Developing Synthetic Enzymes to Treat Inborn Errors of Metabolism

开发合成酶来治疗先天性代谢缺陷

• 批准号: 10540317
• 负责人: Nikhil Unni Nair
• 金额: $ 15.37万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-13 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10540317
• 关键词: Acute; Adolescent; Adult; Amino Acids; Amino Acids Activation; Ammonia; Anabolism; Animals; Biochemistry; Branched-Chain Amino Acids; Caregivers; Child; Chronic; Clinical; Computer Analysis; Computer Models; Computer Simulation; Data; Deamination; Descriptor; Development; Diet; Directed Molecular Evolution; Disease; Distal; Drug Kinetics; Engineering; Enzymes; Family; Formulation; Foundations; Funding Mechanisms; Goals; Grant; Inborn Errors of Metabolism; Individual; Infant; Infection; Injectable; Isoleucine; Keto Acids; Kinetics; Lead; Leucine; Libraries; Lyase; Maple Syrup Urine Disease; Metabolic; Metabolism; Modality; Modeling; Monitor; Mutagenesis; Mutation; Nature; Neurologic; Newborn Infant; Nutrient; Outcome; Oxidoreductase; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phenylalanine; Phenylalanine Ammonia-Lyase; Phenylketonurias; Probability; Property; Protein Engineering; Protein-Restricted Diet; Quality of life; Quantum Mechanics; Reaction; Residual state; Resolution; Site; Supplementation; System; Techniques; Technology; Testing; Thermodynamics; Toxic effect; Valine; Variant; Work; amino acid therapy; cofactor; design; dietary restriction; enzyme activity; enzyme model; enzyme replacement therapy; enzyme substrate complex; high throughput screening; improved; innovation; isovaleric acidemia; molecular mechanics; novel; programs; risk mitigation; simulation; success; synthetic enzyme; therapeutic development; translational potential; Acute; Adolescent; Adult; Amino Acids; Amino Acids Activation; Ammonia; Anabolism; Animals; Biochemistry; Branched-Chain Amino Acids; Caregivers; Child; Chronic; Clinical; Computer Analysis; Computer Models; Computer Simulation; Data; Deamination; Descriptor; Development; Diet; Directed Molecular Evolution; Disease; Distal; Drug Kinetics; Engineering; Enzymes; Family; Formulation; Foundations; Funding Mechanisms; Goals; Grant; Inborn Errors of Metabolism; Individual; Infant; Infection; Injectable; Isoleucine; Keto Acids; Kinetics; Lead; Leucine; Libraries; Lyase; Maple Syrup Urine Disease; Metabolic; Metabolism; Modality; Modeling; Monitor; Mutagenesis; Mutation; Nature; Neurologic; Newborn Infant; Nutrient; Outcome; Oxidoreductase; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phenylalanine; Phenylalanine Ammonia-Lyase; Phenylketonurias; Probability; Property; Protein Engineering; Protein-Restricted Diet; Quality of life; Quantum Mechanics; Reaction; Residual state; Resolution; Site; Supplementation; System; Techniques; Technology; Testing; Thermodynamics; Toxic effect; Valine; Variant; Work; amino acid therapy; cofactor; design; dietary restriction; enzyme activity; enzyme model; enzyme replacement therapy; enzyme substrate complex; high throughput screening; improved; innovation; isovaleric acidemia; molecular mechanics; novel; programs; risk mitigation; simulation; success; synthetic enzyme; therapeutic development; translational potential

Project Summary. The severe, acute, and chronic developmental and neurological impacts seen in branched chain ketoacid dehydrogenase deficient Maple Syrup Urine Disease (BCKD-deficient MSUD) and isovaleryl‐CoA dehydrogenase deficient Isovaleric Acidemia (IVD-deficient IVA) seen in newborns are due to the presence of high concentrations of leucine, isoleucine, and valine in their system. Patients with these disorders are limited to manage their condition though a low-protein diet and nutrient supplementation, which is often inadequate, difficult to adhere to, and can still lead to metabolic decompensation. Management strategies include reduction and restriction of toxic metabolites and substrates, promotion of anabolism and stimulation of residual enzyme activity along with activation of amino acid and ketoacid scavenging pathways. Even then, the quality of life of patients is poor, as is for their caregivers since patients need to be monitored closely to avoid metabolic crisis precipitated either by infection, diet, or other reasons. Thus, there is significant need for new medications that can benefit infants, children, adolescents, and adults. This work is based on the hypothesis that high systemic concentrations of offending amino acid(s) in patients can be reduced using high activity enzymes, in a manner like how Pegvaliase reduces phenylalanine concentrations in phenylketonuria (PKU) patients. Core to this work is implementation of a twofold approach that combines experimental directed evolution techniques and computations enzyme design.

项目摘要。 分支链酮酸酸中看到的严重，急性和慢性发育和神经系统影响 脱氢酶缺乏枫糖浆尿液疾病（BCKD缺乏症）和isOvaleryl-COA 在新生儿中，脱氢酶缺乏的脱氢酶血症（IVD缺陷IVA）是由于存在 其系统中的高浓度亮氨酸，异亮氨酸和瓣膜。这些疾病的患者有限 通过低蛋白质饮食和补充营养的养分来管理它们的病情，通常不足 难以遵守，并且仍然会导致代谢代谢。管理策略包括减少 毒性代谢物和底物的限制，促进合成代谢和刺激残留酶 活性以及氨基酸和酮酸清除途径的激活。即使那样，生活的质量 患者很差，因为需要密切监测患者以避免代谢危机，因为他们的护理人员也很差 通过感染，饮食或其他原因引起。那是非常需要新药的 可以使婴儿，儿童，青少年和成人受益。这项工作基于以下假设 可以使用高活性酶以某种方式降低患者中违反氨基酸的浓度 就像斑谷降低苯酮尿（PKU）患者中苯丙氨酸浓度的方式一样。这项工作的核心 是实施双重方法，该方法结合了实验性定向进化技术和 计算酶设计。