Evaluating Focused Ultrasound as a Non-Invasive Strategy for Delivering AAV Gene Therapy in Rett Syndrome

Pahang, Denise Emily

Evaluating Focused Ultrasound as a Non-Invasive Strategy for Delivering AAV Gene Therapy in Rett Syndrome 10 views

Author

Pahang, Denise Emily, Biomedical Engineering - School of Engineering and Applied Science, University of Virginia 0009-0005-8463-2818

Advisors

Bajikar, Sameer , MD-CELL Cell Biology , University of Virginia

Abstract

Neurodevelopmental disorders (NDDs) affect a significant proportion of the pediatric population and are often caused by mutations in dosage-sensitive “Goldilocks” genes such as MECP2. Loss of function of MECP2 leads to Rett syndrome (RTT) while overexpression leads to MECP2 duplication syndrome. Although viral gene therapy has shown promise in restoring gene function and reversing disease phenotypes, clinical translation remains limited due to challenges in delivering therapeutics across the blood-brain barrier (BBB). Current approaches rely on one-time invasive intracranial or intrathecal injections, constraining precise control of gene dosage and increasing immune and safety risks.
To address this challenge, we evaluated focused ultrasound (FUS) as a strategy to transiently open the BBB and enable targeted delivery of adeno-associated virus (AAV) gene therapy delivered in a minimally invasive, systemic manner to a mouse model of Rett syndrome (Mecp2+/-). We first performed proof of concept studies using MRI and neuronavigation-guided FUS to demonstrate that FUS treatment caused localized BBB opening, with no evidence of edema or microhemorrhage. Evans Blue and cavitation detection showed that BBB opening, and safety characteristics were comparable to wild-type controls.
To assess delivery, AAV9-GFP vectors under neuron-specific (hSyn) or ubiquitous (CMV) promoters were intravenously administered during FUS. FUS-treated animals showed localized transgene expression while non-FUS controls exhibited no overt GFP signal. These findings support FUS as a non-invasive and scalable platform for targeted central nervous system (CNS) AAV delivery without invasive injections for Rett and other dosage-sensitive NDDs.

Degree

MS (Master of Science)

Keywords

Rett Syndrome; Focused Ultrasound; AAV Gene Therapy; Neurodevelopmental Disorders; Blood-Brain Barrier Opening

Language

English

Rights

Issued Date

2026-04-20

Suggested Citation

Pahang, Denise Emily. Evaluating Focused Ultrasound as a Non-Invasive Strategy for Delivering AAV Gene Therapy in Rett Syndrome. University of Virginia, Biomedical Engineering - School of Engineering and Applied Science, MS (Master of Science), 2026-04-20, https://doi.org/10.18130/cf6e-2k35.