Targeting aldose reductase: A Phase IIb/III trial for the novel use of Epalrestat to treat Congenital Disorders of Glycosylation (PMM2-CDG)

总结 先天性糖基化障碍（CDG）是一组超过150种疾病，其特征是能力有限， 将聚糖附着在蛋白质和脂质上。最常见的形式，磷酸甘露糖突变酶-2活性丧失 （PMM 2-CDG）是一种孤儿疾病，影响全球约1500例患者。CDG通常表现为 在生命的最初几年中是严重的疾病，并且在20%的婴儿病例中是致命的。PMM 2-CDG儿童有 一系列症状，包括肌张力减退、共济失调、神经病、严重延迟的语言和运动 发育不全无法行走智商40到70成年患者表现出轻度至重度的身体和精神 残疾。 目前CDG的治疗仅包括姑息治疗。未批准使用任何治疗剂。更换 用单糖如甘露糖-1-磷酸、半乳糖、岩藻糖以及其它膳食 补充剂，在PMM 2-CDG中几乎没有显示出功效。疾病的严重程度与酶的程度相关 损失：<7%的酶活性是致命的，而>50%的活性不产生症状。 Maggie's Pearl发现了几种化合物，可以增加突变PMM 2酶的活性， PMM 2-CDG的几种模型，包括来源于PMM 2患者的成纤维细胞。这些化合物中有许多是 醛糖还原酶抑制剂（阿里斯），其中之一，依帕司他，似乎是一个安全的候选药物。已经 在日本用于治疗成人糖尿病神经病变超过27年。然而，该药物未被批准 在美国的任何迹象。 Maggie's Pearl已经在一项单一患者试验中测试了依帕司他。这位年轻患者刚出院后就显示出阳性结果 治疗4个月，依帕司他18个月后无不良反应。拟议的SBIR将扩大 本研究是一项双盲、单交叉试验，在30名儿童PMM 2-CDG患者中进行了为期3年的研究。 年在这项试验中，依帕司他的类似成功将为全球患者提供改变生活的改善。

SUMMARY Congenital Disorders of Glycosylation (CDG) is a group of over 150 diseases characterized by limited ability to attach glycans to proteins and lipids. The most common form, loss of phosphomannose mutatase-2 activity (PMM2-CDG), is an orphan disease affecting approximately 1500 patients worldwide. CDG typically presents as severe disease in the first few years of life and is lethal in 20% of infantile cases. Children with PMM2-CDG have a range of symptoms, including hypotonia, ataxia, neuropathy, severely delayed language and motor development, inability to walk, and IQ of 40 to 70. Adult patients display mild to severe physical and mental disabilities. Current treatment for CDG consists only of palliative care. No therapeutic is approved for use. Replacement therapies with monosaccharides, such as mannose-1-phosphate, galactose, fucose, as well as other dietary supplements, have shown little efficacy in PMM2-CDG. Severity of disease is correlated with degree of enzyme loss: <7% enzyme activity is lethal, whereas >50% activity yields no symptoms. Maggie’s Pearl has discovered several compounds that increase the activity of the mutant PMM2 enzyme in several models of PMM2-CDG, including fibroblasts derived from PMM2 patients. Many of these compounds are aldose reductase inhibitors (ARIs), and one of them, Epalrestat, appears to be a safe drug candidate. It has been used for over 27 years in Japan for treatment of diabetic neuropathy in adults. However, the drug is not approved for any indication in the US. Maggie’s Pearl has tested Epalrestat in a single-patient trial. The young patient showed positive results after just 4 months of treatment, with no adverse effects after 18 months of Epalrestat. The proposed SBIR will expand this study to a double blind, single-crossover trial of 30 childhood PMM2-CDG patients over the course of three years. Similar success of Epalrestat in this trial would offer life-changing improvements for patients worldwide.