Membrane repair as a therapeutic intervention for treating Becker Muscular Dystrophy
膜修复作为治疗贝克尔肌营养不良症的治疗干预措施
基本信息
- 批准号:10761285
- 负责人:
- 金额:$ 29.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-21 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAmino Acid MotifsAmino Acid SequenceBecker Muscular DystrophyBindingBinding ProteinsBiochemicalBiological AssayBiotechnologyCardiac MyocytesCardiovascular systemCell Culture TechniquesCellsCessation of lifeChemistryChinese Hamster Ovary CellClinicalClinical TreatmentClinical TrialsCollaborationsCompensationComplementary therapiesCultured CellsCytoskeletal ProteinsDataDevelopmentDiseaseDoctor of PhilosophyDoseDuchenne muscular dystrophyDystrophinEngineeringEscherichia coliFutureGenerationsGenesGenetic DiseasesGoalsHeart InjuriesHumanInbred BALB C MiceInvestigational New Drug ApplicationKnockout MiceLaboratoriesLettersLinkMeasurementMedicalMembraneMetabolismMethodsModelingMusMuscleMuscle CellsMuscle DevelopmentMuscle functionMuscular AtrophyMuscular DystrophiesMutationMyoblastsMyocardiumMyopathyOhioPathologyPatient-Focused OutcomesPatientsPharmacologic SubstancePhasePhenotypePhosphatidylserinesPredispositionProceduresProductionPropertyProteinsProtocols documentationRandomizedRecombinantsRecording of previous eventsResearchRodent ModelSiteSkeletal MuscleSmall Business Innovation Research GrantSourceTRIM MotifTherapeuticTherapeutic InterventionToxic effectToxicokineticsUnited States Food and Drug AdministrationUniversitiesWorkclinical developmentcohortcommercializationdysferlinopathiesefficacy testingefficacy trialimmunogenicityimprovedimproved outcomeinterestmanufacturemetabolic abnormality assessmentmouse modelmuscle physiologymuscular structurenovelnovel therapeuticsoverexpressionpreclinical efficacypreclinical trialprofessorprotein functionrepairedrestorationscale upskeletalstability testingsuccesstechnology platformtherapeutic proteintherapy developmentubiquitin-protein ligase
项目摘要
PROJECT ABSTRACT
The goal of this combined Phase I/II SBIR project is to accomplish key milestones in commercializing a
protein therapeutic for Becker muscular dystrophy (BMD) that will enhance the repair capacity of muscle cell
sarcolemmal membranes compromised by mutations in the dystrophin gene that reduce the expression level
or function of the dystrophin protein. Many mutations in the dystrophin gene result can in BMD while others
result in the more severe Duchenne muscular dystrophy (DMD). Myos Inc. is developing a novel recombinant
construct of the tripartite protein 72/mitsugumin 53 (TRIM72/MG53), an essential regulator of membrane repair
in skeletal and cardiac muscle. It is known that rhMG53 therapy ameliorates disease pathology in a dystrophin
deficient mouse model and models of other muscular dystrophies, strongly suggesting that it may enhance
repair and restoration of muscle function in BMD. However, recent potential toxicity concerns make the original
rhMG53 protein sequence suboptimal for protein therapy. Therefore, we engineered a new version of the
rhMG53 protein for use in treating BMD by optimizing its functional and biochemical properties. This Phase I/II
project will further develop this novel protein by producing the data necessary to support an investigational new
drug (IND) application to the U.S. Food and Drug Administration (FDA) through three specific aims. Aim 1 will
develop Chemistry, Manufacturing, and Control (CMC) protocols for production of this protein. Optimization of
protein production from Chinese Hamster Ovary (CHO) cell cultures will be conducted at a CMO focused on
protein production in CHO cells. We will also conduct stability testing up to 24 months for the protein as part of
the studies in this aim. The deliverables will be a scale-up protocol for production of this protein and generation
of protein for aims 2 and 3. Aim 2 will complete a pre-clinical trial for the efficacy of this protein in treating a
mouse model of BMD. This aim will involve a preclinical efficacy trial for three doses of the protein in a mouse
model of BMD. Randomized cohorts of BMD mice will be treated with for 8-45 weeks and changes in the
dystrophy phenotype will be determined through various measurements of skeletal and cardiac muscle
structure and function. The deliverable for this aim will be to resolve if the protein can effectively treat a rodent
model of BMD. Aim 3 will conduct immunogenicity and toxicity studies for protein in mice. This assessment will
involve toxicity studies, including repeated-dose studies, toxicokinetic assessment, metabolic studies and
immunogenicity assessment, in BALB/c mice. These studies will be conducted at Myos and a CRO with a long
history of conducting such studies. The deliverable here will be completing these studies so the data can be
used to guide regulatory filings. Successful completion of this project will result in sufficient data to prepare an
IND application to the FDA for use in clinical trials for the treatment of BMD.
项目摘要
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Noah Weisleder其他文献
Noah Weisleder的其他文献
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{{ truncateString('Noah Weisleder', 18)}}的其他基金
Translational development of recombinant protein therapeutic for LGMD2B
LGMD2B 重组蛋白治疗剂的转化开发
- 批准号:
10483343 - 财政年份:2022
- 资助金额:
$ 29.55万 - 项目类别:
Optimizing membrane repair for the treatment of Duchenne muscular dystrophy
优化膜修复治疗杜氏肌营养不良症
- 批准号:
9910186 - 财政年份:2019
- 资助金额:
$ 29.55万 - 项目类别:
Calcium Regulation in the Progression of Muscular Dystrophy
肌营养不良症进展中的钙调节
- 批准号:
8436127 - 财政年份:2011
- 资助金额:
$ 29.55万 - 项目类别:
Calcium Regulation in the Progression of Muscular Dystrophy
肌营养不良症进展中的钙调节
- 批准号:
8230611 - 财政年份:2011
- 资助金额:
$ 29.55万 - 项目类别:
Calcium Regulation in the Progression of Muscular Dystrophy
肌营养不良症进展中的钙调节
- 批准号:
8073247 - 财政年份:2011
- 资助金额:
$ 29.55万 - 项目类别:
Calcium Regulation in the Progression of Muscular Dystrophy
肌营养不良症进展中的钙调节
- 批准号:
7532263 - 财政年份:2008
- 资助金额:
$ 29.55万 - 项目类别:
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