Tigem’s Post

First-in-human study of a 3-year-old patient with GNAO1 encephalopathy showed significant improvement in motor skills, reduction in seizures, and overall positive outcomes. Mutations in the GNAO1 gene lead to severe pediatric encephalopathy, with pathogenic variants stratifying into 3 classes in their responsiveness to zinc. The finding suggests a new standard of care for GNAO1-related disorders and support the need for further clinical trials. Read full paper free-access in Med by Cell Press. Yonika Arum Larasati Moritz Thiel Alexey Koval Denis Silachev Anne Koy Vladimir Katanaev #GNAO1 #pediatricencephalopathy #neurologicaldisorders #genetics #zincsupplementation #clinicaltrial #openaccess https://lnkd.in/ePCqkjC7

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive lung disease urgently needing new therapies. Current treatments only delay disease progression, leaving lung transplant as the sole remaining option. Recent studies support a model whereby IPF arises because alveolar epithelial type II (AT2) cells, which normally mediate distal lung regeneration, acquire airway and/or mesenchymal characteristics, preventing proper repair. Mechanisms driving this abnormal differentiation remain unclear. We performed integrated transcriptomic and epigenomic analysis of purified AT2 cells which revealed genome-wide alterations in IPF lungs. The most prominent epigenetic alteration was activation of an enhancer in thyroid receptor interactor 13 (TRIP13), although TRIP13 was not the most significantly transcriptionally upregulated gene. TRIP13 is broadly implicated in epithelial-mesenchymal plasticity. In cultured human AT2 cells and lung slices, small molecule TRIP13 inhibitor DCZ0415 prevented acquisition of the mesenchymal gene signature characteristic of IPF, suggesting TRIP13 inhibition as a potential therapeutic approach to fibrotic disease. Eugene Golts Zea Borok Laura Crotty Alexander UC San Diego Health Center for Transplantation at UC San Diego Health

#Researchers from the Perelman #School of #Medicine at the University of Pennsylvania and the #Brain Research Institute at Niigata #University in #Japan have uncovered the mechanism by which the TREX1 gene mutation causes retinal #vasculopathy with cerebral #leukoencephalopathy (RVCL), a rare and deadly disease. The mutation in the #TREX1 #gene, which is responsible for maintaining #DNA integrity, leads to accelerated DNA damage, resulting in #premature aging and breakdown of small #blood vessels in various organs, including the brain and eyes. This #damage mirrors the breakdowns seen in radiation injuries and interrupts the DNA repair process, causing cells to age prematurely and stop dividing. The study, published in #Nature Communications, highlights the broader implications of this discovery for other aging-related diseases, such as #cardiovascular diseases, autoimmune disorders, and cancer. Elevated levels of TREX1, which increase with age, were found to make cells more susceptible to damage from chemotherapy and to increase the risk of breast cancer, similar to the effects seen with BRCA1 and BRCA2 mutations. The researchers are hopeful that targeting TREX1 could lead to new treatments for RVCL and potentially other diseases linked to aging. They are exploring the possibility of lowering TREX1 levels, correcting the mutation, or blocking its DNA-damaging effects. Additionally, the study suggests that existing FDA-approved medications might be repurposed to treat RVCL by impacting TREX1 levels. This research not only provides a clearer understanding of RVCL but also offers insights into the DNA damage theory of aging, with potential implications for a wide range of human conditions associated with aging. #Ariti #nextohuman #health #healthcare #people #peoplefirst #pharmaceutical #medical https://lnkd.in/gzwUdDZ5

Are Disease-Modifying Treatments on the Horizon for Patients With #ARVC? Gene therapy targeting the underlying desmosomal mutation and approaches to prevent myocardial fibrosis independent of the specific genetic defect by increasing cardiac levels of FGF21 may be on the horizon for patients. https://okt.to/mOF1sy

📣📣📣Daily article sharing! Molecular and cellular processes underlying Unverricht-Lundborg disease—prospects for early interventions and a cure ✍ Eva Žerovnik  Explor Neurosci. 2024;3:295–308  DOI: https://lnkd.in/gAwjekgJ Received: April 19, 2024 Accepted: June 05, 2024 Published: July 18, 2024 Academic Editor: Jinwei Zhang, University of Exeter Medical School, UK This article belongs to the special issue "Epilepsy". Abstract: A short overview of the main features of progressive myoclonus epilepsies (PMEs), such as Lafora disease (LD), neuronal ceroid lipofuscinoses (NCLs), and myoclonus epilepsy with ragged-red fibers (MERRF) is given. The stress of this review paper is put on one of the PME’s, the Unverricht-Lundborg disease (ULD)—EPM1, which is caused by mutations in the human cystatin B gene (stefin B is an alternative protein’s name). However, different other genes/proteins were found mutated in patients presenting with EPM1-like symptoms. By understanding their function and pathophysiological roles, further insights into the underlying processes of EPM1 can be obtained. On a broader scale, common pathophysiological mechanisms exist between ULD, LD and NCLs, such as, reactive glia, synaptic remodeling, neuronal hyperexcitability, impairements in the lysosomal/endocytosis system, cytoskeletal functions, and mitochondria. Oxidative stress is also in common. By understanding the underlying molecular and cellular processes, early interventions, better therapies and eventually, by using modern stem cell, gene editing or replacement methods, a cure can be expected. Keywords: Progressive myoclonus epilepsy, neurodegeneration, ubiquitin proteasome system, mitochondrial impairment, autophagy, monogene diseases, oxidative stress, cystatin B Welcome to read!

Paper of the Week: This week’s paper by Meuleman et al. published in JASN investigated the role of terminal pathway activation in C3 glomerulopathy, a rare kidney disease caused by overactivation of the complement alternative pathway. In a retrospective analysis of 42 patients, the authors found that 88% of kidney biopsies showed C5b-9 deposits, indicating terminal pathway activation. Patients with high C5b-9 deposits had significantly higher chronicity scores and poorer kidney outcomes. Transcriptomic analysis revealed that one-third of 847 immune-related genes were upregulated in C3 glomerulopathy biopsies compared to controls. Clustering based on gene expression identified a subgroup of biopsies with high C5b-9 deposits that also had enriched immune and fibroblastic signatures. These findings suggest that terminal pathway activation in C3 glomerulopathy is linked to a distinct histological phenotype and worse disease prognosis. Read more at this link! https://lnkd.in/eXDHeyM4

📣📣📣Daily article sharing! Molecular and cellular processes underlying Unverricht-Lundborg disease—prospects for early interventions and a cure ✍ Eva Žerovnik  Explor Neurosci. 2024;3:295–308  DOI: https://lnkd.in/g468JcN2 Received: April 19, 2024 Accepted: June 05, 2024 Published: July 18, 2024 Academic Editor: Jinwei Zhang, University of Exeter Medical School, UK This article belongs to the special issue "Epilepsy". Abstract: A short overview of the main features of progressive myoclonus epilepsies (PMEs), such as Lafora disease (LD), neuronal ceroid lipofuscinoses (NCLs), and myoclonus epilepsy with ragged-red fibers (MERRF) is given. The stress of this review paper is put on one of the PME’s, the Unverricht-Lundborg disease (ULD)—EPM1, which is caused by mutations in the human cystatin B gene (stefin B is an alternative protein’s name). However, different other genes/proteins were found mutated in patients presenting with EPM1-like symptoms. By understanding their function and pathophysiological roles, further insights into the underlying processes of EPM1 can be obtained. On a broader scale, common pathophysiological mechanisms exist between ULD, LD and NCLs, such as, reactive glia, synaptic remodeling, neuronal hyperexcitability, impairements in the lysosomal/endocytosis system, cytoskeletal functions, and mitochondria. Oxidative stress is also in common. By understanding the underlying molecular and cellular processes, early interventions, better therapies and eventually, by using modern stem cell, gene editing or replacement methods, a cure can be expected. Keywords: Progressive myoclonus epilepsy, neurodegeneration, ubiquitin proteasome system, mitochondrial impairment, autophagy, monogene diseases, oxidative stress, cystatin B Welcome to read!

Researchers have discovered clonal hematopoiesis as a new, independent risk factor for heart disease, offering fresh insights and treatment possibilities. - Clonal hematopoiesis, caused by acquired mutations in blood stem cells, directly contributes to atherosclerosis, reshaping our understanding of heart disease risks. - This breakthrough identifies the mutations as a cause, not a consequence, of cardiovascular disease, settling a long-standing debate. - Colchicine, an ancient anti-inflammatory drug, shows promise in reducing cardiovascular risks associated with these mutations, particularly in the TET2 gene. - These findings pave the way for personalized medicine strategies, targeting the specific mutations to prevent heart disease. #HeartHealth #MedicalResearch #PersonalizedMedicine - Researchers utilized advanced DNA sequencing and noninvasive imaging to study over 4,000 individuals, confirming the link between clonal hematopoiesis and heart disease. - The studies were conducted by CNIC in collaboration with global institutions, showing colchicine’s potential as a low-cost, widely available solution. - Future studies will explore how genetic profiles and lifestyle choices might further influence the effects of clonal hematopoiesis. https://lnkd.in/gjra_guw

Researchers from China have made a significant breakthrough in treating hypertrophic cardiomyopathy (HCM), a common genetic heart disease that causes thickening of the heart muscle. The team developed a novel gene therapy approach using CRISPR-Cas9 technology to correct the genetic mutation responsible for HCM in mice. The treatment successfully reversed the disease's progression and improved heart function without any adverse effects. This groundbreaking research paves the way for future clinical trials and potential treatment options for patients with HCM, offering hope for those affected by this debilitating condition. #HypertrophicCardiomyopathy #GeneTherapy #CRISPR #HeartDisease #MedicalBreakthrough #GeneticMutation #HeartHealth #MedicalResearch #ClinicalTrials #FutureOfMedicine https://lnkd.in/ehVgMKAQ

🔬 Advancements in Cardiovascular Research: The Role of Colchicine in TET2-Mutant Clonal Hematopoiesis A recent study published in the European Heart Journal delves into the potential of colchicine, an established anti-inflammatory medication, to mitigate accelerated atherosclerosis associated with TET2-mutant clonal hematopoiesis (CH). Key Insights: 1. Context and Importance: TET2 mutations are increasingly recognized as significant contributors to heightened cardiovascular risk due to their association with vascular inflammation. This study aims to elucidate the protective effects of colchicine in this specific genetic context. 2. Research Methodology: The investigation utilized a mouse model of TET2-mutant CH and analyzed extensive clinical data from prominent biobanks to explore the relationship between colchicine prescription and myocardial infarction risk in affected individuals. 3. Major Findings: The study concluded that colchicine effectively prevented the development of accelerated atherosclerosis in the mouse model and was associated with a reduced incidence of myocardial infarction in human subjects with TET2 mutations. Importantly, these protective effects were not observed with other genetic mutations, highlighting the specificity of colchicine's action. 4. Clinical Implications: These findings suggest that colchicine could play a critical role in the management of cardiovascular risks for patients harboring TET2 mutations. The study sets the stage for future clinical trials aimed at developing precision medicine strategies tailored to specific genetic profiles. For those interested in exploring the full study and its implications further, please refer to the original article. #CardiovascularResearch #Colchicine #Atherosclerosis #TET2 #PrecisionMedicine #HealthcareInnovation