Rewiring Decline: Targeting Early Neurodegeneration in Sanfilippo Syndrome Through Gene Correction and Molecular Parallels with Alzheimer’s Disease

Abstract

Sanfilippo syndrome (MPS III) is a rare but very serious neurodegenerative disorder that affects children. It happens when the body can’t break down a molecule called heparan sulfate, which then builds up in the brain and causes inflammation, damage, and shrinkage over time. Most kids look healthy when they’re born, but between ages two and six, they start losing speech and motor skills, and the diagnosis usually comes too late. This project focuses on figuring out what happens early in the brain, fixing the genetic glitch that causes it, and finding a way to get that fix where it actually works.

The first aim looks at early brain changes in Sanfilippo and compares them to Alzheimer’s to see if the same patterns show up in gene expression or inflammation. The second aim uses CRISPR to fix the mutated gene in patient-derived neurons and see if that helps the cells recover. The third aim is about building a delivery system that can cross the blood-brain barrier using monoclonal antibodies so that treatment can actually reach the brain.

All three aims build on each other. If this works, it could finally give better options for Sanfilippo and maybe even help us understand other neurodegenerative diseases too.