Pilot of a new non-viral vector for therapeutic nucleic acid delivery to the CNS

Over 7 million Americans suffer from Alzheimer’s Disease (AD), presenting a major health burden to patients and their caregivers, and claiming over a hundred thousand lives annually. AD remains without any effective cure or treatments, despite decades of research into small molecule- and antibody-based therapeutics. In contrast, next-generation therapeutic nucleic acids (TNAs) such as short interfering RNAs (siRNAs), anti-sense oligonucleotides (ASOs), and messenger RNAs (mRNAs) have major potential to treat AD due to their ability to modulate the expression of nearly any gene in any cell-type, if only they can be delivered safely and effectively to target brain cells that reside across the blood-brain barrier. Non-viral vectors are a promising new class of delivery vectors that could in principle transport TNAs to specific regions and cell types of the brain for potent, durable gene modulation to revolutionize clinical treatment of AD and other neurodegenerative and neurological disorders and diseases. The intrathecal administration route has emerged as a leading technique for delivering TNAs as it bypasses the intractable problems associated with blood-brain barrier crossing and is well-suited for clinical translation. However, there is a lack of non-viral delivery technologies that are well tolerated with wide therapeutic windows, can incorporate several different TNA modalities including both oligonucleotide and long nucleic acid cargos, can be repeatedly administered, are simple to manufacture to treat large patient populations, and can target specific regions and cell types of the CNS. Nucleic acid nanoparticles (NANPs) are a unique, new non-viral vector that address many of the desired performance properties. This project seeks to develop NANP formulations that distribute to specific CNS regions and cell types after intrathecal administration to deliver therapeutic siRNAs and mRNAs for downstream treatment of AD. Success of this research would establish a non-viral vector for these therapeutic modalities that can be used to treat AD and a range of neurological and neurodegenerative disorders of the CNS beyond AD. Project Number: 1R21AG099044-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Mark Bathe (+1 co-PI) | Institution: MASSACHUSETTS INSTITUTE OF TECHNOLOGY, CAMBRIDGE, MA | Award Amount: $466,340 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 BBBT-X (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11301088