Sandhoff Disease

Azafaros announces completion of 12-week Phase 2 RAINBOW study evaluating lead asset nizubaglustat in rare disease patients Major milestone reached in bringing new treatment options to patients and their families. Leiden, The Netherlands, March 12, 2024 – Azafaros B.V. today announced the completion of its 12-week Phase 2 clinical study, RAINBOW (Phase 2 RAINBOW studyNCT05758922). The randomized, double-blind, placebo-controlled study, conducted in Brazil, involved 13 patients from the age of 12 years who are affected by GM2 gangliosidosis or Niemann-Pick disease type C (NPC). The aim of the RAINBOW study is to determine the safety, pharmacodynamics, and pharmacokinetics of two different doses of nizubaglustat in patients, in order to identify the target dosage for Azafaros’ planned Phase 3 pivotal studies. The main part of the study is now complete, and patients are entering the extension phase, in which all of them will be given the study drug. Top line results of the RAINBOW study are expected to be announced in Q2 2024 and presented to the scientific community later this year. Prof. Dr. Roberto Giugliani, Chief of the Medical Genetics Clinical Research Group at the Hospital de Clinicas de Porto Alegre and Lead Principal Investigator for the study, said: “This is an important milestone because nizubaglustat has a dual mode of action that represents a leap forward from other agents. This dual activity targets some of the fundamental biology of the diseases with high potency and it might offer promise in pivotal studies.” Chris Freitag, Chief Medical Officer at Azafaros, said: “This is a major milestone on our journey to provide patients and their families with a potentially transformative treatment. With the RAINBOW data, we will be able to identify the optimal dose for a pediatric population in our Phase 3 efficacy study, which we plan to initiate as soon as the dose is determined, and the required approvals are in place. We are looking forward to presenting the data from RAINBOW to the scientific community. Azafaros is grateful to the patients and their families who made the decision to participate in this study.” About nizubaglustat Nizubaglustat is a small molecule, orally available and brain penetrant azasugar with a unique dual mode of action, developed as a potential treatment for rare lysosomal storage disorders with neurological involvement, including GM1 and GM2 gangliosidoses and Niemann-Pick disease type C (NPC). Nizubaglustat has received the following designations and support: United States Food and Drug Administration (FDA) Rare Pediatric Disease Designations (RPDD) for the treatment of GM1 and GM2 gangliosidoses and NPC. Orphan Drug Designations (ODD) for GM2 gangliosidosis (Sandhoff and Tay-Sachs Diseases) and NPC. Fast Track Designation and IND clearance for GM1 and GM2 gangliosidoses. European Medicines Agency (EMA) Orphan Medicinal Product Designation (OMPD) for the treatment of GM2 gangliosidosis. UK Medicines and Healthcare Products Regulatory Agency (MHRA) Innovation Passport for the treatment of GM1 and GM2 gangliosidoses. About GM1 and GM2 Gangliosidoses GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs and Sandhoff diseases) are lysosomal storage disorders caused by the accumulation of GM1 or GM2 gangliosides respectively, in the central nervous system (CNS), resulting in progressive and severe neurological impairment and early death. These diseases mostly affect infants and children, and no disease-modifying treatments are currently available. About Niemann-Pick Disease Type C (NPC) Niemann-Pick disease type C (NPC) is a progressive, life-limiting neurological lysosomal storage disorder caused by mutations in the NPC1 or NPC2 gene and aberrant endosomal-lysosomal trafficking, leading to the accumulation of various lipids, including gangliosides in the CNS. The onset of disease can happen throughout the lifespan of an affected individual, from prenatal life through adulthood. About Azafaros Azafaros is a clinical-stage company founded in 2018 with a deep understanding of rare genetic disease mechanisms, a compound library from Leiden University, and led by a team of highly experienced industry experts. Azafaros aims to build a pipeline of disease-modifying therapeutics to offer new treatment options to patients and their families. By applying its knowledge, network and courage, the Azafaros team challenges traditional development pathways to rapidly bring new drugs to the rare disease patients who need them. Azafaros is supported by a syndicate of leading Dutch and Swiss investors including Forbion, BioGeneration Ventures, BioMedPartners, Asahi Kasei Pharma Ventures, and Schroders Capital. Media ICR Consilium Amber Fennell, Ashley Tapp +44 (0)20 3709 5700 Azafaros@consilium-comms.com

BOSTON, Feb. 1, 2024 /PRNewswire/ -- National Tay-Sachs & Allied Diseases Association (NTSAD), leader in the worldwide fight to treat and cure Tay-Sachs, Canavan, GM1, and Sandhoff diseases, is hosting the first-ever, Externally-Led Patient-Focused Drug Development (EL-PFDD) Meeting for GM2 gangliosidoses (Tay-Sachs and Sandhoff diseases) on February 15, 2024, 9:30am-3pm Eastern. EL-PFDD meetings give the U.S. Food and Drug Administration (FDA) and other key stakeholders, including medical product developers, health care providers, regulatory agencies, an important opportunity to hear from patients and their families about the symptoms that matter most to them, the impact the disease has on patients' daily lives and their experiences with currently available treatments. This input can inform FDA's decisions and oversight during drug development and their review of marketing applications. Nearly 30 people will share their stories and experiences with infantile, juvenile, or late onset GM2, including adult patients, parents, caregivers, and bereaved family members. Other presenters include Jacqueline Karp, MD, U.S. FDA Center for Drug Evaluation and Research; Florian Eichler, MD, Massachusetts General Hospital; Cynthia Tifft, MD, PhD, National Institutes of Health; and Kathleen Flynn, NTSAD CEO. "NTSAD was founded by families. They are the experts on living with these devastating rare, genetic diseases, and their voices should be heard," said NTSAD CEO Kathleen Flynn. This virtual meeting will be livestreamed via YouTube, open to the public, free to attend, but advance registration is required. There will be opportunities to call in, submit comments, or participate in live polling. To learn more about the GM2 EL-PFDD meeting, register to attend, or submit comments, visit . Meeting sponsors include Sanofi, Cure Tay-Sachs Foundation, New York Area Fund, Mathew Forbes Romer Foundation, Azafaros, and JCR Pharmaceuticals. About NTSAD One of the oldest patient advocacy organizations, NTSAD supports families and individuals globally through one-on-one support, mentoring and peer groups, information and resources, and its Annual Family Conference. NTSAD also advocates for patients and advances research. Since 2002, the organization has awarded more than $4.7 million in grants that attracted more than $30 million in research investments, leading to the development of potential therapies for Tay-Sachs, Canavan, GM1, and Sandhoff diseases. For more information, visit NTSAD.org. SOURCE National Tay Sachs and Allied Diseases Association Inc

引言溶酶体贮积症(LSDs)是一种以遗传和代谢性溶酶体功能障碍为特征的60多种退行性疾病，具有相当大的健康和经济负担。然而，由于溶酶体缺陷导致功能细胞进行性死亡的机制仍然不完全清楚，并且缺乏针对LSDs的广谱治疗方法。2024年1月22日，浙江大学徐平龙、沈承勇及李欣然共同通讯在Nature Cell Biology 在线发表题为“Innate immune sensing of lysosomal dysfunction drives multiple lysosomal storage disorders”的研究论文，该研究发现导致LSDs的各种基因异常，包括Hexb、Gla、Npc1、Ctsd和Gba，都有共同的特性，可以强大地自激活神经元内在的cGAS-STING信号，驱动神经元死亡和疾病进展。这种信号是由神经元中dsDNA和DNA传感器cGAS的过度细胞质聚集引发的。基因消融cGAS或STING，用DNA酶消化神经元胞质dsDNA，修复神经元溶酶体功能障碍，可减轻Sandhoff病、Fabry病和niemmann-pick病的症状，显著减少神经元损失。因此，该研究确定了介导多种LSDs发病机制的普遍机制，揭示了溶酶体缺陷与先天免疫之间的内在联系，并提出了治疗LSDs的统一策略。LSDs是一组以溶酶体功能障碍为特征的60多种遗传和代谢性疾病。大多数LSDs是常染色体隐性突变和单基因突变，主要使溶酶体水解酶和转运蛋白失活，导致溶酶体和细胞质中各种物质积聚。LSDs在临床上是异质性的，四分之三的LSDs涉及中枢神经系统的神经元储存问题和随后的细胞死亡，导致大量的神经功能缺陷，如认知能力下降、共济失调、癫痫和智力残疾，以及肌肉、脾脏和骨骼的缺陷，以及生长迟缓。例如，逐渐破坏脑和脊髓神经元的Sandhoff病，是由Hexb基因突变和β-己糖氨酸酶A和B失活引起的，导致神经元中GM2神经节苷脂沉积，最终导致神经退行性变。Sandhoff病的早期发病会导致运动技能丧失，并导致癫痫发作、视力和听力丧失以及智力残疾；患有Sandhoff病的人通常活不过幼儿期。遗憾的是，到目前为止，还没有治愈Sandhoff病病的方法。目前，用于治疗LSDs的现有疗法，包括酶替代疗法(ERT)、底物还原疗法(SRT)和药理学伴侣，仅覆盖有限比例的疾病，成本非常高，反应性有限。基因组编辑为LSD治疗方案开辟了新的视野；然而，这种方法仍处于起步阶段，仅得到动物模型实验的支持。因此，迫切需要研究一种有效和普遍的治疗方法。神经元天生易受溶酶体储存的影响，因为这些终末分化的细胞不能通过细胞分裂稀释底物和受损的细胞器。主流观点认为，溶酶体损伤可引发细胞凋亡、坏死、焦亡、铁死亡等细胞死亡模式。溶酶体储存引起的应激还会诱导溶酶体膜通透性，并将溶酶体成分(如组织蛋白酶)释放到细胞质中，从而导致溶酶体细胞死亡，这可能导致一种称为Sjögren综合征的自身免疫性疾病的发生。脑外伤后神经元溶酶体膜通透性可导致自噬受损和神经元细胞死亡。内质网应激被认为是溶酶体贮积病中常见的细胞凋亡调节因子。然而，从溶酶体功能障碍到神经元死亡的确切体内途径尚不清楚。神经炎症是LSDs的常见病理特征，主要涉及行为表型前的小胶质细胞激活和星形胶质细胞增生。然而，各种LSDs中溶酶体功能障碍、免疫反应和神经元死亡之间的分子和细胞联系机制尚不清楚。模式图（Source: Nature Cell Biology ）该研究发现由于溶酶体附近胞质dsDNA和cGAS蛋白的异常积累，cGAS-STING信号在过多的LSDs中是组成性的和过度活跃的。LSDs中神经元内在cGAS-STING信号的异常激活导致神经元死亡、神经炎症和运动功能障碍。cGAS和STING都是体内疾病发生的必要条件。通过神经元DNA酶重组消化多余的细胞质dsDNA，大大减轻了这些疾病的表型。因此，该研究确定了cGAS-STING机制是溶酶体储存的关键传感器，并提出了各种LSDs发病机制中通用和可靶向的信号通路。原文链接：https://www-nature-com.libproxy1.nus.edu.sg/articles/s41556-023-01339-x               责编|探索君排版|探索君文章来源|“iNature”End往期精选围观王晓红教授团队：绘制单次冷冻囊胚移植成功的女性植入期外周血microRNA动态表达谱，开拓领域创新研究热文维生素B12在细胞重编程与组织再生中发挥关键作用！热文不孕症治疗新方向！又一导致女性不孕的关键因素被发现热文Let-7家族miRNA或为癌症潜在免疫治疗靶点热文一项最新发现或可用于阿尔茨海默病药物开发点击“阅读原文”，了解更多~