Royal Free London NHS Foundation Trust’s Post

📃Scientific paper: Clinical features of autosomal recessive polycystic kidney disease in the Japanese population and analysis of splicing in PKHD1 gene for determination of phenotypes Abstract: Background Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene. The clinical spectrum is often more variable than previously considered. We aimed to analyze the clinical features of genetically diagnosed ARPKD in the Japanese population. Methods We conducted a genetic analysis of patients with clinically diagnosed or suspected ARPKD in Japan. Moreover, we performed a minigene assay to elucidate the mechanisms that could affect phenotypes. Results PKHD1 pathogenic variants were identified in 32 patients (0–46 years). Approximately one-third of the patients showed prenatal anomalies, and five patients died within one year after birth. Other manifestations were detected as follows: chronic kidney disease stages 1–2 in 15/26 (57.7%), Caroli disease in 9/32 (28.1%), hepatic fibrosis in 7/32 (21.9%), systemic hypertension in 13/27 (48.1%), and congenital hypothyroidism in 3 patients. There have been reported that truncating mutations in both alleles led to severe phenotypes with perinatal demise. However, one patient without a missense mutation survived the neonatal period. In the minigene assay, c.2713C > T (p.Gln905Ter) and c.6808   1G > A expressed a transcript that skipped exon 25 (123 bp) and exon 41 (126 bp), resulting in an in-frame mutation, which might have contributed to the milder phenotype. Missense mutations in cases of neonatal demise did not show splicing abnormalities. Conclusion Clinical manifestations ranged... Discover the rest of the scientific article on es/iode ➡️https://etcse.fr/bv4

Researchers in the University of Tartu are investigating mechanisms and potential treatments for a rare disease! Wolfram syndrome (WS) is a rare hereditary neurodegenerative disease caused by biallelic mutations in the WFS1 gene, encoding the transmembrane glycoprotein Wolframin. Symptoms of the syndrome include juvenile-onset type 1 diabetes as well as vision and hearing loss. The brainstem and hippocampus are among the most affected regions in WS. Scientists from the University of Tartu have previously shown that the renin-angiotensin-aldosterone system (RAAS) is significantly affected in Wfs1-deficient rats. RAAS regulates, for example, the volume of body fluids and blood pressure, and its dysbalance has been associated with cancer, diabetes, and neurodegenerative diseases. There is no cure for Wolfram syndrome, but drug-repurposing efforts have found various potential disease-modifying treatments. Our clients from the University of Tartu investigated whether RAAS is affected in the central nervous system of WS rats and how liraglutide (LIR), developed for the treatment of diabetes, affects RAAS gene expression. They found that several important genes were downregulated in WS rats compared to wild-type. The products of these genes are involved in inflammatory responses as well as cell proliferation, survival and plasticity. Crucially, the impact of Wfs1-deficiency on the components of the renin-angiotensin-aldosterone system seems to depend on stress – chronic stress in WS rats can aggravate RAAS dysbalance and accelerate the course of the disease. Additionally, it was found that LIR did not normalize the expression of RAAS genes in the brains of WS rats. This means that the neuroprotective effect of LIR comes from modifying some other signaling pathway(s). Every step towards understanding the mechanism of the disease is an important step towards effective treatment! We cheer on to all developments in the treatment of rare diseases!   The paper is freely available here: https://lnkd.in/dQDPG7ih Check here for a short overview in Estonian: https://lnkd.in/d8ArgzSi The Thermo Fisher Scientific products used: ·       SuperScript™ III Reverse Transcriptase ·       QuantStudio 12K Flex Real-Time PCR System ·       Taqman Gene Expression Mastermix ·       TaqMan Gene Expression Assays: Ace, Ace2, Agtr1a, Agtr1b, Agtr2, Bdkrb1, Bdkrb2 and Mas1 #WolframSyndrome #rarediseases #ResearchEstonia #GeneExpression #RAAS Thermo Fisher Scientific

Our work is finally published! "PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development" Type 2 Diabetes is a multifactorial disorder. Genetic component plays a huge part in lowering the threshold to T2D risk in individuals. To elucidate the role of East Asian-specific PAX4 gene variant in predisposing individuals to elevated T2D risk, we recruited human participants, created various human iPSC models, employed CRISPR/Cas9 gene editing, utilized human pancreatic beta cell models, and performed many molecular and functional assays. We demonstrate that i) PAX4 has a role in human endocrine cell development, ii) its variants negatively impact beta cell development, and therefore iii) contribute to the formation of pancreatic beta cells with lower insulin content and poorer secretory function. Collectively, our work contributes to a better understanding of how PAX4 coding variants can influence T2D risk.   We have worked relentlessly for the past few years to see through this piece of work. Nicole Krentz, our hard work paid off! Special thanks to Prof Anna Gloyn, Prof E Shyong Tai, Prof Andrew Tan and Adrian Teo for the support and supervision. Sincere thanks to all co-authors whom have helped push the work to completion (Chan Jun Wei, Soumita Ghosh, Shih Ling Kao, Daphne Gardner and more...). A true demonstration of Teamwork at its finest!   Open access: https://lnkd.in/gGA8senS

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

Cystic Fibrosis Research – Chloe’s Fund   Around 10 years ago our family set up Chloe’s Fund at the University of Aberdeen.   It is in memory of our elder daughter who died of cystic fibrosis 18 years ago at the age of 23.   We have sponsored 2 PhD students and a third started Q4 last year.   The work is supervised by two outstanding medical research professors – Heather Watson () and Adilia Warris. ()   Here’s a summary of what’s going on:   Understanding the Effects of Cystic Fibrosis Treatments on the Immune System    Cystic fibrosis (CF) is a rare genetic disease that affects the lungs and other organs. It is caused by mutations in a gene called CFTR. People with CF have thick mucus in their lungs, making them prone to infections and inflammation. Over the years, treatments have improved, especially with the introduction of CFTR modulators in 2012. These medications aim to fix the root problem by targeting the faulty protein caused by the CF gene mutation, leading to better outcomes for patients.  However, while these treatments have shown promise in improving lung function and reducing symptoms, their effects on the immune system are not fully understood. We aim to explore how CFTR modulators influence the immune response, specifically focusing on certain immune cells like neutrophils and macrophages. These cells play a crucial role in fighting off infections in the lungs of CF patients.  By understanding how CFTR modulators influence the immune system, the study aims to shed light on potential side effects and ways to optimize treatments for people with CF. Ultimately, this research could pave the way for new therapeutic strategies that not only correct the underlying genetic defect but also bolster the body's natural defences against infections in people with CF.    Chloe’s Fund can be found here. https://lnkd.in/d5BPNtm  

Sickle cell disease and its variants are the most prevalent hereditary blood disorders, impacting 100 million individuals worldwide. The term sickle cell disease includes a group of common inherited genetic disorders characterized by a point mutation in the gene encoding the beta subunit of hemoglobin (HBB). This genetic change involves a homozygous missense mutation [Glu6Val, rs334] in the beta-globin gene, which, when deoxygenated, leads to the polymerization of hemoglobin S (Hb S). This single DNA base alteration sets off a chain of physiological consequences that can affect various organs and systems. The polymerization of two mutant sickle beta-globin subunits causes red blood cells to adopt a crescent or sickle shape, hence the name sickle cell disease (SCD). SCD is a very serious disease. It can be life-threatening. It can lead to anemia (a shortage of red blood cells), causing fatigue and possibly damage to blood vessels and vital organs. There is no single best treatment for all people with SCD. To date, the only cure for SCD is a bone marrow or stem cell transplant. At the same time bone marrow or stem cell transplants are very risky and can have serious side effects, including death. To support research and advances in the treatment of Sickle cell disease, BTL Biotechno Labs Pvt. Ltd., as a leading supplier of life science research products, is offering a comprehensive range of research products related to Sickle cell disease including haemoglobin beta S, C, A, F, epsilon and delta antibodies, ELISA kits, ready-to-use RNA, and many others. BTL Biotechno Labs Pvt. Ltd. are committed to making these high-quality research products accessible to the Indian scientific community at competitive and affordable prices.   For more details, please contact us @ https://lnkd.in/d2FEZ8k2 #researchanddevelopment #lifescience #biotechnology #pharmaceuticalcompanies #pharmcology #sicklecelldisease #sicklecellanemia #RBC #sickleshapedrbc #hemoglobinbeta #hemoglobinS #hemoglobinC #hemoglobinA #hemoglobinF #hemoglobinepsilon #hemoglobindelta #antibodies #hemoglobinantibodies #elisa #sirna #btlbiotechnolabspvtltd

BREAKING NEWS: FDA advisers see no roadblocks for gene-editing treatment for sickle cell disease Exciting news for both the sickle cell community and the PMWC 2024 program! A panel of FDA experts said today that a groundbreaking treatment for sickle cell disease was safe enough for clinical use, setting the stage for likely federal approval by Dec. 8 of a powerful potential cure for an illness that afflicts more than 100,000 Americans. The treatment involves using CRISPR to edit the genetic code of a patient's bone marrow cells, which can then be transplanted back into the patient's body. This process has been shown to be highly effective in curing sickle cell disease in clinical trials, with patients experiencing significant improvements in their symptoms and quality of life. We are thrilled to see such promising advancements in personalized medicine and look forward to exploring them further at the PMWC 2024 conference. The gene-editing treatment for sickle cell disease using CRISPR aligns perfectly with our track on gene and cell therapies for rare diseases, chaired by Yael Weiss of Mahzi Therapeutics and Peter Marks of the FDA. This track will cover topics such as biomarkers and endpoints for small populations, empowering patient advocacy in rare disease therapies, and novel clinical design approaches. This is a significant step forward in the field of gene editing and personalized medicine, and it offers hope to millions of people who are affected by sickle cell disease. We look forward to seeing the positive impact this new treatment will have on patients and their families and discussing it further at PWMC 2024. https://lnkd.in/dCY3HUgm #SickleCell #CRISPR #GeneEditing #PersonalizedMedicine #FDAapproval #PMWC24 #RareDiseases #GeneTherapies #CellTherapies #Healthcare #MedicalBreakthroughs PMWC - Precision Medicine World Conference

📃Scientific paper: Clinical features of autosomal recessive polycystic kidney disease in the Japanese population and analysis of splicing in PKHD1 gene for determination of phenotypes Abstract: Background Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene. The clinical spectrum is often more variable than previously considered. We aimed to analyze the clinical features of genetically diagnosed ARPKD in the Japanese population. Methods We conducted a genetic analysis of patients with clinically diagnosed or suspected ARPKD in Japan. Moreover, we performed a minigene assay to elucidate the mechanisms that could affect phenotypes. Results PKHD1 pathogenic variants were identified in 32 patients (0–46 years). Approximately one-third of the patients showed prenatal anomalies, and five patients died within one year after birth. Other manifestations were detected as follows: chronic kidney disease stages 1–2 in 15/26 (57.7%), Caroli disease in 9/32 (28.1%), hepatic fibrosis in 7/32 (21.9%), systemic hypertension in 13/27 (48.1%), and congenital hypothyroidism in 3 patients. There have been reported that truncating mutations in both alleles led to severe phenotypes with perinatal demise. However, one patient without a missense mutation survived the neonatal period. In the minigene assay, c.2713C > T (p.Gln905Ter) and c.6808   1G > A expressed a transcript that skipped exon 25 (123 bp) and exon 41 (126 bp), resulting in an in-frame mutation, which might have contributed to the milder phenotype. Missense mutations in cases of neonatal demise did not show splicing abnormalities. Conclusion Clinical manifestations ranged... Discover the rest of the scientific article on es/iode ➡️https://etcse.fr/bv4

#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.