Developing Synthetic Enzymes to Treat Inborn Errors of Metabolism

开发合成酶来治疗先天性代谢缺陷

基本信息

批准号：
10281241
负责人：
Nikhil Unni Nair
金额：
$ 19.07万
依托单位：
TUFTS UNIVERSITY MEDFORD
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-13 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10281241
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 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 Isovaleryl-CoA dehydrogenase 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 Risk Site Supplementation System Techniques Technology Testing Thermodynamics Toxic effect Translations Valine Variant Work amino acid therapy base design dietary restriction enzyme activity enzyme model enzyme replacement therapy enzyme substrate complex high throughput screening improved innovation isovaleric acidemia model design molecular mechanics novel programs simulation success synthetic enzyme therapeutic development

项目摘要

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。支链酮酸对发育和神经系统的严重、急性和慢性影响脱氢酶缺陷型枫糖浆尿病（BCKD 缺陷型 MSUD）和异戊酰辅酶 A 新生儿中出现的脱氢酶缺乏型异戊酸血症（IVD 缺乏型 IVA）是由于存在患有这些疾病的患者体内亮氨酸、异亮氨酸和缬氨酸的浓度很高。通过低蛋白饮食和营养补充来控制病情，但这往往是不够的，难以坚持，并且仍然可能导致代谢失代偿管理策略包括减少。和限制有毒代谢物和底物，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如此，生活质量也会受到影响。患者及其护理人员都很贫穷，因为需要密切监测患者以避免代谢危机由于感染、饮食或其他原因而引发，因此非常需要新的药物。可以使婴儿、儿童、青少年和成人受益这项工作是基于高系统性的假设。可以使用高活性酶以某种方式降低患者体内有害氨基酸的浓度例如 Pegvaliase 如何降低苯丙酮尿症 (PKU) 患者的苯丙氨酸浓度，这是这项工作的核心。是双重方法的实现，结合了实验定向进化技术和计算酶设计。