Generation of a Large Animal Model of Sialidosis to Enable Future Translation of Novel Therapeutics
Generation of a Large Animal Model of Sialidosis to Enable Future Translation of Novel Therapeutics
批准号:
10578286
负责人:
Heather L Gray-Edwards
金额:
$50.56万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
已结题
起止时间:
2023-01-01 至 2024-12-31
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
中文摘要
项目总结
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Global AAV gene therapy of Tay-Sachs disease in sheep.
-
批准号:9243030
-
项目类别:
-
资助金额:$16.91万
-
财政年份:2016
-
负责人:Heather L Gray-Edwards
-
依托单位:
Global AAV gene therapy of Tay-Sachs disease in sheep.
-
批准号:10063918
-
项目类别:
-
资助金额:$18.94万
-
财政年份:2016
-
负责人:Heather L Gray-Edwards
-
依托单位:
In vivo magnetic resonance-based analysis of inherited neurologic disease after g
-
批准号:8527241
-
项目类别:
-
资助金额:$6.22万
-
财政年份:2013
-
负责人:Heather L Gray-Edwards
-
依托单位:
In vivo magnetic resonance-based analysis of inherited neurologic disease after g
-
批准号:8657391
-
项目类别:
-
资助金额:$6.55万
-
财政年份:2013
-
负责人:Heather L Gray-Edwards
-
依托单位:
In vivo magnetic resonance-based analysis of inherited neurologic disease after g
-
批准号:8837710
-
项目类别:
-
资助金额:$6.87万
-
财政年份:2013
-
负责人:Heather L Gray-Edwards
-
依托单位:
海外基金