Novel therapeutic approaches to target GNE Myopathy

GNOE肌病(GNEM)是一种罕见的成人发病的严重衰弱的肌肉疾病，在所有种族中影响1-9：100万人。GNEM的特点是骨骼肌萎缩和虚弱，在发病后10至20年内导致严重丧失能力和生活质量下降。它是由编码唾液酸生物合成所需的双功能酶的gne基因突变引起的，并导致肌肉组织中唾液酸的低唾液酸化。目前还没有得到批准的治疗方法，研究工作表明，增加唾液酸化的治疗方法，如ManNAc和Neu5Ac，显示出低吸收和高胃肠不良反应。研究受到鲜为人知的作用机制和缺乏决定临床发展的生物标记物的进一步挑战。ProDGNE旨在通过欧洲和加拿大临床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，它会成为一种积极的治疗方法，增加GNEM患者细胞中的唾液酸，并显示出与临床测试的药物相比更高的稳定性。ProDGNE联盟的目标是进行原则证明研究，促进GNEM创新治疗化合物的开发。复合疗效将在体外患者来源的细胞和体内复制这种病理的GNEM动物模型中进行测试。此外，将评估作用机制、安全性和潜在的脱靶情况，以及用于监测疗效的翻译后修饰和基因组生物标记物。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，使一种先导化合物准备好在为期3年的项目结束时进入临床试验，并满足IRDiRC开发罕见疾病疗法的主要目标。

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.