Permanent alteration of PCSK9 in vivo genome editing
Permanent alteration of PCSK9 in vivo genome editing
批准号:
9307483
负责人:
Kiran Musunuru
金额:
$40.25万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-05-01 至 2021-02-28
关键词:
AdenovirusesAdultAntibodiesAutomobile DrivingBloodCardiovascular DiseasesCardiovascular systemCause of DeathCell LineCholesterolClinicalClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsComplexCoronary heart diseaseCytosineDNA SequenceDependovirusFamilyFrameshift MutationFutureGenesGenomicsGuide RNAHepatocyteHumanHuman GeneticsHuman GenomeHybridsIn VitroIndividualInjection of therapeutic agentKnock-outLDL Cholesterol LipoproteinsLightLiverLow Density Lipoprotein ReceptorMammalian CellMusMutationNonhomologous DNA End JoiningNonsense MutationNucleotidesPatientsPharmaceutical PreparationsPharmacologyPreventionPreventive therapyProductionProprotein ConvertasesProteinsPublishingResidual stateRiskRisk ReductionSafetySamplingSiteStreptococcus pyogenesSubtilisinsSystemTechnologyTestingThymineTimeTransplantationVaccinationWorkbasecardiovascular risk factordeep sequencingdisorder riskexperiencegain of function mutationgenome editinggenome-wide analysishumanized mousehypercholesterolemiain vivoloss of function mutationmouse modelnew technologynucleaseprematurerepairedsuccesstherapeutic target
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target for the
prevention of coronary heart disease (CHD). A gene specifically expressed in and secreted from the liver, and
believed to function primarily as an antagonist to the low-density lipoprotein receptor (LDLR), PCSK9 was
originally identified as the cause of autosomal dominant hypercholesterolemia in some families, with gain-of-
function mutations in the gene driving highly elevated LDL cholesterol (LDL-C) levels and premature CHD. In
subsequent studies, individuals with single loss-of-function mutations in PCSK9 were found to experience a
significant reduction of both LDL-C levels (~30%–40%) as well as CHD risk (88%). Notably, even individuals
with two loss-of-function mutations in PCSK9—resulting in ~80% reduction in LDL-C levels—appear to suffer
no adverse clinical consequences.
The ability to permanently alter the human genome has been made possible by the technology now commonly
known as genome editing. Recently published clustered regularly interspaced short palindromic repeats
(CRISPR)/CRISPR‐associated (Cas) systems use Streptococcus pyogenes Cas9 nuclease that is targeted to
a genomic site by complexing with a synthetic guide RNA that hybridizes a 20-nucleotide DNA sequence
(protospacer) immediately preceding an NGG motif (PAM, or protospacer-adjacent motif) recognized by Cas9.
CRISPR-Cas9 generates a double-strand break (DSB) that is usually repaired by non-homologous end-joining
(NHEJ), which is error-prone and conducive to frameshift mutations resulting in gene knock-out. A newer
version of Cas9 termed a “base editor” selectively edits cytosine bases to thymine, without the need for DSBs,
and thus may represent a safer means by which to introduce knock-out nonsense mutations.
In light of the observed high efficiencies of CRISPR-Cas9 in mammalian cells in vitro, we seek to assess
whether a one-time delivery of CRISPR-Cas9 can be used to permanently disrupt the human PCSK9 gene in
vivo efficiently and safely and, if so, the optimal CRISPR-Cas9 system to use for this purpose. Success in
completing this translational project will provide critical information on the feasibility of an in vivo genome-
editing approach that could ultimately yield a one-shot, long-term therapy that permanently reduces blood LDL-
C levels and thus serves as a “vaccination” against cardiovascular disease.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Postnatal and Prenatal Therapeutic Base Editing for Metabolic Diseases
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批准号:10668614
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项目类别:
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资助金额:$641.57万
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财政年份:2023
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负责人:Kiran Musunuru
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依托单位:
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批准号:10668615
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资助金额:$106.93万
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财政年份:2023
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依托单位:
LEAD PROJECT 1: PHENYLKETONURIA (PKU)
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批准号:10668618
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资助金额:$106.93万
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财政年份:2023
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负责人:Kiran Musunuru
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依托单位:
Diagnosis, Prevention, And Treatment Of Cardiovascular Diseases With Genome Editing
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批准号:10339415
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项目类别:
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资助金额:$81.25万
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财政年份:2019
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负责人:Kiran Musunuru
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依托单位:
Diagnosis, Prevention, And Treatment Of Cardiovascular Diseases With Genome Editing
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批准号:10112299
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项目类别:
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资助金额:$81.25万
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财政年份:2019
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负责人:Kiran Musunuru
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依托单位:
Diagnosis, Prevention, And Treatment Of Cardiovascular Diseases With Genome Editing
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批准号:9896848
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项目类别:
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资助金额:$81.08万
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财政年份:2019
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负责人:Kiran Musunuru
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依托单位:
Diagnosis, Prevention, And Treatment Of Cardiovascular Diseases With Genome Editing
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批准号:10561719
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项目类别:
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资助金额:$81.25万
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财政年份:2019
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负责人:Kiran Musunuru
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依托单位:
High-throughput screening and stem cell modeling of causal eQTL variants
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批准号:9242768
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项目类别:
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资助金额:$34.15万
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财政年份:2016
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负责人:Kiran Musunuru
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依托单位:
Stem Cells Models of Familial Combined Hypolipidemia
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批准号:9198670
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项目类别:
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资助金额:$40.15万
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财政年份:2016
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负责人:Kiran Musunuru
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依托单位:
Stem Cells Models of Familial Combined Hypolipidemia
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批准号:9212742
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项目类别:
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资助金额:$40.25万
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财政年份:2016
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负责人:Kiran Musunuru
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依托单位:
Functional studies of KLF14, a putative master regulator of metabolism
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批准号:8886598
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项目类别:
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资助金额:$38.03万
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财政年份:2015
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负责人:Kiran Musunuru
-
依托单位:
Stem Cell Models of Familial Combined Hypolipidemia
-
批准号:8420564
-
项目类别:
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资助金额:$41.89万
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财政年份:2013
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负责人:Kiran Musunuru
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依托单位:
High-throughput screening and stem cell modeling of causal eQTL variants
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批准号:8826773
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项目类别:
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资助金额:$31.4万
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财政年份:2013
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负责人:Kiran Musunuru
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依托单位:
Stem Cell Models of Familial Combined Hypolipidemia
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批准号:8792243
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项目类别:
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资助金额:$41.21万
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财政年份:2013
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负责人:Kiran Musunuru
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依托单位:
Stem Cell Models of Familial Combined Hypolipidemia
-
批准号:8603286
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项目类别:
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资助金额:$41.0万
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财政年份:2013
-
负责人:Kiran Musunuru
-
依托单位:
Genetic and functional analyses of a novel locus associated with LDL-C and MI
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批准号:8464344
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项目类别:
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资助金额:$24.9万
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财政年份:2010
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负责人:Kiran Musunuru
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依托单位:
Genetic and functional analyses of a novel locus associated with LDL-C and MI
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批准号:8066615
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项目类别:
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资助金额:$13.8万
-
财政年份:2010
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负责人:Kiran Musunuru
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依托单位:
Genetic and functional analyses of a novel locus associated with LDL-C and MI
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批准号:8531330
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项目类别:
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资助金额:$23.7万
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财政年份:2010
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负责人:Kiran Musunuru
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依托单位:
Genetic and functional analyses of a novel locus associated with LDL-C and MI
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批准号:8656389
-
项目类别:
-
资助金额:$24.4万
-
财政年份:2010
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负责人:Kiran Musunuru
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依托单位:
Genetic and functional analyses of a novel locus associated with LDL-C and MI
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批准号:7771138
-
项目类别:
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资助金额:$13.73万
-
财政年份:2010
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负责人:Kiran Musunuru
-
依托单位:
海外基金