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Develop pan-specific antibody against mutant glycyl-tRNA synthetase for treating CMT2D

开发抗突变甘氨酰-tRNA合成酶的泛特异性抗体来治疗 CMT2D

基本信息

批准号：
10541284
负责人：
Xiang-Lei Yang
金额：
$ 44.38万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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：
2021-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541284
关键词：
Affect Affinity Amino Acyl-tRNA Synthetases Animals Antibodies Antibody Therapy Antigens Autoantibodies Awareness Axon Binding Biological Biological Assay Biological Markers Blood Body Weight Charcot-Marie-Tooth Disease Clinical Clinical Chemistry Collection Complete Blood Count Creatine Kinase Data Development Disease Disease model Distal Drug Kinetics Electrophysiology (science)Engineering Exhibits Extracellular Space GARS gene Genetic Heterogeneity Goals Hand Strength Histology Histopathology Hybridomas Immunization Immunoglobulin G Ligase Light Maintenance Measures Medical Membrane Proteins Mendelian disorder Molecular Conformation Monitor Monoclonal Antibodies Morphology Motor Motor Neurons Mus Muscle Muscular Atrophy Mutation Myositis Nerve Neuromuscular Junction Neuropilin-1 Organ Weight Pathologic Pathology Patients Peptides Performance Peripheral Peripheral Nervous System Pharmacodynamics Phase Physiology Plasma Proteins Scheme Sensory Signal Pathway Site Source Specificity Syndrome Therapeutic Therapeutic Monoclonal Antibodies Toxic effect Work base biophysical properties design dimer disease phenotype disorder subtype efficacy study efficacy testing gene therapy human disease in vivo insight motor neuron degeneration mouse model mutant neurofilament novel novel strategies receptor receptor binding remediation response targeted treatment treatment duration treatment strategy

项目摘要

Abstract Charcot-Marie-Tooth (CMT) disease type 2D is caused by dominant mutations in GARS, encoding glycyl-tRNA synthetase (GlyRS). CMT is a clinically and genetically heterogeneous collection of disorders in which peripheral motor and sensory axons degenerate. The diseases specifically affect the peripheral nervous system and are characterized by progressive motor neuron degeneration, muscle atrophy, and sensory loss. None of the CMT disease subtypes have a targeted treatment, thus CMT remains an unmet medical need. The genetic heterogeneity makes it unlikely that a single therapy will be effective for all forms of CMT. Although gene therapies have emerged strongly for monogenic diseases such as CMT, the large number of different mutations involved, and the small number of patients affected by each mutation render classic gene therapy onerous for CMT2D. Identifying a causal treatment strategy applicable to different mutations in GARS would therefore be the most attractive therapeutic approach for CMT2D. Also, being able to directly engage with the GlyRS protein itself is key to CMT2D remediation. Our previous work has established that a major source of the toxicity of the CMT-causing mutant GlyRS is originated from the extracellular space, where mutant proteins aberrantly interact with Neuropilin 1 (Nrp1) receptor and antagonize a signaling pathway important for motor neuron maintenance. We designed a novel strategy based on our structural insight of the GlyRS mutants. We found that different CMT2D mutations caused a shared conformational change in GlyRS that exposes new protein surfaces at the dimer interface to solution. By using two different peptides from the dimer interface of GlyRS as antigens for immunization, we have successfully obtained two monoclonal antibodies (mAbs) (one for each peptide) from mouse hybridomas that can block the pathological Nrp1 interaction and exhibit promising pan-mutant selectivity. These two mAb candidates will be characterized for their biophysical properties, and used for conducting pharmacodynamic, pharmacokinetic, and in vivo efficacy studies in a mouse model of the human disease to evaluate whether they have sufficient biological activity to warrant further development to treat CMT2D.

摘要