Manipulation of microRNA for CNS delivery: implication to treatment of neurological LSD
Manipulation of microRNA for CNS delivery: implication to treatment of neurological LSD
批准号:
10201374
负责人:
Dao Pan
金额:
$55.65万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-09-15 至 2022-08-31
关键词:
3&apos Untranslated RegionsAdultAllogenicAlzheimer&aposs DiseaseBehaviorBehavioralBiodistributionBlood - brain barrier anatomyBlood CirculationBrainBrain DiseasesCapillary Endothelial CellCapsidCell TherapyCellsChildhoodDNA cassetteDataDependovirusDevelopmentDiseaseDown-RegulationDrug Delivery SystemsEnzymesEpigenetic ProcessErythroidExcisionFoundationsFrequenciesFunctional disorderFutureGene TransferGeneticGlycosaminoglycansGoalsHematopoietic Stem Cell TransplantationHistopathologyHumanHybridsIGF Type 2 ReceptorIGF2 geneIGF2R geneIndividualInheritedInjectionsIntravenousKnock-outL-IduronidaseLive BirthLuciferasesLysosomal Storage DiseasesLysosomesMediatingMedicalMessenger RNAMetabolicMetabolic DiseasesMicroRNAsModelingModificationMucopolysaccharidosis IMucopolysaccharidosis I HMusMutagenesisNerveNerve DegenerationNeurodegenerative DisordersNeurologicOrganParkinson DiseasePathologicPathway interactionsPatientsPenetrationPeriodicalsPlayPoriferaProductionProteinsPublic HealthRecombinantsReporterRepressionResolutionRoleSeveritiesSiteSpecificitySystemTherapeuticTransfectionTranslationsUp-RegulationVariantVascular Endothelial CellVisceraladeno-associated viral vectorbasebrain cellcaspase 14cell typecerebral capillarycerebral microvasculaturecorrectional systemdesignenzyme replacement therapyenzyme therapyimprovedin vivoinhibitor/antagonistmacromoleculemouse modelnervous system disordernovelnovel therapeuticspostnatal periodpreclinical evaluationpromoterprototypereceptorreceptor downregulationreceptor expressiontherapeutic enzymetraffickingtranscytosistransgene expression
中文摘要
摘要
英文摘要
Abstract
Lysosomal storage disorders (LSDs) are a group of inherited metabolic diseases characterized by a dysfunction
in lysosomes, with cumulative frequency of 1 in 7000 live births (although individually rare). Over 2/3 of LSD
patients present an involvement of the central nerve system (CNS) with a broad spectrum of severity (nLSD),
which makes LSDs the most common cause of pediatric neurodegenerative disease. Allogeneic hematopoietic
stem cell transplantation (HSCT) or enzyme replacement therapy (ERT) by periodical injection of recombinant
enzyme are main treatment options for nLSD. However, they are largely unsuccessful in reversing neurological
complications due to the poor penetration of the enzymes across the blood-brain-barrier (BBB) to the CNS, a
major obstacle in treating nLSD. The cation-independent mannose-6-phosphate receptor (M6PR, also called
IGF2R) plays a critical role in lysosomal enzyme trafficking and intercellular transfer of most lysosomal enzymes,
which is essential for metabolic cross-correction in treating LSDs. Developmental decline of M6PR on the BBB
during early postnatal period in mouse and human has been documented, which is attributable to the lack of
CNS enzyme delivery. Using a dual luciferase reporter system with site-mutagenesis, we have recently
discovered that microRNA-143 (miR143) modulate M6PR protein levels on BBB-forming brain capillary
endothelial cells (BrMV) by targeting to 3' untranslated region of M6PR mRNA. Using a mouse model of Hurler
syndrome (severe mucopolysaccharidosis type I, MPS I), which is caused by the deficiency of α-L-iduronidase
(IDUA), we further demonstrated functional rescue of M6PR-mediated IDUA transfer in the brain of double-
knockout (MPS/miR-143KO) mice with long-term CNS therapeutic benefits, as well as in human vascular
endothelial cells by down-regulation of miR-143 with miR-143-sponge sequences. The data provide strong
scientific premise for the development of a novel CNS-targeted approach that would be applicable in treating
many neurologic LSDs involving M6PR pathway, or in delivering brain therapeutics that can adapting M6PR-
mediated transcytosis pathway. In this proposal, we aim to develop a novel adeno-associated viral vector (AAV)-
based translatable platform to “restore” M6PR pathway on mature BBB for advanced delivery of therapeutic
enzymes into the CNS with 3 aims, including developing optimal artificial miR143 inhibitor (143in) and expression
cassette(s) for efficient and targeted reduction of miR143 on BrMV (aim 1), examination of biodistribution and
“off-target” expression and effects in mice with AAV-143in delivery (aim 2), as well as preclinical evaluation of
BBB-targeted AAV/miR143in in correcting CNS abnormalities in MPS I mice by enzyme therapy derived from
genetically modified erythroid/ megakaryocytic lineages (aim 3). The impact of the study is driven by the unmet
medical need for efficient treatment of inherited nLSDs AND the major limitation of drug-delivery across the BBB.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.3389/fnmol.2022.944883
发表时间:
2022
期刊:
FRONTIERS IN MOLECULAR NEUROSCIENCE
影响因子:
4.8
作者:
[Zhang, Zhenting, Wang, Xiaohong, Lin, Yi, Pan, Dao]
通讯作者:
Pan, Dao
Advancing CNS drug delivery via epigenetic modulation
-
批准号:10679755
-
项目类别:
-
资助金额:$58.37万
-
财政年份:2023
-
负责人:Dao Pan
-
依托单位:
Gaucher disease:Treatment of neurodegenerative disease
-
批准号:8723918
-
项目类别:
-
资助金额:$41.03万
-
财政年份:2013
-
负责人:Dao Pan
-
依托单位:
Gaucher disease:Treatment of neurodegenerative disease
-
批准号:9290966
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项目类别:
-
资助金额:$41.45万
-
财政年份:2013
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负责人:Dao Pan
-
依托单位:
Gaucher disease:Treatment of neurodegenerative disease
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批准号:9069618
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项目类别:
-
资助金额:$41.45万
-
财政年份:2013
-
负责人:Dao Pan
-
依托单位:
Genetic Therapy for CNS Manifestations in MPS I via BBB-targeted Protein Delivery
-
批准号:7567421
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项目类别:
-
资助金额:$32.81万
-
财政年份:2008
-
负责人:Dao Pan
-
依托单位:
Genetic Therapy for CNS Manifestations in MPS I via BBB-targeted Protein Delivery
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批准号:7692967
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项目类别:
-
资助金额:$32.81万
-
财政年份:2008
-
负责人:Dao Pan
-
依托单位:
Genetic Therapy for CNS Manifestations in MPS I via BBB-targeted Protein Delivery
-
批准号:8130702
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项目类别:
-
资助金额:$32.16万
-
财政年份:2008
-
负责人:Dao Pan
-
依托单位:
Genetic Therapy for CNS Manifestations in MPS I via BBB-targeted Protein Delivery
-
批准号:7913103
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项目类别:
-
资助金额:$2.01万
-
财政年份:2008
-
负责人:Dao Pan
-
依托单位:
Genetic Therapy for CNS Manifestations in MPS I via BBB-targeted Protein Delivery
-
批准号:8321014
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项目类别:
-
资助金额:$32.16万
-
财政年份:2008
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负责人:Dao Pan
-
依托单位:
In Vivo BM Stem Cell Gene Transfer for MPS type I
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批准号:6923451
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项目类别:
-
资助金额:$18.63万
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财政年份:2005
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负责人:Dao Pan
-
依托单位:
In Vivo BM Stem Cell Gene Transfer for MPS type I
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批准号:7039094
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项目类别:
-
资助金额:$21.82万
-
财政年份:2005
-
负责人:Dao Pan
-
依托单位:
Core--Real-time quantitative PCR
-
批准号:6861200
-
项目类别:
-
资助金额:$6.46万
-
财政年份:2004
-
负责人:Dao Pan
-
依托单位:
Core--Real-time quantitative PCR facility
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批准号:6442594
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项目类别:
-
资助金额:$10.62万
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财政年份:2001
-
负责人:Dao Pan
-
依托单位:
Core--Real-time quantitative PCR facility
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批准号:6325547
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项目类别:
-
资助金额:$10.62万
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财政年份:1995
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负责人:Dao Pan
-
依托单位:
Core--Real-time quantitative PCR
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批准号:7342411
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项目类别:
-
资助金额:$7.23万
-
财政年份:--
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负责人:Dao Pan
-
依托单位:
Core--Real-time quantitative PCR
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批准号:7062722
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项目类别:
-
资助金额:$6.65万
-
财政年份:--
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负责人:Dao Pan
-
依托单位:
Core--Real-time quantitative PCR
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批准号:7552030
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项目类别:
-
资助金额:$7.3万
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财政年份:--
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负责人:Dao Pan
-
依托单位:
Core--Real-time quantitative PCR
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批准号:7177716
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项目类别:
-
资助金额:$6.85万
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财政年份:--
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负责人:Dao Pan
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依托单位:
海外基金