ATP2A1

在一项新的研究中，Hidetoshi Sakurai实验室利用由患者衍生的诱导性多能干细胞（iPS）产生的骨骼肌细胞成功地再现了强直性肌营养不良1型的病理，并展示了它们用于药物疗效的定量评估。 在一项新的研究中，来自日本京都大学iPS细胞研究与应用中心的Hidetoshi Sakurai实验室利用由患者衍生的诱导性多能干细胞（iPS）产生的骨骼肌细胞成功地再现了强直性肌营养不良1型（Myotonic Dystrophy type 1, DM1）的病理，并展示了它们用于药物疗效的定量评估。相关研究结果于2023年1月11日发表在Scientific Reports期刊上，论文标题为“Establishment of quantitative and consistent in vitro skeletal muscle pathological models of myotonic dystrophy type 1 using patient-derived iPSCs”。 DM1被认为是成人中最常见的肌肉萎缩症，但目前还没有治疗方法。为了发现和开发新的治疗性药物，迫切需要设计一种使用人类细胞的评估系统，以便能够忠实地再现DM1患者的病理。 DM1是一种遗传性疾病，由DMPK（dystrophia myotonica-protein kinase）基因中CTG重复序列的异常扩增引起。由发生CTG扩增的DMPK基因产生的异常RNA诱导聚集，从而导致剪接因子MBNL1（muscleblind-like splicing regulator 1）在细胞核中的功能丧失。由此导致的MBNL1介导的基因剪接的破坏被认为是DM1发病的主要机制。 利用他们之前设计的直接和间接分化方案（分别在有或没有诱导MYOD表达的情况下），这些作者能够利用DM1患者衍生的iPS细胞产生骨骼肌细胞（下称DM1骨骼肌细胞），并再现了DM1中的多种细胞病理变化，如MBNL1蛋白聚集物的形成和DMD、BIN1和ATP2A1等基因的剪接缺陷。 在MyoD-DM1-hiPSC分化而来的肌管中，MBNL1在细胞核内聚集。图片来自Scientific Reports, 2023, doi:10.1038/s41598-022-26614-z。 这些作者接下来使用这些分化的细胞来评估候选药物，看它们是否有能力逆转所观察到的细胞病变。他们用CAG25处理分化的DM1骨骼肌细胞，其中CAG25是一种反义寡核苷酸，以前在临床前研究中已被证明对DM1病理有治疗作用。一致的是，分化的DM1骨骼肌细胞中的MBNL1聚集和剪接缺陷都被CAG25处理所拯救，这表明这些分化的骨骼肌细胞可以作为一种平台，根据已知的DM1病理学定量地评估药物疗效。 这种新构建的基于DM1患者衍生的iPS细胞产生的分化骨骼肌细胞的药物评估系统有望为未来发现和开发针对DM1的有效治疗药物做出贡献。（生物谷 Bioon.com） 参考资料： Ryu Kawada et al. Establishment of quantitative and consistent in vitro skeletal muscle pathological models of myotonic dystrophy type 1 using patient-derived iPSCs. Scientific Reports, 2023, doi:10.1038/s41598-022-26614-z.

NEW YORK, NY and CROWN POINT, IN – June 3, 2022 – JDRF and Neurodon, in collaboration with the Indiana University (IU) School of Medicine and the Universite Libre de Bruxelles (ULB), have initiated a two-year research and development partnership aimed at advancing Neurodon’s proprietary small molecule activators of the sarco/endoplasmic reticulum calcium ATPase (SERCA), a key regulator of intracellular calcium that is vital to proper beta cell function and shown to be reduced in type 1 diabetes (T1D). Neurodon will work with Dr. Carmella Evans-Molina of the IU School of Medicine and Dr. Decio L. Eizirik of the ULB, both prominent physician scientists with research programs focused on understanding the role of beta cell dysfunction and death in T1D progression. The project will assess the potential of Neurodon’s small molecules as new therapeutics that improve beta cell health in T1D and selected forms of monogenic diabetes. The $920,000 grant will be funded from JDRF to Neurodon under the Industry Discovery & Development Partnerships (IDDP) program that focuses on commercialization of therapeutics and devices for the treatment, cure, and prevention of T1D. The funded research involves testing Neurodon’s novel SERCA activators in customized T1D models developed by the Evans-Molina and Eizirik labs at the IU School of Medicine and the ULB, respectively. The work focuses on assessing the compounds’ ability to beneficially modulate intrinsic beta cell stress pathways involved in T1D progression. Neurodon’s compounds, by correcting aberrant cellular calcium, have been shown to alleviate a process called endoplasmic reticulum (ER) stress that is activated early during the evolution of T1D and contributes to beta cell loss. Importantly, markers of ER stress are present in human islets of organ donors with T1D, and Drs. Evans-Molina and Eizirik have obtained data suggesting a marked loss of beta cell SERCA activity with subsequent loss of ER calcium in models of diabetes, resulting in ER stress and reduced beta cell function and survival. These findings suggest that interventions focused on the preservation and restoration of ER calcium may improve beta cell health and survival in T1D. “JDRF is the preeminent advocate and supporter for T1D research innovation in the world, and we are excited that they appreciate the importance and potential of cellular calcium regulation in T1D,” said Dr. Russell Dahl, CEO of Neurodon. “In addition to the JDRF’s crucial support for this endeavor, Carmella and Decio are pioneers in elucidating how impaired calcium handling in the beta cell contribute to diabetes pathogenesis, thus we have an immense amount of intellectual firepower in this collaboration to make significant strides towards a game-changing therapeutic for patients.” “There is growing appreciation for the role that beta cell stress pathways play in the development of T1D. We are delighted to work with Neurodon and Dr. Eizirik to test the hypothesis that restoration of SERCA activity and ER calcium may interrupt T1D progression and immune-mediated beta cell destruction. At the present time, very few drug targets in T1D are focused on the beta cell. This project is really uniquely positioned to address a fundamental gap in our understanding of T1D pathogenesis, while expanding our search for potential disease-modifying therapies,” said Dr. Carmella Evans-Molina of the IU School of Medicine. “Accumulating evidence suggest that T1D develops in the context of a misguided dialogue between the immune system and the beta cells. Most attempts to revert disease have up to now focused on the immune system only, which is akin of attempting to fly an airplane with a single wing. We clearly need the two wings here, i.e. re-educating the immune system and protecting the beta cells. The new compounds developed by Neurodon provide a potentially very interesting approach to protect beta cells. We are thus very happy with the support received by the JDRF to develop this collaborative project with Dr Evans-Molina and our Neurodon colleagues and look forward to starting the work!” said Dr. Decio L. Eizirik of the UBL. “JDRF support is bringing together complementary expertise between Neurodon and T1D academic collaborators. The small molecule activators being developed by Neurodon could result in a therapeutic strategy to slow or halt disease progression by protecting beta cells from the stress they encounter because of T1D,” said Dr. Frank Martin, Senior Director of Research at JDRF. About Neurodon Neurodon is developing disease-modifying drugs for diabetes, neurodegeneration, and other life-threatening diseases. Neurodon’s patented molecules target a key pathway called ER stress. ER stress is triggered by various factors arising from disease and is a key feature of type 1 and type 2 diabetes, inflammation, and neurodegenerative disorders like Alzheimer’s and Parkinson’s diseases. Neurodon deploys its proprietary ER stress-based technology platform to discover small molecules that can reduce the cellular dysfunction that is the root cause of many diseases. In addition to demonstrating the ability to regulate glucose and preserve insulin function in animal models and pancreatic beta cells from human donors, neurodon’s drug candidates are orally available and well-tolerated in animals with repeat dosing. For more information, visit . About JDRF JDRF’s mission is to accelerate life-changing breakthroughs to cure, prevent and treat T1D and its complications. To accomplish this, JDRF has invested more than $2.5 billion in research funding since our inception. We are an organization built on a grassroots model of people connecting in their local communities, collaborating regionally for efficiency and broader fundraising impact, and uniting on a national stage to pool resources, passion, and energy. We collaborate with academic institutions, policymakers, and corporate and industry partners to develop and deliver a pipeline of innovative therapies to people living with T1D. Our staff and volunteers throughout the United States and our five international affiliates are dedicated to advocacy, community engagement and our vision of a world without T1D. For more information, please visit jdrf.org or follow us on Twitter (@JDRF), Facebook (@myjdrf), and Instagram (@jdrfhq).