Developing a Noninvasive Gene Therapy for Alzheimer's Disease

We aim to develop a non-invasive, nanoparticle-based therapy that delivers small interfering RNA into the brain to silence CD33, an Alzheimer’s risk gene, and slow disease progression.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and a leading cause of dementia, yet effective treatments remain unavailable. This project explores a novel strategy targeting CD33, an immune receptor regulating microglial activity. Using a novel humanized CD33 mouse model, we will deliver siRNA molecules via proprietary nanoparticles designed for microglial uptake and evaluate their CD33 silencing potential. Importantly, we will use an intranasal delivery route to enable direct access of these particles to the brain. This work could advance RNA-based therapies for AD.

While CD33 is a well-validated genetic risk factor for Alzheimer’s disease, no therapeutic currently exists to lower CD33 in the brain, a gap this proposal directly addresses. Our approach is the first to combine optimized CD33 siRNA with a head-to-head comparison of nanoparticle chemistries and non-invasive routes (including intranasal delivery, which bypasses the blood-brain barrier) in a humanized CD33 mouse model that recapitulates the human protein targeted in patients. This integrated platform, drug, carrier, route, and disease-relevant model tested together, provides a translationally meaningful path that conventional gene therapy approaches have not yet achieved.

If successful, this work will deliver the first non-invasive, gene-targeted therapy for Alzheimer’s disease aimed at microglia, the brain’s immune cells, offering patients a potential treatment that addresses a root genetic driver of the disease rather than only its symptoms. Beyond Alzheimer’s, the optimized nanoparticle platform will provide a generalizable strategy for delivering RNA-based therapeutics to the brain, accelerating drug development for other neurodegenerative and neurological disorders. More broadly, validating nanoparticle delivery as a route to silence genes in microglia could reshape how the field approaches gene therapy for the central nervous system.