Generation of a Large Animal Model of Sialidosis to Enable Future Translation of Novel Therapeutics
生成唾液酸贮积症的大型动物模型,以实现新疗法的未来转化
基本信息
- 批准号:10578286
- 负责人:
- 金额:$ 50.56万
- 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:2023-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AdolescentAdvanced DevelopmentAnimal ModelAnimalsAtaxiaAttenuatedAutopsyBiochemicalBiological AssayBiological MarkersBlindnessBreedingCRISPR/Cas technologyCellsCessation of lifeChemistryChildhoodClinicClinicalClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCollaborationsComplete Blood CountDataData SetDatabasesDependovirusDevelopmentDevelopmental Delay DisordersDiseaseDoseElectroencephalographyElectroporationEmbryoEnsureEnzymesEvaluationExhibitsFelis catusFibroblastsFunctional Magnetic Resonance ImagingFutureGangliosidosis GM1GenerationsGenesGeneticGenetic DiseasesGerm LinesGlycopeptidesGoalsGuide RNAHeterozygoteHistopathologyHumanImageImplantLearningLifeLipomucopolysaccharidosesLysosomal Storage DiseasesMagnetic Resonance ImagingMedicalModelingMusMutationMutation AnalysisMyoclonusNational Human Genome Research InstituteNatural HistoryNeuraminidaseNeurodegenerative DisordersNeurologicNeurologic ExaminationOligosaccharidesOrganOutcome MeasurePathogenesisPathologicPatientsPeripheralPersonsPhenotypePhysical ExaminationPhysiciansPoint MutationResearchRibonucleoproteinsRouteSamplingSandhoff DiseaseSeizuresSerumSheepSialic AcidsStandardizationTay-Sachs DiseaseTechnologyTestingTherapeuticTranslatingTranslational ResearchTranslationsUnited States National Institutes of HealthValidationVeterinariansViral Genesaccess restrictionsclinical trial implementationclinically relevantcognitive testingdisease phenotypeenzyme activityexperienceexperimental studyfallsfetalfirst-in-humangene therapygenome editinghuman datahuman modelinfancyloss of functionmouse modelnervous system disordernovel therapeuticspre-clinicalpreservationprime editingprogramsrapid testingresearch clinical testingsheep modelsialylationsomatic cell nuclear transfersuccesstherapeutic developmenttherapeutic evaluationtreatment strategytrial design
项目摘要
Project Summary
Sialidosis is a rare, fatal, neurological disorder caused by a mutation in the NEU1 gene resulting in vision loss,
seizures, involuntary myoclonus, and ataxia. Our team has a strong track record in brining gene therapies to
the clinic and has plans to develop a gene therapy to treat sialidosis. Our previous experience has shown that
testing in large animal models of human genetic diseases better approximates what will happen and patients
and use of these models increases the likelihood of efficacy. We have developed a founder sheep with a
mutation like type 1 sialidosis patients and will breed him to generate a colony of animals. Since the last
submission we have created several severe mutations using CRISPR/spCas9 editing, therefore in this aim we will
use Prime genome editing of embryos, to recreate two human mutations (Type 1 and Type 2) with the end goal
of a mutation that recapitulates the human condition (Aim 1). We will evaluate each model for its ability to
reliably mimic sialidosis then select the best model (Aim 2). This phenotyping includes in-life clinical metrics like
MRI, EEG, EMG, neurological and cognitive testing as well as in depth post-mortem assays to determine if it
reproduces biochemical and histopathological aspects of disease. External evaluation of in-life clinical testing
will be performed by our clinical collaborator Dr. Tifft. Additionally, Dr. Tifft will make human samples available
for comparison with the new sheep model. The biochemical aspects of disease will be externally validated by
by Dr. d’Azzo (the leader in field of sialidosis) and pathological features characterized by Dr. Koehler a veterinary
neuropathologist. After completion of these studies, this fully validated model will be used to learn more about
sialidosis as a disorder, and also used in the development of an adeno associated viral gene therapy or other
future treatment strategies for sialidosis.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Heather L Gray-Edwards其他文献
Cardiovascular manifestations of feline Sandhoff disease after intravenous AAV gene therapy
- DOI:
10.1016/j.ymgme.2016.11.090 - 发表时间:
2017-01-01 - 期刊:
- 影响因子:
- 作者:
Lauren E Ellis;Randolph Winter;Heather L Gray-Edwards;Stacy Maitland;Ashley E Randle;Robert Edwards;Miguel Sena-Esteves;Douglas R Martin;Raymond Y Wang - 通讯作者:
Raymond Y Wang
Heather L Gray-Edwards的其他文献
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{{ truncateString('Heather L Gray-Edwards', 18)}}的其他基金
Global AAV gene therapy of Tay-Sachs disease in sheep.
绵羊泰萨克斯病的全球 AAV 基因治疗。
- 批准号:
9243030 - 财政年份:2016
- 资助金额:
$ 50.56万 - 项目类别:
Global AAV gene therapy of Tay-Sachs disease in sheep.
绵羊泰萨克斯病的全球 AAV 基因治疗。
- 批准号:
10063918 - 财政年份:2016
- 资助金额:
$ 50.56万 - 项目类别:
In vivo magnetic resonance-based analysis of inherited neurologic disease after g
基于体内磁共振的遗传性神经系统疾病分析
- 批准号:
8527241 - 财政年份:2013
- 资助金额:
$ 50.56万 - 项目类别:
In vivo magnetic resonance-based analysis of inherited neurologic disease after g
基于体内磁共振的遗传性神经系统疾病分析
- 批准号:
8657391 - 财政年份:2013
- 资助金额:
$ 50.56万 - 项目类别:
In vivo magnetic resonance-based analysis of inherited neurologic disease after g
基于体内磁共振的遗传性神经系统疾病分析
- 批准号:
8837710 - 财政年份:2013
- 资助金额:
$ 50.56万 - 项目类别:
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