомаркер оптической совместимости для дифференцирования оптического неврита.

Фон/цели: Наследственная оптическая нейропатия Лебера (LHON) часто неправильно диагностируется на ранних этапах как идиопатический единичный оптический неуриит (SION) или многоклерозовый оптический неврал (MS-ON) из-за раннего возраста пациентов, потери субакутного зрения и нарушения центрального визуального поля. Цель этого ретроспективного исследования состояла в том, чтобы оценить изменения в перипиллярном RNFL и GCLT с течением времени у пациентов с ранним LHON, MS-ON и SION, с тем чтобы провести различие между наследственной нейропатией (LHON) и оптическим неуриитом (ON) на ранних стадиях

NLRX1 limits inflammatory neurodegeneration in the anterior visual pathway.

Chronic innate immune activation in the central nervous system (CNS) significantly contributes to neurodegeneration in progressive multiple sclerosis (MS). Using multiple experimental autoimmune encephalomyelitis (EAE) models, we discovered that NLRX1 protects neurons in the anterior visual pathway from inflammatory neurodegeneration. We quantified retinal ganglion cell (RGC) density and optic nerve axonal degeneration, gliosis, and T-cell infiltration in Nlrx1-/- and wild-type (WT) EAE mice and found increased RGC loss and axonal injury in Nlrx1-/- mice compared to WT mice in both active immu

Совпадение с Такаясу Артеритом и множественным склерозом: обзор скрипта и доклад по делу.

ВВЕДЕНИЕ: Такайасу-артерит (ТА) и множественный склероз (МС) являются как иммунизированными заболеваниями, которые могут сосуществовать, при этом ТА вызывает сосудистое воспаление, а MS - обезвоживание, вызванное аберрантной активностью Т-клеток. Совпадение этих условий подчеркивает наличие общих иммунных механизмов, таких, как регулирование " Т-клеток " и высвобождение цитокина, что подчеркивает необходимость нюансированного понимания их взаимодействия, которое изучается в ходе описательного обзора зарегистрированных случаев. Мы рассказываем обо всех зарегистрированных случаях насил

Primary choroidal lymphoma with extrascleral extension and bone marrow involvement: a case report.

Primary extranodal marginal zone B-cell lymphoma (EMZL) of the choroid is a rare condition with a handful of cases reported in the literature. Here, we report a challenging case of primary EMZL of the choroid with extrascleral extension and bone marrow involvement. An 86-year-old male presented with 2 years of progressive vision loss in his left eye. Fundus examination revealed yellow-white subretinal infiltrates at the posterior pole. Ultrasonography detected diffuse choroidal thickening with retrobulbar hypoechoic mass. One year later, an inferior exudative retinal detachment developed. Ultr

Влияние различных методов лечения на толщину спины у пациентов с множественным склерозом: обзор.

Множественный склероз (MS) — аутоиммунное расстройство, воздействующее на центральную нервную систему с различными клиническими проявлениями, такими, как оптический неврит, сенсорные расстройства и синдромы головного мозга. Происхождение заболеваний контролируется с помощью таких методов, как сканирование МРТ, шкала инвалидности и томография оптической согласованности (OCT), которые могут обнаруживать утончённую сетчатку сетчатки, даже при отсутствии оптического невраита. MS прогрессирует в нейродегенерации, особенно транссинптической дегенерации, которая выходит за рамки первоначального места

Oroxylin A: A Promising Flavonoid for Prevention and Treatment of Chronic Diseases.

There have been magnificent advancements in the understanding of molecular mechanisms of chronic diseases over the past several years, but these diseases continue to be a considerable cause of death worldwide. Most of the approved medications available for the prevention and treatment of these diseases target only a single gene/protein/pathway and are known to cause severe side effects and are less effective than they are anticipated. Consequently, the development of finer therapeutics that outshine the existing ones is far-reaching. Natural compounds have enormous applications in curbing seve

Fructosamine-3-Kinase as a Potential Treatment Option for Age-Related Macular Degeneration.

Age-related macular degeneration is the leading cause of blindness in the developed world. Since advanced glycation end products (AGEs) are implicated in the pathogenesis of AMD through various lines of evidence, we investigated the potential of fructosamine-3-kinase (FN3K) in the disruption of retinal AGEs, drusenoid material and drusenoid lesions in patients with AMD. AGE-type autofluorescence was measured to evaluate the effects of FN3K on glycolaldehyde-induced AGE-modified neural porcine retinas and unmodified human neural retinas. Eye pairs from cigarette-smoke- and air-exposed mice were