A Novel Vector Strategy to Feasibilize Cellular Therapy for Heart Disease
A Novel Vector Strategy to Feasibilize Cellular Therapy for Heart Disease
批准号:
10746971
负责人:
Zhi Hong Lu
金额:
$19.44万
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
项目状态:
未结题
起止时间:
2023-08-01 至 2025-07-31
关键词:
AddressAdenovirusesAdverse effectsBiomedical EngineeringCAR T cell therapyCapsidCell TherapyChemistryClinicalClustered Regularly Interspaced Short Palindromic RepeatsCouplingDNADependovirusDevelopmentDiseaseEngineeringFiberGene ExpressionGenerationsGenesGeneticGenetic TranscriptionGenomeGuide RNAHeartHeart DiseasesHumanImaginationIn SituIn VitroInterventionKnock-inLinkMediatingMethodsMusNational Heart, Lung, and Blood InstituteOrganPan GenusPatientsProductionProteinsReportingRunningSafetySerotypingSimian AdenovirusesSpecificitySumSurfaceSystemT-LymphocyteTechniquesTechnologyTimeTissuesTransgenesViralVirusbase editingcell typechimeric antigen receptor T cellsclinical practicecoronary fibrosiscostdelivery vehicledesigngene delivery systemimprovedin vivomouse modelnanovectorneoplasticnovelpractical applicationpragmatic implementationreceptorrepairedtechnology platformtechnology validationtherapeutic genome editingtransduction efficiencytransgene expressionvector
中文摘要
摘要
英文摘要
ABSTRACT
Recently, the potential of cellular therapy based upon genetic reprogramming of T cells via CAR-T technology
has been explored for diseases of the heart, and the promise embodied in this strategy has captured popular
and scientific imagination. However, in current clinical CAR-T cell therapy practice, extracorporeal methods must
be applied, which represent a major time and cost barrier restricting wider implementation of this technology.
Thus, robust methods to generate CAR-T in situ, within the patients, would greatly facilitate the practical
application of this promising approach. For this, we propose to develop a robust gene delivery system consisting
of a conjoined “SAd.AAV” nano-vector with multiple T cell-tropic adeno-associated viruses (AAVs) conjugated to
a clinically approved, T-cell tropic simian (chimpanzee) adenovirus 36 (SAd) on its capsid's surface. Of note,
both capsid-engineered SAd and AAVs are able to selectively target various tissues including T cells with high
transduction efficiencies, and we hypothesized that SAd.AAV may therefore provide superior targeting through
the combined effects of both engineered viral capsids targeting different receptors on the same tissue or cell
type. Importantly, AAVs carrying single-stranded knock-in donor DNA templates have been widely shown to
support high editing efficiency of homology directed repair (HDR). Furthermore, the robust but transient
expression of gene editor by SAd also provides highly desirable “hit-and-run” gene editing reducing potential
adverse effects associated with prolonged editor expression after the on-target editing is achieved. Therefore,
by virtue of the advantages of each virus in gene editing, SAd.AAV potentially increases the tissue targeting
specificity and efficiency and improves safety of existing CRISPR-Cas gene editing therapies. As a proof of
concept, after constructing and characterizing the first T cell-targeted SAd.AAV, we plan to achieve efficient
production of the heart disease-specific CAR-T cells in vivo with an SAd.AAV gene editing platform to knock-in
a switchable CARi transgene in the T cells in vivo. A proof-of-principle demonstration of in vivo production of
gene-edited switchable CARi-T cells will establish a key platform for follow-on studies of CARi-T interventions in
murine models of heart diseases. We furthermore anticipate that the SAd.AAV can be rapidly redesigned to
target a wide variety of clinically important organs relevant to the NHLBI for gene editing-based therapies.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Correction of globin gene mutations by gene targeting
-
批准号:6792313
-
项目类别:
-
资助金额:$5.05万
-
财政年份:2004
-
负责人:Zhi Hong Lu
-
依托单位:
Correction of globin gene mutations by gene targeting
-
批准号:6904426
-
项目类别:
-
资助金额:$5.35万
-
财政年份:2004
-
负责人:Zhi Hong Lu
-
依托单位:
海外基金