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1至9：1，000，000人。GNEM的特征是骨骼肌萎缩和虚弱，导致发病后10至20年内严重丧失能力和生活质量下降。它是由GNE基因突变引起的，GNE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酸化。目前还没有批准的治疗方法，对唾液酸化增加疗法（如ManNAc和Neu5Ac）的研究工作显示吸收率低，胃肠道不良反应高。研究还面临着作用机制知之甚少和缺乏生物标志物来确定临床发展的挑战。ProDGNE旨在通过欧洲和加拿大专家在临床GNEM、唾液酸、有机合成和OMICS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，当在细胞内加工时，它成为一种活性疗法，增加GNEM患者细胞中的唾液酸，并与临床测试药物相比具有更高的稳定性。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。将在患者来源的细胞中体外测试化合物功效，并在复制病理的GNEM动物模型中体内测试化合物功效。此外，还将评估作用机制、安全性和潜在的脱靶，以及用于监测疗效的翻译后修饰和“OMIC”生物标志物。该联盟将满足监管里程碑，并与临床和患者合作伙伴密切合作，在3年项目结束时准备好进入临床试验的先导化合物，并解决IRDiRC的主要目标，即开发罕见疾病的疗法。

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.