Liver Xenotransplantation using CRISPR-modified Porcine Organs
使用 CRISPR 修饰的猪器官进行肝脏异种移植
基本信息
- 批准号:10333323
- 负责人:
- 金额:$ 75.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdhesionsAllograftingAnimal OrganAntibodiesBindingBloodBlood Coagulation DisordersBlood Coagulation FactorBlood PlateletsCRISPR/Cas technologyCandidate Disease GeneCardiacCellular ImmunityClinicalClustered Regularly Interspaced Short Palindromic RepeatsCoagulation ProcessComplementConsumptionCryopreservationDataEndogenous RetrovirusesEngineeringEvaluationFamily suidaeFrightFunctional disorderGenesGeneticGenetic EngineeringGoalsHeartHumanImmune responseImmunologicsImmunosuppressionInfectionInflammationInfusion proceduresInjuryInvestigationIschemiaKidneyKnock-inKnock-outLifeLiverModelingModificationOrganOrgan DonorOutcomePapioPathway interactionsPatientsPerfusionPhysiologicalPrimatesProductionProtein EngineeringProteinsRecoveryRegimenReperfusion InjuryReperfusion TherapyReportingResourcesRiskSavingsSiteSourceSpecificitySystemTechniquesTechnologyTestingTimeTissuesTransplantationTreatment ProtocolsVertebral columnWorkXenograft procedureZoonosesadaptive immune responseallotransplantattenuationclinical applicationclinically relevantdesignex vivo perfusionexperiencegenetic payloadgraft dysfunctionheart xenograftimprovedimproved outcomein vitro Assayin vivoindustry partnerliver transplantationliver xenograftnovelpig genomeporcine modelpreventprotein protein interactionsuccesssynergismtooltransmission processtransplant modeltransplantation therapyvascular bed
项目摘要
PROJECT SUMMARY / ABSTRACT
Liver transplantation has failed to reach its full potential for saving lives due to the inadequate organ supply.
Every year thousands of potentially salvageable patients die awaiting an allograft, hundreds of others receive a
`marginal” donor organ, often in desperate circumstances, and a many times this number of potential recipients
are never offered listing for lifesaving organs due to the need to ration this precious but limited resource. Liver
xenotransplantation offers a potential solution to the organ shortage but clinical application has been stymied
by four principle hurdles: 1) risk of zoonotic infection of humans, 2) the vigorous immune response mounted to
xenogeneic tissues, and 3) physiologic incompatibilities due to species divergence arising in a rarity of protein:
protein interactions, and if these obstacles can be consistently overcome, the 4) need to identify a clinically
applicable IS regimen.
A new tool with unprecedented potential to address these barriers to widespread application of
xenotransplantation is found in technology such as CRISPR-Cas9 that dramatically increases gene editing
specificity and efficiency. A powerful example is found in recent work by our industry partner, eGenesis, who
used CRISPR-Cas9 to rid the pig genome of 62 copies of functional porcine endogenous retroviruses
(PERVs), essentially eliminating the risk of PERV transmission to an organ recipient. In the current proposal,
we explore the ability of advanced gene editing to address immunologic and physiologic barriers that cause
immediate graft dysfunction of liver xenografts when transplanted into a translational baboon model.
With the general goal preventing initial xenograft dysfunction (IXD) to gain long term survival of pig liver
xenografts in baboon recipients, studies in Aim I will focus on two recently identified potential impediments to
xenograft survival: 1) ischemia reperfusion injury, and 2) platelet consumption. Recent findings in cardiac
xenotransplantation studies have exposed the critical contribution of IR injury to early heart xenograft demise.
Our wealth of experience with ex vivo liver perfusion and also xeno liver perfusion with human blood and the
recently reported technique for ischemia free liver transplants should yield a definitive answer to this question.
Aim II will focus on understanding the impact of gene edits that: 1) eliminate expression of the three major
antibody targets of preformed human anti-pig antibodies, 2) gain expression of human proteins designed to
address complement and coagulation dysregulation occurring with porcine liver xenotransplants in NHP, and
3) mitigate innate and cell-mediated immunity and inflammation. To accomplish this, we will take advantage of
liver transplant, ex vivo liver perfusion with human blood and in vitro assays well established in our lab and a
panel of CRISPR modified pigs with varied expression of genetic edits.
项目摘要/摘要
项目成果
期刊论文数量(0)
专著数量(0)
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专利数量(0)
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JAMES FRANCIS MARKMANN其他文献
JAMES FRANCIS MARKMANN的其他文献
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{{ truncateString('JAMES FRANCIS MARKMANN', 18)}}的其他基金
Liver Xenotransplantation using CRISPR-modified Porcine Organs
使用 CRISPR 修饰的猪器官进行肝脏异种移植
- 批准号:
10089398 - 财政年份:2020
- 资助金额:
$ 75.49万 - 项目类别:
Liver Xenotransplantation using CRISPR-modified Porcine Organs
使用 CRISPR 修饰的猪器官进行肝脏异种移植
- 批准号:
9974026 - 财政年份:2020
- 资助金额:
$ 75.49万 - 项目类别:
Liver Xenotransplantation using CRISPR-modified Porcine Organs
使用 CRISPR 修饰的猪器官进行肝脏异种移植
- 批准号:
10561616 - 财政年份:2020
- 资助金额:
$ 75.49万 - 项目类别:
Expanding the Liver Transplant Organ Pool through Ex Vivo Liver Perfusion
通过离体肝脏灌注扩大肝移植器官库
- 批准号:
9310237 - 财政年份:2016
- 资助金额:
$ 75.49万 - 项目类别:
Mechanisms of B Cell-Dependent Transplantation Tolerance
B 细胞依赖性移植耐受的机制
- 批准号:
8608994 - 财政年份:2006
- 资助金额:
$ 75.49万 - 项目类别:
Mechanisms of B Cell-Dependent Transplantation Tolerance
B 细胞依赖性移植耐受的机制
- 批准号:
8811397 - 财政年份:2006
- 资助金额:
$ 75.49万 - 项目类别:
Mechanism of anti-CD45 induced transplantation tolerance
抗CD45诱导移植耐受的机制
- 批准号:
7599695 - 财政年份:2006
- 资助金额:
$ 75.49万 - 项目类别:
Mechanism of anti-CD45 induced transplantation tolerance
抗CD45诱导移植耐受的机制
- 批准号:
7557931 - 财政年份:2006
- 资助金额:
$ 75.49万 - 项目类别:
Mechanisms of B cell-Dependent Transplantation Tolerance
B 细胞依赖性移植耐受的机制
- 批准号:
10062841 - 财政年份:2006
- 资助金额:
$ 75.49万 - 项目类别:
Mechanisms of B cell-Dependent Transplantation Tolerance
B 细胞依赖性移植耐受的机制
- 批准号:
10308033 - 财政年份:2006
- 资助金额:
$ 75.49万 - 项目类别:
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