Translational studies on cerebrospinal fluid (CSF)-directed gene therapy for global neurometabolic brain disease
脑脊液(CSF)定向基因治疗全球神经代谢性脑疾病的转化研究
基本信息
- 批准号:10599930
- 负责人:
- 金额:$ 61.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:Adverse eventAffectAlpha-mannosidaseAnimal ModelAnimalsAutopsyBathingBrainBrain DiseasesBrain imagingCell TransplantationCellsCentral Nervous SystemCerebral DominanceCerebral VentriclesCerebrospinal FluidClinicalClinical TrialsComplementary DNADefectDevelopmentDiffusion Magnetic Resonance ImagingDiseaseDisease MarkerDisease ProgressionDisease modelDoseEndosomesEnzymesExtracellular SpaceFamily FelidaeFelis catusGene DeliveryGene Transduction AgentGene therapy trialGenesGeneticHereditary DiseaseHistologicHumanImaging TechniquesImmune responseInfusion proceduresInjectionsInvestigational TherapiesLaboratoriesLesionLiquid substanceLongevityLysosomal Storage DiseasesLysosomesMagnetic Resonance ImagingMagnetic Resonance SpectroscopyMannoseMannosidaseMapsMeasurementMediatingMendelian disorderMetabolicMethodsModelingMonitorMutationNeurologicOligosaccharidesOrgan TransplantationPathologyPatientsProteinsProtocols documentationRecoveryResolutionRodentRouteSerumSeverity of illnessStructural GenesStructureTestingTransduction GeneTranslatingTranslationsVertebral columnadeno-associated viral vectoradvanced diseasealpha-Mannosidosisbrain cellbrain sizecellular transductioncisterna magnacomparativeeffective therapyeffectiveness evaluationenzyme replacement therapygene correctiongene productgene therapygray matterhuman diseasehuman modelimprovedlateral ventriclemutantnervous system disordernon-invasive imagingreceptor mediated endocytosisresponsetranslational modeltranslational studytreatment responsetreatment strategyvectorwhite matter
项目摘要
ABSTRACT
A major barrier to effective treatment of the central nervous system (CNS) in most inherited diseases is
that pathology is present throughout the brain because the metabolic defect is present in most brain cells.
Thus, global distribution of the gene or gene product is required. Several gene therapy strategies are being
investigated for treatment of global brain lesions. However, all of the approaches have significant
shortcomings, which become apparent in large animal models of human diseases. Development of more
effective treatments in these models will facilitate translation into clinical usage.
This project will investigate AAV vector mediated gene delivery into the brain by infusion into the
cerebrospinal fluid (CSF), which can result in disseminated delivery of a gene in a large animal brain. The
disease model to be evaluated is alpha-mannosidosis (AMD) in the cat, a lysosomal storage disorder (LSD)
caused by mutations in the lysosomal enzyme (LE) structural gene, alpha-mannosidase (MANB). The strategy
for treatment is based on cross-correction, in which transfer of a normal copy of the MANB cDNA into AMD
cells results in the metabolic correction of those gene-transduced cells. Furthermore, the genetically corrected
cells release normal MANB enzyme, which is taken up by surrounding cells and corrects them metabolically as
well. This well-established cross-correction mechanism is the basis for treatments of most LSDs.
The disease progression and improvement from treatment will be monitored in living animals by clinical
neurological assessment, life-span increases, serum and CSF analyses, and non-invasive brain imaging by
magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI). In post-mortem animals, the
disease correction will be analyzed quantitatively for distribution of vector transduction, increases in MANB
enzymatic activity, reduction of mannose-containing oligosaccharide substrate accumulation, histopathological
changes, and potential adverse host responses.
We will address important issues affecting translation by investigating strategies to attain more
complete correction of the brain: in Aim 1 we will investigate the effects of alternative routes of CSF delivery;
in Aim 2 we will investigate the effects of dose escalation on the extent of resolution of pathology; and in Aim 3
we will determine the effectiveness of therapy when initiated at progressively more severe stages of disease to
evaluate the potential to ameliorate advanced disease.
摘要
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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JOHN H WOLFE其他文献
JOHN H WOLFE的其他文献
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{{ truncateString('JOHN H WOLFE', 18)}}的其他基金
Translational studies on cerebrospinal fluid (CSF)-directed gene therapy for global neurometabolic brain disease
脑脊液(CSF)定向基因治疗全球神经代谢性脑疾病的转化研究
- 批准号:
10379947 - 财政年份:2019
- 资助金额:
$ 61.29万 - 项目类别:
Translational studies on cerebrospinal fluid (CSF)-directed gene therapy for global neurometabolic brain disease
脑脊液(CSF)定向基因治疗全球神经代谢性脑疾病的转化研究
- 批准号:
9893931 - 财政年份:2019
- 资助金额:
$ 61.29万 - 项目类别:
Translational studies on cerebrospinal fluid (CSF)-directed gene therapy for global neurometabolic brain disease
脑脊液(CSF)定向基因治疗全球神经代谢性脑疾病的转化研究
- 批准号:
9763064 - 财政年份:2019
- 资助金额:
$ 61.29万 - 项目类别:
Disseminated gene delivery to the CNS by human iPSC-derived neural stem cells
通过人类 iPSC 衍生的神经干细胞将播散性基因传递至 CNS
- 批准号:
9204865 - 财政年份:2015
- 资助金额:
$ 61.29万 - 项目类别:
Disseminated gene delivery to the CNS by human iPSC-derived neural stem cells
通过人类 iPSC 衍生的神经干细胞将播散性基因传递至 CNS
- 批准号:
8894955 - 财政年份:2015
- 资助金额:
$ 61.29万 - 项目类别:
Disseminated gene delivery to the CNS by human iPSC-derived neural stem cells
通过人类 iPSC 衍生的神经干细胞将播散性基因传递至 CNS
- 批准号:
8997131 - 财政年份:2015
- 资助金额:
$ 61.29万 - 项目类别:
Gene Transfer and NMR Studies in Alpha-Mannosidosis Brain
α-甘露糖苷沉积症脑中的基因转移和核磁共振研究
- 批准号:
8068082 - 财政年份:2010
- 资助金额:
$ 61.29万 - 项目类别:
Stem Cell Transplantation for Neurogenetic Disease
干细胞移植治疗神经遗传性疾病
- 批准号:
7459697 - 财政年份:2007
- 资助金额:
$ 61.29万 - 项目类别:
Stem Cell Transplantation for Neurogenetic Disease
干细胞移植治疗神经遗传性疾病
- 批准号:
8094219 - 财政年份:2007
- 资助金额:
$ 61.29万 - 项目类别:
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