Yale University has received a USD 1.38 million NIH cooperative agreement from the National Institute of Neurological Disorders and Stroke to develop a CRISPR-based genome editing therapy targeting the tau-coding gene MAPT as a treatment for Alzheimer's disease, with the first-year award covering the budget period from April 2026 through March 2027.
The project, led by a team of four principal investigators including Kevin Navin Sheth, Jiangbing Zhou, Stephen M. Strittmatter, and Yong-Hui Jiang, centers on a non-viral brain delivery platform called stimuli-responsive traceless engineering platform ribonucleoproteins, or STEP RNPs, to shuttle CRISPR machinery into neuronal cells following intrathecal administration. The research is entirely preclinical, with aims spanning delivery optimization in neuronal systems, characterization in mouse Alzheimer's disease models, and preliminary biodistribution and tau-reduction studies in nonhuman primates.
The grant is structured as a U01 cooperative agreement under funding opportunity RFA-NS-24-037, a mechanism that involves more active NIH program participation than a standard investigator-initiated R01 research project grant. The total first-year award of USD 1,379,599 comprises USD 821,801 in direct costs and USD 557,798 in indirect costs, administered through the Yale University School of Medicine's neurosurgery department. The overall project period extends to March 2031.
The scientific rationale draws on a body of preclinical and early clinical work establishing tau as a viable therapeutic target in Alzheimer's disease. Antisense oligonucleotide approaches targeting MAPT have demonstrated tau reduction and a generally acceptable safety profile in clinical testing, but ASO-based therapies require repeated administration to maintain efficacy because their effects are transient. The Yale team's central argument is that CRISPR-based somatic genome editing at the genomic level could, in principle, produce durable tau reduction from a single administration, removing the burden of repeated dosing that has constrained ASO programs.
The delivery challenge has historically been the rate-limiting step for brain-directed genome editing. Viral vectors carry immunogenicity and manufacturing concerns, while direct delivery of CRISPR ribonucleoproteins to the central nervous system has faced barriers related to efficiency and cell-type specificity. The STEP RNP platform is designed to address those barriers through stimuli-responsive chemistry that allows the RNP complex to shed its engineering modifications after reaching target cells, a feature the team describes as traceless. Preliminary work cited in the grant application showed that a single intrathecal dose of the lead STEP RNP construct, designated cRNP, produced brain-wide editing of neuronal cells and long-term therapeutic effects in models of neurodevelopmental disease, providing the translational rationale for extending the approach to Alzheimer's disease.
The three-aim structure of the project reflects a staged preclinical development pathway. The first aim focuses on optimizing STEP RNPs specifically for neuronal delivery and MAPT editing efficiency. The second aim moves into Alzheimer's disease mouse models to characterize the therapeutic effects of MAPT-targeted genome editing on tau pathology and behavioral outcomes. The third aim initiates nonhuman primate studies to assess RNP biodistribution and the degree of tau reduction achievable in a larger-brained species more relevant to eventual human translation.