Development of a novel HIBM2 mouse model and therapy

描述(申请人提供)：遗传性包涵体肌病II型(HIBM2)，又称野中氏远端肌病、股四头肌节约性肌病和伴有边框空泡的远端肌病，是一种常染色体遗传性疾病，导致进行性肌肉无力，与骨骼肌纤维内包涵体的形成有关。HIBM2的致病基因为gne，编码UDP-N-乙酰氨基葡萄糖异构体酶/N-乙酰甘露糖异构体-6激酶。Gne是唾液酸生物合成所必需的基因，唾液酸是一种存在于所有人体组织中的重要糖类。尽管HIBM2的遗传基础已经确定，但目前还没有有效的治疗方法。这项提议将实现两个具体目标。首先，它将为HIBM2创建一个新的小鼠模型，其中小鼠唾液酸谱反映了通常在人类中发现的唾液酸谱。人类缺乏合成某些形式的唾液酸的能力，而这种唾液酸存在于所有低等哺乳动物中。HIBM2是一种与唾液酸生物合成缺陷有关的疾病，而CMP-唾液酸也负向调节GNE的活性。因此，创建一种模仿人类多糖的小鼠模型对于了解人类唾液酸在疾病中的作用至关重要。这一新模型还将提供一个工具，可以更容易地评估潜在的葡聚糖疗法。其次，这笔赠款将直接检验关于HIBM2发病机制的新假说，并开发一种新的基因疗法，如果成功，可以应用于患者。

DESCRIPTION (provided by applicant): Hereditary Inclusion Body Myopathy Type II (HIBM2), also called Nonaka distal myopathy, quadriceps sparing myopathy and distal myopathy with rimmed vacuoles, is an autosomal genetic disorder that results in progressive muscle weakness and is associated with the development of inclusion bodies within skeletal myofibers. The gene responsible for HIBM2 has been identified as GNE, which encodes the UDP-N-acetylglucosamine epimerase/N- acetylmannosamine-6 kinase. GNE is gene required for biosynthesis of sialic acid, an essential glycan found in all human tissues. Despite the identification of the genetic basis for HIBM2, no effective therapies are currently available for this disease. This proposal will accomplish two specific aims. First, it will create a new mouse model for HIBM2 where the mouse sialic acid repertoire reflects the sialic acid repertoire normally found in humans. Humans lack the ability to synthesize certain forms of sialic acid that are present in all lower mammals. HIBM2 is a disease related to defective sialic acid biosynthesis, and CMP-sialic acid also negatively regulates GNE activity. Therefore, creating a mouse model that mimics human glycans is essential to understanding the role of human sialic acids in the disease. This new model will also provide a tool that will allow easier assessment of potential glycan therapies. Second, this grant will directly test a novel hypothesis regarding HIBM2 pathogenesis and develop a novel gene therapy that, if successful, could be applied to patients.