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

靶向醛糖还原酶：依帕司他新用途治疗先天性糖基化障碍 (PMM2-CDG) 的 IIb/III 期试验

• 批准号: 10480649
• 负责人: Ethan Perlstein
• 金额: $ 69.99万
• 依托单位: MAGGIE'S PEARL, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-03 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10480649
• 关键词: 7 year old; Acetazolamide; Address; Adult; Adverse effects; Adverse event; Affect; Age; Alanine Transaminase; Aldehyde Reductase; Animal Model; Antithrombin III; Aspartate Transaminase; Ataxia; Biological Assay; Caring; Charcot-Marie-Tooth Disease; Chemistry; Child; Childhood; Climacteric; Clinic; Clinical; Clinical Research; Clinical Trials; Complete Blood Count; Congenital disorders of glycosylation; Cross-Over Trials; Data; Defect; Development; Diabetic Neuropathies; Disease; Disease Progression; Documentation; Double-Blind Method; Drug Kinetics; Duct (organ) structure; Economics; Elasticity; Enzymes; FDA approved; Failure to Thrive; Fibroblasts; Fucose; Funding; Future; Galactose; Genotype; Growth; Hematology; Hepatic; Human; In Vitro; International; International Normalized Ratio; Japan; L-Iditol 2-Dehydrogenase; Language Delays; Libraries; Life; Lipids; Liver; Measurement; Measures; Metabolic; Modeling; Molecular Chaperones; Monosaccharides; Motor; Muscle hypotonia; Mutation; Myocardial dysfunction; Neurologic; Neuropathy; Oral; Orphan Drugs; Palliative Care; Pathogenicity; Pathology; Patient-Focused Outcomes; Patients; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phase; Phosphomannomutase; Plant Roots; Polysaccharides; Protein Glycosylation; Proteins; Prothrombin time assay; Psyche structure; Rare Diseases; Replacement Therapy; Safety; Serum; Severities; Severity of illness; Small Business Innovation Research Grant; Symptoms; Testing; Therapeutic; Time; Transferrin; Urine; Walking; care providers; commercialization; diabetic; dietary supplements; disability; drug candidate; effective therapy; enzyme activity; hereditary neuropathy; improved outcome; infancy; inhibitor; kidney dysfunction; link protein; mannose 1-phosphate; mannose 6 phosphate; mutant; novel; patient population; pediatric patients; polyol; prevent; prospective; stem; success; total measurement Bilirubin

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.

概括 糖基化（CDG）的先天性疾病是一组超过150种疾病，其特征有限 将聚糖连接到蛋白质和脂质上。最常见的形式是磷酸糖突变酶2活性的丧失 （PMM2-CDG）是一种孤儿疾病，影响了全球约1500名患者。 CDG通常呈现为 在生命的头几年中，严重疾病，在20％的婴儿病例中致命。患有PMM2-CDG的孩子 一系列症状，包括低骨，共济失调，神经病，语言和运动严重延迟 发育，无法行走以及40至70的智商。成年患者表现出轻度至重度的身体和精神 残疾。 当前的CDG治疗仅由姑息治疗组成。没有批准使用治疗。替代品 单糖的疗法，例如甘露糖1-磷酸，半乳糖，富藻糖以及其他饮食 补充剂显示出PMM2-CDG的效率很小。疾病的严重程度与酶程度相关 损失：<7％的酶活性是致命的，而> 50％的活性没有症状。 玛姬的珍珠发现了几种化合物，可增加突变体PMM2酶的活性。 PMM2-CDG的几种模型，包括源自PMM2患者的成纤维细胞。这些化合物中有许多是 醛糖降低了抑制剂（ARIS），其中一种是epalrestat，似乎是安全的候选药物。它一直 在日本使用了27多年的成人治疗糖尿病神经病。但是，该药物未获得批准 对于美国的任何迹象。 玛姬（Maggie）的珍珠（Pearl）在一次患有试验中测试了Epalrestat。年轻患者仅在 4个月的治疗，在18个月后没有不良反应。拟议的SBIR将扩大 这项研究对30个儿童期PMM2-CDG患者进行了双盲，单跨试验 年。在这项试验中，Epalrestat的类似成功将为全球患者提供改变生活的改善。