Novel therapeutic approaches to target GNE Myopathy

GNE肌病（GNEM）是一种罕见的成人发病的严重衰弱性肌肉疾病，在所有种族中影响100至900万人。GNEM的特点是骨骼肌萎缩和无力，在发病后10至20年内导致严重的行为能力丧失和生活质量下降。它是由GNE基因突变引起的，该基因编码唾液酸生物合成所需的双功能酶，并导致肌肉组织中的低唾液化。目前还没有批准的治疗方法，而且对唾液分泌增加疗法（如ManNAc和Neu5Ac）的研究表明，这些疗法的吸收低，对胃肠道的不良反应高。研究进一步受到未知的作用机制和缺乏确定临床发展的生物标志物的挑战。progne旨在通过欧洲和加拿大专家在临床GNEM、唾液酸、有机合成和组学方面的独特联合合作来克服这些障碍。我们开发了一种前药，当在细胞内处理时，成为一种有效的治疗方法，增加GNEM患者细胞中的唾液酸，与临床测试的药物相比，显示出更高的稳定性。ProDGNE联盟旨在进行原理验证研究，促进GNEM创新治疗化合物的开发。复方疗效将在患者来源的体外细胞和体内复制病理的GNEM动物模型中进行测试。此外，还将评估作用机制、安全性和潜在的脱靶性，以及用于监测疗效的翻译后修饰和“OMIC”生物标志物。该联盟将达到监管里程碑，并与临床和患者合作伙伴密切合作，在3年项目结束时准备一个先导化合物进入临床试验，并解决IRDiRC的主要目标，即开发罕见病治疗方法。

GNE myopathy (GNEM) is a rare adult-onset severely debilitating muscle disease which affects 1 to 9:1,000,000 people among all ethnicities. GNEM is characterised by atrophy and weakness of skeletal muscles, resulting in severe incapacity and loss of quality of life within 10 to 20 years following onset. It is caused by mutations in the GNE gene, which encodes a bifunctional enzyme required for sialic acid biosynthesis, and results in hypo-sialylation in muscle tissue. There are no approved therapies and research efforts on sialylation-increasing therapies such as ManNAc and Neu5Ac have shown low absorption and high gastro-intestinal adverse effects. Research is further challenged by poorly-known mechanisms of action and an absence of biomarkers to determine clinical development. ProDGNE aims to overcome these obstacles through a unique joint collaboration among European and Canadian experts in clinical GNEM, sialic acid, organic synthesis, and -OMICS. We developed a prodrug that, when processed within cells, becomes an active therapy, increasing sialic acid in GNEM patient cells and demonstrating a higher stability when compared to clinically tested drugs. The ProDGNE consortium aims to perform proof of principle studies fostering the development of innovative therapeutic compounds for GNEM. Compound efficacy will be tested in vitro in patient derived cells and in vivo in GNEM animal models that replicate the pathology. Moreover, the mechanism of action, safety, and potential off-target will be assessed as well as post-translational modifications and ‘OMIC’ biomarkers to be utilized to monitor efficacy. The consortium will meet regulatory milestones and work closely with clinical and patient partners to have a lead compound ready to enter clinical trials at the end of the 3-year project and to address the major IRDiRC objective to develop therapies for Rare Diseases.