ACTA2 Alliance’s Post

Spastic paraplegia type 50 (SPG50) is caused by mutations within the AP4M1 gene, which encodes a subunit of the adaptor protein complex 4 (AP4). This complex takes part in the intracellular trafficking of glutamate receptors. SPG50 is an ultra-rare, progressive neurodegenerative disorder that is characterized by developmental delays, speech impairments, seizures, and the progressive paralysis of all four limbs. Depending on the whether both copies of the gene are mutated—the disease could be fatal by the time the individual reaches adulthood. Currently it’s thought that 80 children globally are affected by SPG50. In 2019, there was a single child diagnosed with the disease in Canada, and in 2022—that child was enrolled as the single patient in a clinical study to see if AAV (adeno-associated vector) gene therapy could be beneficial. The coding sequence for this particular gene (AP4M1) is fairly small—only 1,359 base pairs, which is within the size range of DNA that can be inserted into an AAV vector. What researchers & clinicians did—they took a healthy copy of AP4M1 encoded into an AAV vector & via of an injection into the spinal cord, delivered the healthy copy to the child’s cerebrospinal fluid. As with all clinical studies, the primary endpoints were to check the safety & tolerability of the treatment, with secondary endpoints being the efficacy of treatment. A year after initial treatments, the child didn’t seem to be showing any types of serious side effects & the rare condition didn’t seem to be progressing. In addition, there were potential signs of improvement—such as the child being able to stand with their heels on the ground. It will be interesting to see how many of the other children could benefit from the treatment, & whether the treatment would be able to ‘extend’ their lives to where they could possibly live somewhat normal lives. #raredisorders #genetherapy #clinicaltrials 

Only a parent trying to save their child from a deadly or life-limiting, ultra-rare disease can truly understand the urgency, desperation and responsibility involved in this all too often insurmountable mission. It demands that you put your life on hold, raise millions of dollars, push through so many unforeseen hurdles, and work night and day to create the treatment pathway and coordinate the efforts of researchers, academia, industry, and many others. If you're able to achieve it in time for your child you are among the very few. And it takes something else far more extraordinary to not stop at your own child. And then, to not stop at your child's disease, but to cast your net to help other families achieve the impossible for their children for other ultra rare diseases is something I have no words for. Terry Pirovolakis, thank you for being that Dad. Thank you for "going the extra marathon" day in and day out to also ensure that the science and the pathways behind all of it are shared, so that other families can get there faster. So that we better understand AAV--its capabilities and limitations. So that we might create streamlined "best practices" around gene therapies. So that the regulatory obstacles are fewer. So that the astronomical costs in all of this might some day come down. So that the world can see the human rights and health care crisis of Ultra-Rare Diseases for what they truly are. This paper, published in the esteemed journal Nature Medicine, serves to do all of that. Thank you to the many investigators and others too numerous to mention, who have also worked on our AAV9 CMT4J gene therapy pathway--and SO many other ultra-rare diseases, including: Steven Gray, James Dowling, Carsten Bonnemann, Souad Messahel, PhD, and Cat Lutz. Our journey to reach this same holy grail--like so many of my Rare Disease colleagues--has been long and winding, fraught with obstacles at every turn. My persistence is often waning these days. It is hard to keep fighting. It is difficult to see the light at the end of the tunnel--especially a light that might illuminate some hope for my daughter, after so many years of striving, after so many losses that she has endured from the deadly march of her own progressive, ultra-rare disease. Thank you, Terry, for reminding us what it's all about, for helping me to persist, and for being that kind of incredible human being. Elpida Therapeutics #curecmt4j #ruduffenough @Maximiliano Presa, Robert Burgess, Guy Lenk, Samantha Baxter, Keith Gottlieb, Rachel Thomas https://lnkd.in/ebV3cjuj

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

Until now, the only possible cure for sickle cell disease (SCD) was a bone marrow transplant, which has its own set of challenges. Now, people with SCD – approximately 100,000 Americans – have additional, potentially curative options. The Food and Drug Administration (FDA) recently approved two gene therapies for people 12 and older. One treatment edits a particular gene to reactivate the production of fetal hemoglobin, and the other uses a viral envelope to deliver a healthy hemoglobin-producing gene. “Sickle cell disease impacts every organ. Children are having strokes, and young adults – people in their 30s – are experiencing kidney failure – all because of sickle cell disease. If we can intervene and prevent these complications and let these patients live full lives, that is huge,” says Cece Calhoun, MD, a Yale Medicine hematologist-oncologist. Read here to learn more about these new treatment options for sickle cell disease: https://brnw.ch/21wFuc3 #sicklecelldisease #sicklecell #SCD #crispr #geneediting #hemoglobin Smilow Cancer Hospital

Brian O Mahony was 18 months old when doctors diagnosed him with hemophilia B, a rare blood disorder that affects 1 in 20,000 newborn males. Two older brothers had already died in infancy from the disease, for which there was no treatment at the time. Growing up in the southwestern Irish town of Killarney, O’Mahony, now 64, suffered painful bleeds throughout his childhood and adolescence. And even after injections of factor concentrate from blood plasma became available—providing factor IX, which is missing in those with hemophilia B—the AIDS-tainted blood scandal of the 1980s made such treatments extremely risky. But for the past 4 years, O’Mahony has been virtually symptom-free. In 2019, he became one of the few people in Ireland—and in the world, for that matter—to receive a novel #GeneTherapy that replaces the gene that encodes factor IX, enabling the liver to start making the missing protein on its own. “I live in a country with extremely good hemophilia care,” O’Mahony told Rare Disease Advisor during the 2023 conference of the European Society of Gene and Cell Therapy (ESGCT) here. “My treatment was very good. But 90% of people with hemophilia in India, South Africa, and China have pre-existing antibodies, which preclude them from existing gene therapies.” Explore the insights shared in Larry Luxner's recent #RareCare podcast episode and the accompanying feature article, which delves into the role of #GeneTherapy in changing the treatment landscape for individuals with #Hemophilia: https://lnkd.in/ewUFPk5H Thank you to Margareth C Ozelo, MD, PhD, and Thierry Vandendriessche, PhD, for your valuable contributions to this article. World Federation of Hemophilia / Fédération mondiale de l'hémophilie #Hemgenix uniQure The Irish Haemophilia Society #raredisease

Research Advancements in Sickle Cell Disease: A Brighter Future Sickle Cell Disease (SCD) has posed significant challenges, but recent research advancements are offering new hope. Here’s a look at some of the most promising developments: Gene Therapy: A Beacon of Hope Gene therapy is emerging as a potential game-changer for SCD patients. By correcting the defective gene responsible for SCD, it aims to provide a long-term solution. Clinical trials have shown promising results, with patients experiencing significant improvements. Gene therapy could eventually offer a cure, transforming lives and reducing the need for lifelong treatments. CRISPR and Genetic Editing CRISPR-Cas9 technology allows scientists to precisely modify DNA within cells. Researchers are exploring ways to use CRISPR to correct the sickle cell mutation in hematopoietic stem cells. Early trials have shown the potential to produce healthy red blood cells, offering a new frontier in SCD treatment. New Drug Developments New medications like voxelotor and crizanlizumab are targeting SCD symptoms. Voxelotor increases hemoglobin levels and reduces hemolysis, while crizanlizumab helps prevent painful vaso-occlusive crises. These treatments are improving the quality of life for many SCD patients. Improved Pain Management Advancements in pain management techniques, including novel pharmacological approaches and integrative therapies, are helping patients manage their symptoms more effectively. Research into personalized pain management plans is also underway. Increased Awareness and Advocacy Greater awareness and advocacy efforts are driving more research funding and attention to SCD. Organizations and campaigns worldwide are promoting early diagnosis, better treatment options, and comprehensive care strategies. Collaborative Research Efforts Global collaboration among researchers, healthcare providers, and advocacy groups is accelerating the pace of discovery in SCD. By sharing knowledge and resources, these efforts are leading to more effective solutions. With every breakthrough, we move closer to a world where Sickle Cell Disease is no longer a life sentence but a condition that can be effectively managed and ultimately cured. Stay informed, stay supportive, and together, let's drive the change needed to conquer SCD. #SickleCellAwareness #ResearchAdvancements #GeneTherapy #CRISPR #SickleCellDisease #HealthInnovation #MedicalResearch #CellCareInnovations UNICEF World Health Organization WSA Save the Children International @SCDAAorg @Luminate_DS @MinofHealthUG CAMTech Uganda

Have you ever wondered what impact science can have on our everyday lives? 📈 𝐁𝐎𝐎𝐒𝐓𝐈𝐍𝐆 𝐄𝐂𝐎𝐍𝐎𝐌𝐘 𝐂𝐫𝐞𝐚𝐭𝐢𝐧𝐠 𝐭𝐡𝐞 𝐰𝐨𝐫𝐥𝐝’𝐬 𝐥𝐚𝐫𝐠𝐞𝐬𝐭 𝐫𝐞𝐭𝐢𝐧𝐚𝐥 𝐠𝐞𝐧𝐞 𝐭𝐡𝐞𝐫𝐚𝐩𝐲 𝐜𝐨𝐦𝐩𝐚𝐧𝐲 pioneering the first clinical trials of gene therapy for the diseases choroideremia and X-linked retinal pigmentosa (spin-out company Nightstar) 𝐅𝐢𝐫𝐬𝐭 𝐠𝐞𝐧𝐞 𝐭𝐡𝐞𝐫𝐚𝐩𝐢𝐞𝐬 𝐟𝐨𝐫 𝐡𝐚𝐞𝐦𝐨𝐩𝐡𝐢𝐥𝐢𝐚 development of single-dose gene therapy that restores blood-clotting and can be delivered at 1% of the cost of conventional treatment (spin-out company Freeline Therapeutics) 👩⚕️ 𝐇𝐄𝐀𝐋𝐓𝐇 & 𝐖𝐄𝐋𝐋𝐁𝐄𝐈𝐍𝐆 𝐋𝐢𝐟𝐞𝐬𝐚𝐯𝐢𝐧𝐠 𝐭𝐫𝐞𝐚𝐭𝐦𝐞𝐧𝐭𝐬 𝐟𝐨𝐫 𝐧𝐞𝐮𝐫𝐨𝐦𝐮𝐬𝐜𝐮𝐥𝐚𝐫 𝐝𝐢𝐬𝐞𝐚𝐬𝐞𝐬 𝐢𝐧 𝐜𝐡𝐢𝐥𝐝𝐫𝐞𝐧 approval of the first effective treatments for the genetic diseases Duchene Muscular Dystrophy and Spinal Muscular Atrophy (Spinraza) 𝐂𝐞𝐥𝐥 𝐝𝐢𝐬𝐜𝐨𝐯𝐞𝐫𝐲 𝐨𝐟𝐟𝐞𝐫𝐬 𝐩𝐨𝐭𝐞𝐧𝐭𝐢𝐚𝐥 𝐧𝐞𝐰 𝐚𝐬𝐭𝐡𝐦𝐚 𝐭𝐫𝐞𝐚𝐭𝐦𝐞𝐧𝐭 discovery of cells that secrete an inflammatory molecule, interleukin-13, which can trigger a reaction in asthma patients (clinical trial in progress) 🦀 𝐂𝐀𝐍𝐂𝐄𝐑 𝐓𝐑𝐄𝐀𝐓𝐌𝐄𝐍𝐓𝐒 𝐀𝐧𝐭𝐢-𝐜𝐚𝐧𝐜𝐞𝐫 𝐭𝐫𝐞𝐚𝐭𝐦𝐞𝐧𝐭𝐬 𝐚𝐜𝐫𝐨𝐬𝐬 𝐭𝐡𝐞 𝐰𝐨𝐫𝐥𝐝 development of anti-cancer monoclonal antibodies (e.g.  Ofatumumab and Obinutuzumab for the treatment of leukaemias such as Chronic Lymphocytic Leukemia and Follicular Lymphoma) 𝐓𝐫𝐢𝐚𝐥 𝐢𝐦𝐩𝐫𝐨𝐯𝐞𝐬 𝐩𝐫𝐨𝐬𝐭𝐚𝐭𝐞 𝐜𝐚𝐧𝐜𝐞𝐫 𝐩𝐚𝐭𝐢𝐞𝐧𝐭 𝐡𝐞𝐚𝐥𝐭𝐡 𝐚𝐧𝐝 𝐜𝐚𝐫𝐞 changing the way that men with early-stage prostate cancer are diagnosed and treated 🧓 𝐇𝐄𝐀𝐋𝐓𝐇𝐘 𝐀𝐆𝐈𝐍𝐆 𝐏𝐫𝐞𝐯𝐞𝐧𝐭𝐢𝐧𝐠 𝐟𝐚𝐥𝐥𝐬 𝐢𝐧 𝐨𝐥𝐝𝐞𝐫 𝐩𝐞𝐨𝐩𝐥𝐞 providing the evidence that home adaptation services (e.g. stairlifts, grab-rails, ramps) can help prevent falls 𝐈𝐝𝐞𝐧𝐭𝐢𝐟𝐲𝐢𝐧𝐠 𝐠𝐞𝐧𝐞𝐭𝐢𝐜 𝐫𝐢𝐬𝐤 𝐨𝐟 𝐀𝐥𝐳𝐡𝐞𝐢𝐦𝐞𝐫’𝐬 𝐝𝐢𝐬𝐞𝐚𝐬𝐞 identifying 75 genes associated with an increased risk of developing Alzheimer’s disease 👩💼 𝐈𝐍𝐅𝐎𝐑𝐌𝐈𝐍𝐆 𝐇𝐄𝐀𝐋𝐓𝐇 𝐏𝐎𝐋𝐈𝐂𝐘 𝐔𝐧𝐝𝐞𝐫𝐬𝐭𝐚𝐧𝐝𝐢𝐧𝐠 𝐭𝐡𝐞 𝐭𝐫𝐚𝐧𝐬𝐦𝐢𝐬𝐬𝐢𝐨𝐧 𝐚𝐧𝐝 𝐜𝐨𝐧𝐭𝐫𝐨𝐥 𝐨𝐟 𝐂𝐎𝐕𝐈𝐃-19 providing key data supporting recommendations and policies during the COVID-19 pandemic (school closure policy, social gatherings) 𝐆𝐞𝐧𝐨𝐦𝐞 𝐬𝐞𝐪𝐮𝐞𝐧𝐜𝐢𝐧𝐠 𝐭𝐨 𝐢𝐧𝐟𝐨𝐫𝐦 𝐨𝐮𝐭𝐛𝐫𝐞𝐚𝐤 𝐫𝐞𝐬𝐩𝐨𝐧𝐬𝐞 development of rapid whole genomic sequencing methods (spin-out company Oxford Nanopore Technologies) 🌏 𝐆𝐋𝐎𝐁𝐀𝐋 𝐇𝐄𝐀𝐋𝐓𝐇 𝐏𝐫𝐨𝐭𝐞𝐜𝐭𝐢𝐧𝐠 𝐡𝐮𝐦𝐚𝐧 𝐡𝐞𝐚𝐥𝐭𝐡 𝐟𝐫𝐨𝐦 𝐢𝐧𝐟𝐞𝐜𝐭𝐢𝐨𝐮𝐬 𝐝𝐢𝐬𝐞𝐚𝐬𝐞 𝐢𝐧 𝐥𝐨𝐰-𝐫𝐞𝐬𝐨𝐮𝐫𝐜𝐞 𝐬𝐞𝐭𝐭𝐢𝐧𝐠𝐬 reducing human health risk from cholera, ebola, typhoid, and childhood diarrhoea 𝐈𝐦𝐩𝐫𝐨𝐯𝐢𝐧𝐠 𝐭𝐫𝐞𝐚𝐭𝐦𝐞𝐧𝐭 𝐨𝐟 𝐦𝐞𝐧𝐢𝐧𝐠𝐢𝐭𝐢𝐬 𝐢𝐧 𝐝𝐞𝐯𝐞𝐥𝐨𝐩𝐢𝐧𝐠 𝐜𝐨𝐮𝐧𝐭𝐫𝐢𝐞𝐬 demonstrating the efficacy of low-cost antifungal drug flucytosine Original article: https://lnkd.in/eeRYYijA Author:Buddhini Samarasinghe 304/365

In a ground-breaking development for patients with transfusion-dependent beta thalassemia in England, the National Institute for Health and Care Excellence (NICE) has approved the use of Casgevy on the NHS in England. This marks the first time a gene therapy using the Nobel Prize-winning CRISPR technology will be available through the NHS. Casgevy offers the potential to significantly improve the quality of life for patients by eliminating the need for regular blood transfusions, which are typically required every 3-5 weeks. Unlike traditional treatments, Casgevy is a one-time therapy that results in the production of fetal haemoglobin which effectively compensates for the deficiency in beta-globin seen in these patients. In clinical trials, remarkably over 90% of patients did not require a transfusion for at least a year after treatment. In addition to its approval for beta thalassemia in November 2023, the Medicines and Healthcare products Regulatory Agency (MHRA) also approved Casgevy for the treatment of sickle cell disease. We now wait to see whether NICE ultimately approves the use of Casgevy on the NHS for treatment of patients with sickle cell disease. #MewburnLifeSciences #genetherapy #casgevy #genetherapies #mewburnadvancedtherapeutics

With more than 7,000 rare diseases impacting millions of people, we’re steadfast in our pursuit of curative #GeneTherapies for these individuals with limited options. In order for patients to benefit from advancements in research, the healthcare community must devote concerted efforts to increase early, accurate diagnosis of potentially reversible or curative conditions through expanded #GeneticTesting and newborn screening.    In my recent article in PMLiVE, I discuss how early diagnosis and advances in #GeneTherapy could transform the lives of patients with rare cardiovascular disease, including #DanonDisease, a fatal heart condition that leads to mortality in the majority of male patients at age ~20 and females at age ~40, and for which there are no approved curative or disease-modifying therapies.    At Rocket Pharmaceuticals we’re deeply committed to researching gene therapies for rare, devastating diseases like Danon Disease. Expanded genetic testing and screening will help ensure patients receive an early and accurate diagnosis.

Last week’s news that the FDA approved the first-ever sickle cell treatment using CRISPR gene editing technology is inspiring—and a testament to the potential of groundbreaking science and innovation to improve lives. Still, these therapies will remain out of reach for most of the people in the world who suffer from the debilitating condition.      I’ve long believed that gene therapy could be among the most powerful tools to treat diseases like malaria, HIV, and sickle cell disease. Given the potential of this science, it’s critical for researchers to continue to focus on the greatest unmet needs, including treatments and cures in resource-limited parts of the world where they are needed most. The Bill & Melinda Gates Foundation will continue to support our partners working to develop affordable approaches, including single-dose gene therapies for HIV and sickle cell disease. https://lnkd.in/gcJmcbTJ