PLA2G6

2024年4月11日是第28个世界帕金森病日，今年的主题是：和谐共生，美好生活。帕金森病又称为震颤麻痹，是常见的神经系统退行性病变。现代流行病学调查显示，我国65岁以上人群患病率为1.7%。在中国人口老龄化背景下，PD的发病率又有着随年龄增长而上升的特点。我国大约有超过300万的帕金森病患者，预计到2030年，中国帕金森病患者将达到490万（全球约870万）。帕金森病是一种常见的发生于老年人的神经系统退行性疾病，但是该病也会影响青少年和青年人群，出现罕见的早发型帕金森病（EOPD），约占所有帕金森病的5-10%。早发型帕金森病根据发病年龄又可进一步分为：青年型帕金森病（YOPD）：发病年龄21-50岁；青少年型帕金森病（JP）：发病年龄＜21岁。病因1、遗传因素早发型帕金森病具有明确的遗传易感性和家族聚集性，多数具有阳性家族史，提示遗传因素在其中起到重要作用。目前已有20多个基因明确定位，包括常染色体显性和隐性遗传两种主要遗传方式。常见的常染色体显性遗传基因：SNCA、LRRK2、UCH-L1、VPS35等。常见的常染色体隐性遗传基因：Parkin、PINK1、DJ-1、ATP13A2、PLA2G6等。易感基因：不直接致病，在正常人群中也可检出，但是其存在增加PD的发生风险，例如GBA、MAPT、SNCA等。多个易感基因携带者发生PD的风险显著增高，提示多个微效基因的叠加效应。此外，易感基因之间还存在交互作用。2、心理因素近年来，随着升学和就业压力逐渐增加，青少年型帕金森病在生活中出现得越来越频繁。医学界普遍认为，帕金森病跨年龄发病的病因与心理压力也有关联。   3、其他EOPD还常常与病毒性脑炎、脑外伤、一氧化碳中毒以及药物滥用有关。其中，吸毒引发EOPD病例虽然不多，但也需要引起足够的重视。早在1976年就已发现，在非法合成毒品MPPP（一种类似于吗啡和哌替啶的毒品）时，可以意外生成一种杂质MPTP，后者被证实为能够破坏黑质多巴胺能神经元的神经毒素，这种神经毒素至今仍广泛用于帕金森动物模型的研究中。另外，也有数据显示苯丙胺和甲基苯丙胺（冰毒）均可增加帕金森病的发病风险。临床表现EOPD的临床表现包括运动症状和非运动症状。1、运动症状EOPD的首发症状以运动迟缓多见，也可以肌张力障碍为首发症状。EOPD以强直少动症状为主要表现，静止性震颤、早期平衡功能障碍相对少见；部分患者可伴有肌张力障碍，多见于足部或下肢的局灶型肌张力障碍，通常表现为模式化的扭曲动作，可以呈现震颤样，且可被随意动作诱发或加重。2、非运动症状包括神经精神症状、睡眠障碍、认知功能障碍、便秘等，以抑郁、 不宁腿综合征、成瘾行为较多见，而认知功能障碍、神经精神症状、幻觉等相对少见，嗅觉功能相对保留较好。诊断根据发病年龄≤50岁，必备运动迟缓及至少具备静止性震颤或肌强直中的一项，参照《中国帕金森病的诊断标准(2016版)》 诊断EOPD：   抗帕金森病药物治疗1、左旋多巴制剂：如多巴丝肼、卡左双多巴控释片、左旋多巴/卡比多巴肠内凝胶等。EOPD患者对左旋多巴制剂的反应良好，左旋多巴制剂可显著改善运动症状，但相对容易出现运动并发症。针对伴有智能减退的EOPD患者，一般首选左旋多巴制剂进行治疗；针对力求显著改善运动症状的EOPD患者，一般选择左旋多巴制剂或左旋多巴制剂联合儿茶酚-O-甲基转移酶（COMT）抑制剂进行治疗。注意：对于25岁以下，特别是青少年期及儿童期患者，由于左旋多巴制剂会影响骨骼发育，因此不推荐使用。2、非麦角类DR激动剂：如吡贝地尔、普拉克索、罗匹尼罗、罗替高汀等，可作为不伴智能减退的EOPD患者的单药治疗药物。适用于病程初期的EOPD患者，但较易出现与非麦角类DR激动剂相关的发作性睡眠及冲动控制障碍。注意：对于青少年期患者应慎用，儿童期患者不推荐使用。3、MAO-B抑制剂：如司来吉兰和雷沙吉兰，亦可作为不伴智能减退的 EOPD 患者的单药治疗药物；也可作为左旋多巴制剂的联合药物，特别是对于症状波动的EOPD患者。注意：对于青少年期患者及儿童期患者不推荐使用。4、COMT抑制剂：如恩他卡朋、恩他卡朋双多巴等。恩他卡朋可与多巴丝肼等左旋多巴制剂联合用药，可提高左旋多巴的生物利用度，延长左旋多巴的临床疗效， 改善EOPD患者的运动症状。注意：对于青少年期患者及儿童期患者不推荐使用。5、抗胆碱能药物：如苯海索，对EOPD患者的静止性震颤有效，无静止性震颤的EOPD患者不予推荐。注意：长期服用可导致认知功能损害。对于青少年期及儿童期患者应慎用。6、金刚烷胺：对运动迟缓、肌强直有一定作用，对改善异动症有一定帮助。注意：对于青少年期患者应慎用，儿童期患者不推荐使用。参考文献：[1]中华医学会神经病学分会帕金森病及运动障碍学组，中国医师协会神经内科医师分会帕金森病及运动障碍学组. 早发型帕金森病的诊断与治疗中国专家共识（2021）[J]. 中华神经医学杂志，2021,20 (2)：109-116.[2]中国帕金森病的诊断标准(2016版)撰文 | Anna.An编辑 | Swagpp● 延寿7-8年，还能抗癌！两次登上顶刊：饮料中这种常见成分，还能增强癌症治疗的疗效！● 每周“洗脑”30分钟，让大脑返老还童？Nature最新：改善老年的认知能力，还能缓解阿尔茨海默症的病理！但要注意...● 热议！“交了护理费凭啥还要再花380元请护工？”患者要求取消护工：太贵且不负责，适当提高护理费，护士为啥就不能照顾病人拉屎撒尿？版权说明：梅斯医学（MedSci）是国内领先的医学科研与学术服务平台，致力于医疗质量的改进，为临床实践提供智慧、精准的决策支持，让医生与患者受益。欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。点击下方「阅读原文」 立刻下载梅斯医学APP！

CDMO will perform HQ plasmid production in support of Phase I/II clinical trials for Infantile Neuroaxonal Dystrophy ALDERLEY PARK, England--(BUSINESS WIRE)-- Charles River Laboratories International, Inc. (NYSE: CRL) and the INADcure Foundation, a nonprofit organization whose mission is to support the development of treatments for Infantile Neuroaxonal Dystrophy (INAD) and other forms of PLA2G6-related neurodegeneration (PLAN), today announced a plasmid DNA manufacturing alliance. The collaboration will leverage Charles River’s market leading contract development and manufacturing organization (CDMO) expertise in High Quality (HQ) plasmid DNA production, to manufacture its leading candidate for Phase I/II clinical trials. In INAD patients, a mutation or genetic alteration in the PLA2G6 gene causes mitochondrial and axonal membrane defects that lead to neuronal damage with axonal swellings and accumulation of pre-synaptic spheroids. Leena and Anil Panwala founded the INADcure Foundation in 2016, following the diagnosis of their two-year-old daughter, Ariya. Upon discovering there was no dedicated organization or centralized effort driving INAD research forward, they launched the Foundation with the mission to accelerate research and drive drug discovery. After seven years of unwavering dedication and with the tremendous support of INAD-afflicted families worldwide, the Foundation is furthering the development of a gene therapy treatment specifically designed for children affected by this rare neurodegenerative disease. What is INAD? INAD, otherwise known as phospholipase associated neurodegeneration (PLAN), is a rare disease with no known treatment or cure. Like other neurodegenerative diseases, INAD is progressive, and symptoms include poor motor function, involuntary eye movements, seizures, hearing loss, and difficulty swallowing and breathing. INAD affects over 150 children worldwide with a life expectancy of 10 or less years. Plasmid DNA Manufacturing Services Charles River’s plasmid DNA production, specifically HQ plasmid, combines key features of Good Manufacturing Practice (GMP) manufacture with rapid turnaround times to accelerate the timeline to clinic. Plasmid DNA is a critical starting material for many cell and gene therapy therapeutics and demand continues to outstrip supply. In response to this, Charles River recently announced the opening of a state-of-the-art HQ plasmid manufacturing center of excellence to address these supply shortages and support the growing needs of the cell and gene therapy field. Charles River, with the acquisitions of Cobra Biologics, Vigene Biosciences, and Cognate BioServices, in 2021, has extended its comprehensive cell and gene therapy portfolio to include CDMO capabilities spanning plasmid DNA, viral vector, and cellular therapy production for clinical through to commercial supply. To learn more about plasmid DNA production, watch Andrew Frazer, PhD, Associate Director, Scientific Solutions, Gene Therapy CDMO Services’ on-demand webinar: Advancements in Manufacturing for Rapid Delivery of pDNA Starting Materials. Approved Quotes “The opportunity to work with INADcure is exactly why we do the work we do. Their work is incredibly important to patients with this ultra-rare disorder. We are excited for the INADcure team to achieve this next stage of treatment development.” - Kerstin Dolph, Corporate Senior Vice President, Biologics Solutions, Charles River “Our collaboration with Charles River brings us closer to accomplishing our goal of delivering breakthrough treatments for INAD. We are excited to begin HQ plasmid DNA manufacturing to further develop our treatment with their experienced team. Their invaluable expertise will undoubtedly contribute to the advancement of our gene therapy program.” - Leena Panwala, Founder & Executive Director at INADcure. About INADcure The INADcure Foundation is a 501(c)(3) nonprofit charity whose mission is to support the development of treatments, including a cure, for Infantile Neuroaxonal Dystrophy (INAD) and other forms of PLA2G6-related neurodegeneration (PLAN). Its work includes advancing our understanding of this devastating disease, educating the public about INAD and other forms of PLA2G6-related neurodegeneration, advocating for better access to treatment, and supporting the families and caregivers of children diagnosed with INAD worldwide. For more information, visit . About Charles River Charles River provides essential products and services to help pharmaceutical and biotechnology companies, government agencies and leading academic institutions around the globe accelerate their research and drug development efforts. Our dedicated employees are focused on providing clients with exactly what they need to improve and expedite the discovery, early-stage development and safe manufacture of new therapies for the patients who need them. To learn more about our unique portfolio and breadth of services, visit . View source version on businesswire.com: Contacts Charles River Investor Contact: Todd Spencer Corporate Vice President, Investor Relations 781.222.6455 todd.spencer@crl.com Charles River Media Contact: Amy Cianciaruso Corporate Vice President, Chief Communications Officer 781.222.6168 amy.cianciaruso@crl.com Source: Charles River Laboratories International, Inc. View this news release online at:

Retrotope, based in Los Altos, California, cited data from its Phase II/III trial of RT001 in patients with infantile neuroaxonal dystrophy (INAD). They also reported on a concurrent natural history study of INAD patients’ disease onset and progression. INAD is an ultra-rare, progressive, fatal, infant genetic neurological disorder. It is on a spectrum of diseases called PLA2G6-associated neurodegeneration. A congenital disability in the PLA2G6 enzyme causes an inability to effectively clear the byproducts of lipid peroxidation (LPO), which are toxic. This results in a “death signal” that leads to rapid neuronal cell death in the brains of developing infants. Alex Fay, Assistant Professor of Neurology, University of California, San Francisco and one of the study’s principal investigators, noted, “INAD is an ultra-rare, relentlessly progressive and fatal disease that currently has no approved treatments. This trial compared a group of children with INAD treated with RT001 with a natural history cohort, and the results indicate that RT001 slows progression and prolongs survival compared to no treatment. The findings are striking and suggest that RT001 has the potential to deliver a meaningful impact on neurological function and survival of children with INAD.” RT001 is an isotopically stabilized, synthetic linoleic acid (LA) that Retrotope discovered and developed using its technology platform, which combats the oxidative stress and cellular degeneration that comes from lipid peroxidation (LPO). Polyunsaturated fatty acids (PUFAs) make up the cell and mitochondrial membranes. The LPO process targets PUFAs. Retrotope’s technology generates stabilized PUFAs, such as RT001, incorporating into all membranes and down-regulating LOP to protect membranes from degeneration. The clinical trial included 19 INAD patients and the concurrent natural history of 36 INAD patients as the control group. There were no significant differences between the baseline characteristics in the two cohorts. Patients in the treatment cohort were dosed with RT001 for a minimum of one year with a 30-day treatment-free follow-up. The patients receiving RT001 demonstrated an improvement of 6.42 rank points on the Modified Ashworth Spasticity Scale compared to the control cohort. Similar treatment benefits were observed for the RT001 cohort compared to controls across all five of the efficacy outcomes scales. Progression free survival (absence of pneumonia or death event) was a pre-specified secondary endpoint. The RT001 group demonstrated a statistically significant 82.5% decrease in morbidity risk compared to the controls. A pre-specified exploratory endpoint of survival showed a statistically significant mortality risk decrease of 88.8%. Confirmed deaths were “dramatically lower” in patients receiving RT001 compared to the control group, 11% versus 31%, respectively. “We are very pleased by these topline results and excited to meet with the FDA to discuss the next steps in our ongoing effort to bring RT001 to the INAD patient community,” said Peter G. Milner, Chief Medical Officer of Retrotope. “With clear evidence of benefit on patient survival, as well as consistent improvements observed in all analyzed efficacy endpoints including those which measured vital function and activities of daily living, we believe these study results support the potential of RT001 to address a critical unmet need in hits orphan disease patient population.” Retrotope has ongoing trials for RT001 in amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP) and Friedreich’s ataxia (FA), three of the four most common orphan neurodegenerative diseases. According to Clinical Trials Arena, the company is targeting a funding round in the first quarter of 2022 to raise $100 million. On August 11, the company indicated that it had completed enrollment for its Phase II study of RT001 for progressive supranuclear palsy (PSP). PSP is a progressive, neurodegenerative disease resulting in impaired balance, problems with eye movement, speech, and swallowing, rigid muscle tone, and ultimately, cognitive impairment. It usually affects people between the ages of 60 and 70. It is often misdiagnosed as Parkinson’s disease and Alzheimer’s disease. On April 21, Retrotope completed enrollment of its Phase II trial of RT001 in ALS (Lou Gehrig’s disease). They exceeded the enrollment target of 40 patients in less than six weeks. They expect data from the trial by the end of the year.