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CCR5-mutant monkey model to facilitate the development of novel stem cell-based therapies for AIDS

CCR5突变猴模型促进新型干细胞艾滋病疗法的开发

基本信息

批准号：
9140295
负责人：
THADDEUS G GOLOS
金额：
$ 76.44万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9140295
关键词：
Acquired Immunodeficiency Syndrome Address Allogeneic Bone Marrow Transplantation Allogenic Animals Anti-Retroviral Agents Asians Blood typing procedure Bone Marrow Transplantation CCR5 gene CRISPR/Cas technology CXCR4 gene Cell Line Cell Therapy Cell Transplantation Cells Chlamydia trachomatis Clinical Communicable Diseases Controlled Study Cryptococcus neoformans Development Disease Embryo Engraftment Evaluation Founder Generation Gene-Modified Genes Genetic HIV HIV Infections Haplotypes Hematopoietic Neoplasms Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Hereditary Disease Human In Vitro Infection Institutes Institution Latent Virus Listeria Macaca Macaca fascicularis Methods Modeling Monkeys Mutation Mycobacterium tuberculosis National Heart, Lung, and Blood Institute National Institute of Allergy and Infectious Disease National Institute of Child Health and Human Development National Institute of Neurological Disorders and Stroke Observational Study Patients Plasmodium Predisposition Primates Regimen Research Research Personnel Resource Development Risk SIV Sexual Maturation Simplexvirus Stem cells Techniques Technology Toxoplasma gondii Translations Transplantation Trypanosoma cruzi United States National Institutes of Health Viral Viral reservoir Virus West Nile viral infection West Nile virus Wisconsin blood group cancer genetics genome editing graft vs host disease induced pluripotent stem cell leukemia mutant nonhuman primate novel public health relevance purge simian human immunodeficiency virus standard of care vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): Hematopoietic stem cell (HSC) transplantation has become a standard of care for the treatment of otherwise incurable blood cancers and genetic diseases. The cure of HIV by transplanting CCR5-mutant (CCR5-delta32) HSCs demonstrated the feasibility and power of stem cell-based therapies for eliminating latent virus and controlling AIDS. However, it will be critical to define the spectrum of anti-viral protection, the engraftment threshold of CCR5-mutant HSCs required for protection, and the potential for depletion of the virus reservoir through "allo-effect" following allogeneic HSC transplantation, to facilitate translation to human patients. We propose to develop an MHC-defined CCR5-mutant nonhuman primate (NHP) bone marrow transplantation model at the Wisconsin National Primate Research Center (WNPRC) to address the critical questions of HSC-based therapies for HIV. This model will employ Mauritian Cynomolgus monkeys (MCMs) with well-defined MHC to control genetic factors in the setting of allogeneic bone marrow transplant. In aim 1, we will use CRISPR/Cas9 methods in MCM induced pluripotent stem cell (iPSC) lines to optimize efficient targeting of the MCM CCR5-locus with minimal off-target effects. In aim 2, we will confirm the feasibility and accuracy of CCR5 genomic editing in IVF-derived MCM embryos and generate CCR5-mutant MCMs. In aim 3, we will evaluate the engraftment of WT and CCR5-mutant HSCs in SHIV-infected, MHC and blood group identical MCM recipients using a myeloablative BMT regimen and assess the effect of these transplants on persistence of SHIV infection. The proposed studies will establish a CCR5-mutant MHC- defined NHP model and will demonstrate utility for evaluation of HSC-based therapies for AIDS. Development of these resources will benefit AIDS researchers at multiple NIH institutions, including ORIP, NHLBI, NIAID, NIDKK, NICHD, and NINDS. Although CCR5-mutant mutation protects from HIV infection, the lack of CCR5 is also associated with increased susceptibility to West Nile virus infection, and other infections including Toxoplasma gondii, Mycobacterium tuberculosis, Chlamydia trachomatis, Listeria, and Plasmodium. Thus, for example, access to CCR5-mutant NHPs will open unique opportunities to establish NHP models for West Nile infection for evaluation of vaccine efficacy and advance the use of NHPs for studies of other infections which may require CCR5-mutant hosts to reproduce a disease course observed in susceptible humans. In addition, advances in gene editing technologies in NHP models will facilitate their clinical translation for treatment of genetic disorders in humans.