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:
- 金额:$ 44.38万
- 依托单位:
- 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:
- 关键词:AffectAffinityAmino Acyl-tRNA SynthetasesAnimalsAntibodiesAntibody TherapyAntigensAutoantibodiesAwarenessAxonBindingBiologicalBiological AssayBiological MarkersBloodBody WeightCharcot-Marie-Tooth DiseaseClinicalClinical ChemistryCollectionComplete Blood CountCreatine KinaseDataDevelopmentDiseaseDisease modelDistalDrug KineticsElectrophysiology (science)EngineeringExhibitsExtracellular SpaceGARS geneGenetic HeterogeneityGoalsHand StrengthHistologyHistopathologyHybridomasImmunizationImmunoglobulin GLigaseLightMaintenanceMeasuresMedicalMembrane ProteinsMendelian disorderMolecular ConformationMonitorMonoclonal AntibodiesMorphologyMotorMotor NeuronsMusMuscleMuscular AtrophyMutationMyositisNerveNeuromuscular JunctionNeuropilin-1Organ WeightPathologicPathologyPatientsPeptidesPerformancePeripheralPeripheral Nervous SystemPharmacodynamicsPhasePhysiologyPlasmaProteinsSchemeSensorySignal PathwaySiteSourceSpecificitySyndromeTherapeuticTherapeutic Monoclonal AntibodiesToxic effectWorkbasebiophysical propertiesdesigndimerdisease phenotypedisorder subtypeefficacy studyefficacy testinggene therapyhuman diseasein vivoinsightmotor neuron degenerationmouse modelmutantneurofilamentnovelnovel strategiesreceptorreceptor bindingremediationresponsetargeted treatmenttreatment durationtreatment 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
项目成果
期刊论文数量(0)
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Xiang-Lei Yang其他文献
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{{ truncateString('Xiang-Lei Yang', 18)}}的其他基金
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
- 批准号:
10544795 - 财政年份:2021
- 资助金额:
$ 44.38万 - 项目类别:
Link extracellular function of tRNA synthetase with pathological mechanism of disease
将tRNA合成酶的细胞外功能与疾病的病理机制联系起来
- 批准号:
10630282 - 财政年份:2021
- 资助金额:
$ 44.38万 - 项目类别:
Exploring a new arm of the integrated stress response and its connection to neurodegeneration
探索综合应激反应的新分支及其与神经退行性变的联系
- 批准号:
10303995 - 财政年份:2021
- 资助金额:
$ 44.38万 - 项目类别:
Link extracellular function of tRNA synthetase with pathological mechanism of disease
将tRNA合成酶的细胞外功能与疾病的病理机制联系起来
- 批准号:
10405421 - 财政年份:2021
- 资助金额:
$ 44.38万 - 项目类别:
2015 Translation Machinery in Health & Disease Gordon Research Conference
2015年健康翻译机
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8831351 - 财政年份:2015
- 资助金额:
$ 44.38万 - 项目类别:
Extra-translational roles of aminoacyl tRNA synthetases in connection to disease
氨酰 tRNA 合成酶与疾病相关的翻译外作用
- 批准号:
8326643 - 财政年份:2010
- 资助金额:
$ 44.38万 - 项目类别:
Extra-translational roles of aminoacyl tRNA synthetases in connection to disease
氨酰 tRNA 合成酶与疾病相关的翻译外作用
- 批准号:
8536318 - 财政年份:2010
- 资助金额:
$ 44.38万 - 项目类别:
Extra-translational roles of aminoacyl tRNA synthetases in connection to disease
氨酰 tRNA 合成酶与疾病相关的翻译外作用
- 批准号:
9177065 - 财政年份:2010
- 资助金额:
$ 44.38万 - 项目类别:
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