MAPT-targeting genome editing therapy for Alzheimer's Disease

Alzheimer’s disease (AD) is a devastating condition without effective treatment. 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. Project Number: 1U01NS145214-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Jiangbing Zhou (+3 co-PIs) | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $1,379,599 | Activity Code: U01 | Study Section: Special Emphasis Panel[ZNS1 SRB-Q (13)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11233424