U01DA054170

Advancing Brain Health Research Through Male Germline Editing in Marmosets - Project Summary/Abstract

Neuropsychiatric disorders represent a leading cause of disability, affecting nearly 19% of the US population. Only 9% of neuropsychiatric drugs entering clinical trials reach the market, which is one of the lowest success rates across all therapeutic areas. Fundamental differences between the neurobiology of rodents and humans have been proposed to account for translational failures in the development of effective therapeutic strategies to mitigate neurological or neurodegenerative diseases or disorders. Rodent behavioral assays are also variably effective in predicting clinically effective neuropsychiatric drugs. Nonhuman primates (NHPs) are recognized as a valuable, clinically relevant alternative to span the gap between rodents and humans in the development of therapies designed to advance brain health. Among NHPs, the common marmoset [Callithrix jacchus (CJ)] affords a highly tractable option because of its small size, short lifespan, production of multiple offspring/year, and accurate recapitulation of human neuroanatomy. However, the ultimate utility of the marmoset model remains in its infancy due to the paucity of efficient tools to facilitate studies requiring genetic modification, especially those needed to recapitulate complex aspects of brain health. To address this urgent need, we propose an innovative, more efficient approach to achieve gene editing and transgenesis in marmosets based on the novel use of highly manipulable induced pluripotent stem cells (iPSCs) that can be differentiated to form male germ cells that can ultimately be used to produce transgenic offspring carrying precisely edited alleles of genes relevant to brain health and disease. Specifically, we will combine 1) close proximity to one of two NIH-designated marmoset breeding colonies, maintained at the Southwest National Primate Research Center, 2) experience with NHP pluripotent stem cells, iPSC derivation, and CRISPR/Cas9 editing, 3) a novel strategy to produce transplantable male germ cells from edited CJiPSCs, 4) documented expertise transplanting NHP germ cells into testes to produce sperm, 5) published experience in the use of cutting-edge single-cell genomics and multiparametric integrative epigenomics to assess normality of any cell type, and 6) leading expertise in brain health and disease in general and the neurogenetics of epilepsy in particular. In Aim 1, we will use CRISPR editing to generate mutant ARX alleles and reporter transgenes in CJiPSCs. In Aim 2, we will optimize derivation and transplantation of male CJiPSC-derived germ cells into recipient testes and grafts to foster development of transgenic sperm. In Aim 3, we will assess the impact of ARX mutations on marmoset cortical neuron development and migration. Together, these aims are designed to advance the utility of the marmoset model for brain research based on CRISPR/Cas9 editing of CJiPSCs, male germline-mediated transgenesis, development of CJiPSC-derived brain organoids, and specific knowledge of the neurological impact of ARX mutations.

The University Of Texas At San Antonio

TO SUPPORT BASIC AND CLINICAL NEUROSCIENCE, BIOMEDICAL, BEHAVIORAL AND SOCIAL SCIENCE, EPIDEMIOLOGIC, HEALTH SERVICES AND HEALTH DISPARITY RESEARCH. TO DEVELOP NEW KNOWLEDGE AND APPROACHES RELATED TO THE PREVENTION, DIAGNOSIS, TREATMENT, ETIOLOGY, AND CONSEQUENCES OF DRUG ABUSE AND ADDICTION, INCLUDING HIV/AIDS. TO SUPPORT RESEARCH TRAINING AND RESEARCH SCIENTIST DEVELOPMENT. TO SUPPORT DISSEMINATION OF RESEARCH FINDINGS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) LEGISLATION IS INTENDED TO EXPAND AND IMPROVE THE SBIR PROGRAMS TO EMPHASIZE AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF TECHNOLOGY DEVELOPED THROUGH FEDERAL SBIR RESEARCH AND DEVELOPMENT, INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN THE SBIR PROGRAM. THE LEGISLATION INTENDS THAT THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.279 - Drug Abuse and Addiction Research Programs

National Institute on Drug Abuse (NIDA) [HHS - NIH]

San Antonio, Texas 782491644 United States

Single Zip Code

BRAIN Initiative: Tools for Germline Gene Editing in Marmosets (U01 - Clinical Trial Not Allowed) (RFA-DA-21-006)

Amendment Since initial award the total obligations have increased 370% from $2,568,733 to $12,061,296.