The Promise Of Focused Ultrasound For AAV Gene Therapy Delivery

By Erin Harris, Editor-In-Chief, Cell & Gene
Follow Me On Twitter @ErinHarris_1

Gene therapy’s success hinges on delivery, especially to the brain, where the blood-brain barrier (BBB) remains a formidable obstacle. At Brigham and Women’s Hospital and Harvard Medical School, Research Fellow in Radiology, Bernie Owusu-Yaw, Ph.D., is tackling this challenge head-on. Her work focuses on combining focused ultrasound (FUS) with novel AAV capsids to safely and efficiently deliver gene therapies to the brain. I had the pleasure of talking to Dr. Owusu-Yaw recently, and she shared insights into her research, how it’s evolving, and why it could reshape the landscape of neurological gene therapy.

From Genetic Models to Gene Therapy

Dr. Owusu-Yaw’s journey began in the lab as a neuroscientist focused on rare prion diseases. Her Ph.D. research involved developing humanized mouse models, using both traditional genetic engineering and CRISPR, to study the Prnp Y163X mutation. Unlike typical prion diseases, this mutation manifests with chronic diarrhea and peripheral neuropathy, providing a unique lens through which to examine how prions propagate from peripheral systems to the brain.

That early exposure to gene editing and the molecular underpinnings of neurological disease sparked her interest in therapeutic innovation. A seminar on gene therapies for neurological conditions at Great Ormond Street Hospital deepened that interest and steered her toward postdoctoral research in gene therapy approaches for pediatric epilepsies. Today, under the mentorship of Professor Nicholas Todd, Dr. Owusu-Yaw’s work at Brigham and Women’s has pivoted toward optimizing gene delivery using focused ultrasound.

Targeting the Brain with Precision

Focused ultrasound, when paired with intravenously injected microbubbles, can transiently and non-invasively open the BBB. This temporary permeability allows systemically administered therapeutics — including AAV vectors — to enter the brain. But opening the BBB safely and effectively requires fine-tuning. Dr. Owusu-Yaw’s team selected treatment parameters, intensity, pressure, and microbubble dosage, by balancing efficacy and safety. “We were guided by both safety and efficacy data from prior preclinical studies in mice,” she said. “Our goal was to reliably open the BBB while minimizing the risk of tissue damage such as microhemorrhages.”

Advancing AAV Performance

An equally critical piece of the puzzle is the choice of AAV serotype. While AAV9 showed initial promise, it achieved only modest neuronal transduction (2–10%) in the striatum following ultrasound-mediated BBB opening. A collaborative effort with Dr. Fengfeng Bei led to the development and use of a new AAV-BCP capsid that dramatically increased efficacy, achieving over 40% neuronal transduction in the targeted brain region. “These novel capsids include cell-penetrating peptides in the receptor-binding region,” Dr. Owusu-Yaw explained. “That likely enhances their ability to cross the BBB. Focused ultrasound amplifies this effect, making the combination especially powerful.”

Bridging the Gap to Human Trials

With any new delivery method, safety is paramount. Dr. Owusu-Yaw and her colleagues used Hematoxylin and Eosin staining to assess tissue damage in preclinical models and found no evidence of hemorrhage, even at higher levels of ultrasound exposure. For translation to human studies, more scalable, non-invasive imaging techniques will be required.

Moving from preclinical mouse models to human applications poses a range of challenges, including scaling ultrasound parameters, ensuring precision targeting in a larger and more complex brain, and managing the potential systemic toxicity of AAV vectors. “Our current systems allow for ultrasound steering across multiple user-defined targets, enabling larger and more customizable BBB opening volumes,” Dr. Owusu-Yaw said.

This ability becomes especially important when considering diseases like Huntington’s and Parkinson’s, which affect specific brain regions. Notably, focused ultrasound has already demonstrated safety and reversibility in clinical trials for other CNS diseases including ALS, Alzheimer’s, and glioblastoma.

The next frontier is combining FUS with AAVs — safely. “We’re working to reduce required AAV doses and further improve targeting using cell-specific promoters or liver-detargeted capsids,” she said.

Huntington’s and Parkinson’s in Focus

Given the enhanced neuronal uptake achieved with the novel capsids and FUS, Dr. Owusu-Yaw sees particular promise in neurodegenerative diseases with region-specific pathology. “Huntington’s and Parkinson’s are ideal candidates,” she said. “In Huntington’s, the striatum is primarily affected. In Parkinson’s, it’s the substantia nigra. Focused ultrasound allows us to target these regions with unprecedented precision.”

As Dr. Owusu-Yaw and her team continue to test their methods in non-human primates and refine clinical-scale systems, the path to translation is becoming clearer. “The preclinical data, especially with the new AAV capsids, are extremely encouraging,” she said. “We believe this work will serve as a foundation for clinical trials and ultimately, patient treatment.”

For diseases that have long been constrained by delivery barriers, Dr. Owusu-Yaw’s research offers a new horizon. By combining focused ultrasound and next-generation AAV engineering, this approach may unlock gene therapy’s full potential for the brain, bringing hope to patients with previously untreatable neurological diseases.