Mapt-targeting genome editing therapy for alzheimer's disease - alzheimer's disease (ad) is a devastating condition without effective treatment

The National Institute of Neurological Disorders and Stroke awarded a cooperative agreement to Yale University on April 15, 2026, totaling $1.379 million under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853).

Yale is developing stimuli-responsive traceless engineering platform ribonucleoproteins (STEP RNPs) for brain delivery of CRISPR-based genome editing targeting the MAPT gene to reduce tau protein levels in Alzheimer's disease. The work encompasses three aims: optimizing STEP RNPs for tau-targeting genome editing delivery to neuronal cells; characterizing MAPT-targeting genome editing therapy in mouse models; and preliminarily characterizing RNP delivery and tau reduction in nonhuman primates. The research builds on Yale's prior demonstration that single intrathecal administration of genome editing via CRNP, a lead STEP RNP candidate, enabled brain-wide neuronal cell editing with long-term therapeutic effects in neurodevelopmental disease models.

Performance occurs in Connecticut from April 15, 2026, through March 31, 2031. The $1.379 million represents the obligated amount under this award.

Novel approaches to improving treatment are greatly needed. Accumulating evidence suggests TAU as a viable target for ad therapy. Recent preclinical studies have shown promise in TAU-targeting molecular therapy through suppression of the TAU-coding gene mapt using antisense oligonucleotides (asos). These findings have led to clinical tests, showing TAU reduction therapy to be generally safe and well-tolerated. However, ASO-based therapy is transient, requiring frequent administration for long-term efficacy. Conversely, crispr-based genome editing technology can induce genetic knockouts at the genomic level, offering persistent therapeutic benefits. The most significant hurdle for clinical translation of genome editing therapies has been the lack of safe and efficient delivery methods for the crispr machinery to the brain. In this application, we aim to leverage our recent success in development of stimuli-responsive traceless engineering platform ribonucleoproteins (step rnps) for delivery of crispr-based genome editing to the brain to demonstrate the potential of TAU-targeted genome editing therapy for treatment of ad. In preliminary work, we showed that a single intrathecal administration of genome editing therapy via crnp, a lead step RNP, enabled brain-wide editing of neuronal cells and achieved long-term therapeutic effects for neurodevelopmental diseases. Building on this progress, we propose to optimize step rnps for delivery of genome editing to neuronal cells for TAU reduction in aim 1, to characterize mapt-targeting genome editing therapy for ad treatment in mouse models in aim 2 and to preliminarily characterize RNP delivery and TAU reduction in nonhuman primates (nhps) in aim 3. Successful completion of this application could result in a long-lasting therapy for effective ad management through a single administration and provide a non-viral system for safe and efficient delivery of genome editing to the brain, adaptable for targeting other ad-causing or associated genes.