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: 10616658
• 负责人: Ethan Perlstein
• 金额: $ 55.31万
• 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/10616658
• 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; 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; Metabolic syndrome; Modeling; Molecular Chaperones; Monosaccharides; Motor; Muscle hypotonia; Mutation; Myocardial dysfunction; Neurologic; Neuropathy; Oral; Oral Administration; Orphan Drugs; Palliative Care; Pathogenicity; Pathology; Patient-Focused Outcomes; Patients; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phase; Phosphomannomutase; 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; Transferrin; Urine; Walking; care providers; commercialization; dietary supplements; disability; drug candidate; effective therapy; enzyme activity; hereditary neuropathy; improved; improved outcome; infancy; inhibitor; kidney dysfunction; link protein; mannose 1-phosphate; mannose 6 phosphate; manufacture; model organism; 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.

摘要 先天性糖基化紊乱(CDG)是一组超过150种疾病，其特征是 将多聚糖连接到蛋白质和脂质上。最常见的形式是磷酸甘露糖变异酶-2活性丧失 (PMM2-CDG)是一种孤儿疾病，全球约有1500名患者受到影响。CDG通常呈现为 在婴儿出生后的头几年会出现严重的疾病，在20%的婴儿病例中是致命的。患有PMM2-CDG的儿童 一系列症状，包括低眼压、共济失调、神经病变、严重的语言和运动障碍 发育不良，不能行走，智商在40到70之间。成年患者表现出轻微到严重的生理和精神症状 残疾人士。 目前对CDG的治疗只包括姑息治疗。没有治疗药物被批准使用。更换 单糖治疗，如甘露糖-1-磷酸、半乳糖、岩藻糖，以及其他饮食 补充剂对PMM2-CDG几乎没有效果。病情的严重程度与酶的程度有关 损失：7%的酶活性是致命的，而50%的酶活性不会产生任何症状。 Maggie‘s珍珠公司发现了几种化合物，可以增加突变的PMM2酶的活性 几种PMM2-CDG模型，包括来自PMM2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(ARI)，其中之一，依帕瑞司他似乎是一个安全的候选药物。一直以来 在日本用于治疗成人糖尿病神经病变已超过27年。然而，该药物并未获得批准 在美国寻找任何迹象。 麦琪的珍珠已经在一项单患者试验中测试了依帕雷司他。这位年轻的患者在仅仅几天后就出现了阳性结果 治疗4个月，服药18个月后未见不良反应。拟议的SBIR将扩大 本研究对30例儿童PMM2-CDG患者进行了三个疗程的双盲、单交叉试验 好几年了。在这项试验中，依帕瑞司他的类似成功将为世界各地的患者提供改变生活的改善。