Key Points
- Researchers used in vivo selection to engineer new adeno-associated virus vectors specifically designed for brain gene therapy delivered with focused ultrasound blood-brain barrier opening.
- The newly created gene vectors provided more than a ten-fold improvement in delivering genes to specific regions of the brain.
Engineering Viral Vectors for Acoustically Targeted Gene Delivery
A collaborative team of researchers from Rice University and Caltech recently published their preclinical work using high throughput in vivo selection to engineer new adeno-associated virus (AAV) vectors specifically designed for local neuronal transduction following focused ultrasound blood-brain barrier opening (FUS-BBBO).
Led by Jerzy Szablowski, PhD, at Rice University and Mikhail Shapiro, PhD, at Caltech, the group created gene vectors that provided more than a ten-fold improvement in delivering genes to specific regions of the brain.
“This is an important improvement because higher liver transduction can limit toxicity,” said Dr. Szablowski in Rice University’s press release. “And the improved efficiency of brain delivery means that lower doses of vectors would be needed, potentially reducing the cost of gene therapy.”
Although FUS-BBBO enables AAVs to enter the brain from the bloodstream, natural AAV serotypes have inefficient transduction in the brain plus undesirable transduction into other organs. To address these issues, this research team developed new in vivo techniques for engineering AAV vectors for use with FUS-BBBO. The techniques were successful in improving gene delivery and neuronal transduction at the targeted sites in two different mouse strains tested. Unwanted off-target effects were also reduced.
“Optimizing capsids for use with FUS-BBBO for gene therapy delivery to the brain is a topic of great interest in the focused ultrasound and gene therapy community,” says Frédéric Padilla, PhD, the Foundation’s Gene Therapy Program Director. “This topic was discussed during the Foundation’s fall 2023 Focused Ultrasound for Gene and Cell Therapy workshop, and the Foundation is now pleased to be funding the next phase of this research, which will further optimize the technology.”
If translation to human trials becomes possible, FUS-BBBO–mediated targeted gene delivery to the brain could significantly change the way that many diseases are treated.