LanLab OÜ’s Post

Estonians keep making the World a better place! This time around it is Marite Punapart with a team making great advancements towards finding a cure for Wolfram syndrome. Read more in the article here: https://lnkd.in/dQDPG7ih

SIMPLY: understanding the interplay between immune activity, genetic variation, and DNA methylation is crucial. It provides insights into disease susceptibility, immune responses, and potential therapeutic targets. For patients, this research may pave the way for personalized medicine approaches. By considering an individual’s genetic makeup and immune responsiveness, we could tailor treatments more effectively. In summary, this study sheds light on the intricate relationship between immune stimuli, genetic factors, and DNA methylation in monocytes. It has implications for disease susceptibility and therapeutic strategies. The study by Benjamin Fairfax  et al. investigated how immune activity influences #DNA methylation (#DNAm) in primary monocytes. They examined 190 paired samples from healthy individuals and characterized the consequences of inflammatory stimuli (such as lipopolysaccharide, LPS) on monocyte DNAm. Unlike gene expression changes, which are similarly widespread in response to LPS and IFNγ, DNAm is more sensitive to LPS. Exposure to LPS led to differential methylation at 20,858 immune-modulated CpGs (imCpGs), which are enriched for enhancers and genes implicated in cancer. LPS-Induced Demethylation: Monocyte DNAm showed stimulus-specific focal sensitivity at sites enriched for enhancers. LPS stimulation caused widespread DNA methylation changes in primary monocytes, leading to demethylation at specific loci. The shaping of DNA methylation by LPS is under genetic control. This suggests that individual genetic variation plays a role in determining how monocytes respond to immune activation. The majority of LPS-induced demethylation events involved genes that are commonly mutated in cancer. This finding highlights the potential relevance of immune-induced epigenetic changes in cancer development. University of Oxford Oxford University Hospitals NHS Foundation Trust Wellcome Trust NIHR (National Institute for Health and Care Research) NIHR Oxford Biomedical Research Centre and the Chinese Academy of Medical Sciences Wellcome Trust Centre for Human Genetics, University of Oxford NIHR Oxford Health Biomedical Research Centre (OH BRC) Big Data Institute Health Data Research UK (HDR UK) NIHR Oxford Biomedical Research Centre.

Breaking: New research published by Dr. Rashmi Kanagal-Shamanna highlights link between autoimmune disease (VEXAS), cancer and somatic gene mutations. Here's a summary from Dr. Kanagal-Shamanna: Chronic systemic inflammation, gene mutations, and cancer are closely related in diseases that affect the immune system and blood (such as autoimmune/rheumatological disorders). A recent discovery found that, when a gene called UBA1 is mutated, it can cause an autoimmune disorder called VEXAS syndrome. The UBA1 gene mutation is associated with severe inflammation throughout the body as well as an increased risk of a specific blood cancer called myelodysplastic syndrome (MDS). This means that the UBA1 gene mutation can lead to both inflammation and cancer. Based on this discovery, labs that test for genetic mutations in patients with blood problems are now including the UBA1 gene in their standard (routine) tests. The increased frequency of screening for UBA1 gene mutations has led to its detection in patients who don’t have symptoms associated with VEXAS syndrome as well as in patients with and without a blood cancer diagnosis. These findings have several important implications. First, in the past decade, there have been major advancements in the way we diagnose blood diseases, especially MDS. The diagnosis is now more focused on genetic testing (per latest WHO and International Consensus Classification criteria), but the doctors still need to consider other factors like the microscopic evaluation of bone marrow and blood for “abnormal” or “dysplastic” cells and the patient's clinical symptoms. Therefore, correct diagnoses require careful integration of multiple tests and findings. Second, because the outcomes for patients with autoimmune diseases can vary significantly, it's important to do thorough tests that include both blood counts, genetic testing and microscopic evaluation of blood or bone marrow. This could lead to improvements in how we classify these diseases. Further improvements in the classification systems should consider these suggestions. Clearly defining specific clinicopathologic conditions with known genetic abnormalities will significantly affect patients, leading to better management and outcomes. Lastly, because UBA1 gene mutations are present in precursor blood cells of patients with VEXAS, a diagnosis of blood cancer (such as MDS) should not be necessary for a transplant if it is the right course of action. Access published study here: https://lnkd.in/eascYqgH #research #autoimmunediseases

New research from doctors at the Royal Free Hospital has shown that a ‘boosted’ gene could be a major cause of inflammatory bowel disease (IBD), leading to hopes of more effective treatments being developed. IBD is the umbrella term for two diseases of the intestinal tract – Crohn’s disease and ulcerative colitis, with over half a million people living with one of these debilitating conditions in the UK. Despite increasing prevalence, current treatments do not work in every patient and attempts to develop new drugs often fail due to incomplete understanding of what causes IBD. In research published in Nature today, scientists at UCL and the Royal Free London found that a section of DNA works by ‘boosting’ another gene called ETS2, increasing the amount of protein it makes. The section of DNA is only active in a particular type of immune cell, called macrophages, known to be prevalent in the intestine of patients with IBD. The researchers believe that the boosted ETS2 gene is directly responsible for the inflammation and tissue damage in those patients. The researchers discovered that some existing drugs, currently used for non-inflammatory conditions, can ‘switch off’ the ETS2 gene, but these have significant side effects, so are not suitable for the long-term treatment required. Instead, doctors are now looking to develop a new generation of drugs that inhibit the ETS2 gene, without any damaging side effects. Lead researcher James Lee, a consultant gastroenterologist at the Royal Free Hospital and UCL and group leader of the Genetic Mechanisms of Disease laboratory at the The Francis Crick Institute, said: “IBD usually develops in young people and can cause severe symptoms that disrupt education, relationships, family life and employment. We urgently need better treatments for our patients. “Currently the drugs that can switch off the ETS2 gene are not safe enough for people to take long term as they have side effects in other organs. We are working to find a way to deliver these inhibitors directly to macrophages as this could switch off disease and spell relief for millions of people worldwide. While this is still early days, we believe this is an important discovery and a huge step forward.” This research was funded by Crohn's & Colitis UK, the Wellcome Trust, MRC and Cancer Research UK (CRUK). The researchers also worked with the National Institute of Health Research BioResource and collaborators across the UK and Europe.

iPSCs are contributing to better understanding of human diseases. It was great to see iPSCs being used in a recent study by Dehestani et al, to gain a better understanding of the effects of the leucine-rich repeat kinase 2 (LRRK2) p.G2019S mutation on oligodendroglial lineage cells and their potential role in Parkinson's disease (PD) development and progression. PD is the second most common age-related neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra gene. The exact cause of PD remains elusive, but there are genetic factors have been identified as significant contributors to the disease pathogenesis. In their study they mentioned that, among the various genetic factors associated with PD, the LRRK2 p.G2019S point mutation that results in abnormally high kinase activity, is recognized as one of the most prevalent variants worldwide implicated in the familial form of PD. They also mentioned how recent findings have indicated that oligodendrocytes (ODCs) and their progenitors are vulnerable in PD pathogenesis. In addition, oligodendrocyte precursor cells (OPCs) have been seen to exhibit high endogenous expression of LRRK2 warranting an investigation into the effects that the LRRK2 p.G2019S mutation could have on oligodendroglial lineage cells as it relates to PD. By differentiating patient-specific iPSC lines with the LRRK2 p.G2019S mutation to an oligodendroglial lineage and comparing with healthy controls, they were able to explore the genetic effects of the LRRK2 p.G2019S mutation at an unprecedented level. Their work had some key findings including transcriptomic changes being seen in several pathways, including down-regulation of genes related to semaphorin-plexin pathway in OPCs, and cilium movement in proliferating OPCs, both of which they propose might represent early events in PD pathology. As world leaders in iPSC technology, we are delighted to see how the technology has evolved into being a crucial asset for investigating the mechanisms involved in disease pathogenesis and for exploring potential treatments such as in Dehestani et al for PD. To read the full paper from Dehestani et al, click here: https://hubs.la/Q02RP-270 We are also committed to build better models of diseases including those of a neurodegenerative origin. If you too would like to use iPSCs to fuel your research in the neurodegenerative space, feel free to contact us at [email protected], we'd be happy to help! #iPSCs #StemCells #ParkinsonsDisease

#immunology #medicine #medicalsciences https://lnkd.in/gQ-PihJC #IPEX #syndrome from diagnosis to cure, learning along the way.                                 In the past 2 decades, a significant number of studies have been published describing the molecular and clinical aspects of #immune dysregulation #polyendocrinopathy #enteropathy X-linked (IPEX) syndrome. These studies have refined our knowledge of this rare yet prototypic genetic autoimmune disease, advancing the diagnosis, broadening the clinical spectrum, and improving our understanding of the underlying immunologic mechanisms. Despite these advances, Forkhead box P3 mutations have devastating consequences, and treating patients with IPEX syndrome remains a challenge, even with safer strategies for hematopoietic stem cell transplantation and gene therapy becoming a promising reality. The aim of this review was to highlight novel features of the disease to further advance awareness and improve the diagnosis and treatment of patients with IPEX syndrome.

iPSCs are contributing to better understanding of human diseases. It was great to see iPSCs being used in a recent study by Dehestani et al, to gain a better understanding of the effects of the leucine-rich repeat kinase 2 (LRRK2) p.G2019S mutation on oligodendroglial lineage cells and their potential role in Parkinson's disease (PD) development and progression. PD is the second most common age-related neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra gene. The exact cause of PD remains elusive, but there are genetic factors have been identified as significant contributors to the disease pathogenesis. In their study they mentioned that, among the various genetic factors associated with PD, the LRRK2 p.G2019S point mutation that results in abnormally high kinase activity, is recognized as one of the most prevalent variants worldwide implicated in the familial form of PD. They also mentioned how recent findings have indicated that oligodendrocytes (ODCs) and their progenitors are vulnerable in PD pathogenesis. In addition, oligodendrocyte precursor cells (OPCs) have been seen to exhibit high endogenous expression of LRRK2 warranting an investigation into the effects that the LRRK2 p.G2019S mutation could have on oligodendroglial lineage cells as it relates to PD. By differentiating patient-specific iPSC lines with the LRRK2 p.G2019S mutation to an oligodendroglial lineage and comparing with healthy controls, they were able to explore the genetic effects of the LRRK2 p.G2019S mutation at an unprecedented level. Their work had some key findings including transcriptomic changes being seen in several pathways, including down-regulation of genes related to semaphorin-plexin pathway in OPCs, and cilium movement in proliferating OPCs, both of which they propose might represent early events in PD pathology. As world leaders in iPSC technology, we are delighted to see how the technology has evolved into being a crucial asset for investigating the mechanisms involved in disease pathogenesis and for exploring potential treatments such as in Dehestani et al for PD. To read the full paper from Dehestani et al, click here: https://hubs.la/Q02RP-bp0 We are also committed to build better models of diseases including those of a neurodegenerative origin. If you too would like to use iPSCs to fuel your research in the neurodegenerative space, feel free to contact us at [email protected], we'd be happy to help! #iPSCs #StemCells #ParkinsonsDisease

🧬 A new era in gene therapy is unfolding. 🧬 A groundbreaking study has demonstrated the CRISPR-Cas9 gene-editing tool's ability to repair defective T-cells in Familial hemophagocytic lymphohistiocytosis (FHL) is a rare disease of the immune system that usually occurs in infants and young children under the age of 18 months. Gene therapies are not just future concepts but present realities, changing lives today. Our mission at SeQure Dx is to ensure the safety and efficacy of gene editing through our best-in-class diagnostic technologies. As gene therapies gain approval and enter clinical use, we're here to navigate this new frontier with precision and care. Read More ➡️ https://lnkd.in/ghgzbe8U #genetherapy #crispr #innovation

A single homozygous missense deleterious variant (G52D) of the NUDCD3 [Nuclear Distribution C (NudC) Domain Containing 3] gene disrupts RAG (Recombination Activating)-mediated V(D)J recombination to cause severe combined immunodeficiency (SCID) and the Omen syndrome (OS). https://lnkd.in/d7uJpedu PS: (1) RAG1 (Recombination Activating 1) is involved in activation of immunoglobulin V-D-J recombination.  This protein is involved in recognition of the DNA substrate, but stable binding and cleavage activity also requires RAG2. (2) RAG2 (Recombination Activating 2) is involved in the initiation of V(D)J recombination during B and T cell development. This protein forms a complex with the product of the adjacent recombination activating gene 1, and this complex can form double-strand breaks by cleaving DNA at conserved recombination signal sequences. The recombination activating gene 1 component is thought to contain most of the catalytic activity, while the N-terminal of the recombination activating gene 2 component is thought to form a six-bladed propeller in the active core that serves as a binding scaffold for the tight association of the complex with DNA. (3) Diseases associated with RAG2 include Omen Syndrome and Combined Cellular And Humoral Immune Defects With Granulomas.  (4) Omenn syndrome (OS) is an autosomal recessive disorder characterized by severe combined immunodeficiency (SCID) associated with erythrodermia, hepatosplenomegaly, lymphadenopathy, and alopecia. B cells are mostly absent, T-cell counts are normal to elevated, and T cells are frequently activated and express a restricted T-cell receptor (TCR) repertoire. (5) Severe combined immunodeficiency (SCID) is a rare genetic disorder characterized by a lack of functional T lymphocytes, leading to severe respiratory infections and failure to thrive. It affects both T cells and B cells, resulting in increased susceptibility to infections such as ear infections, pneumonia, oral thrush, and diarrhea. SCID can be caused by genetic mutations in various genes and is inherited in an X-linked recessive or autosomal recessive manner. The most common type is X-linked SCID, while another form is caused by a deficiency of the enzyme adenosine deaminase. SCID is the most severe form of primary immunodeficiencies, with mutations in multiple genes leading to differing clinical presentations.

Gene-editing therapy that could cure blood disorder #thalassaemia for NHS patients NHS patients living with a genetic blood disorder are set to be among the first in the world to benefit from a “life-changing” gene-editing treatment which offers hope of a cure. The one-off gene therapy, Casgevy, has been approved by for use on the NHS in England, from today (8 August), by the National Institute for Health and Care Excellence (NICE) for older children and adults with a severe form of thalassaemia. The NHS in England is among the first healthcare systems in the world to offer the treatment, with an estimated 460 patients in England currently living with transfusion-dependent beta thalassaemia, aged 12 and older, potentially eligible for the therapy which uses gene-editing CRISPR technology. It will be offered at seven highly specialist NHS centres across the country within weeks, with the therapy being manufactured in the UK. Thalassaemia is the name for a group of inherited conditions that affect a substance in the blood called haemoglobin. Most patients who could be eligible for this treatment currently need transfusions every 3-5 weeks to survive, which have a major impact on their quality of life. In international clinical trials, 93% of patients with beta thalassaemia did not need a blood transfusion for at least a year after having the treatment, and it is hoped that the therapy could be a lifetime cure. The therapy, Casgevy (exagamglogene autotemcel), works by editing a gene in a patient’s bone marrow stem cells so that the body produces functioning haemoglobin – it is the first approved therapy to use the Nobel Prize-winning CRISPR technology. https://lnkd.in/edfFZB-q