A new method developed by a research team led by Jerzy Szablowski of Rice University offers hope for treating brain disorders through gene therapy. The innovative approach could transform treatments for inherited conditions and mental health issues by targeting specific brain regions with new precision. The researchers’ work was recently published in Nature Communications.
Gene therapy can potentially correct genetic defects, but delivering therapeutic genes to the brain has presented significant challenges. Traditional noninvasive methods lack efficacy, target the entire brain versus only diseased regions, and may affect healthy tissue, leading to potential toxicity.
“A commonly used alternative is to drill a hole in the skull and insert a needle into the brain, but this operation is invasive and carries its own risks,” said Szablowski, an assistant professor of bioengineering.
The research team has developed a process that allows the vectors, or vehicles used to deliver genetic material to brain cells, to enter the target regions while preventing the cells from bleeding. The technique involves injecting modified gene delivery vectors into the bloodstream, enabling them to travel to the brain.
Some vectors used by clinics called adeno-associated viral vectors (AAVs) can enter the brain after focused ultrasound treatment, but they tend to enter the brain with limited efficiency and transduce many other tissues within the body. Researchers have modified AAVs to give them the ability to propagate more efficiently.
The researchers hypothesized that by modifying the vector layer they could find protein sequences that result in improved distribution in the brain, but only in regions stimulated with ultrasound. Furthermore, they theorized that they could find vectors that could simultaneously reduce liver transduction, which is one of the main targets of common gene delivery vectors and one of the biggest sources of toxicity in gene therapies.
To identify the best vectors, the researchers injected 1.3 billion variants into mice and stimulated specific brain regions with ultrasound. They discovered thousands of promising candidates by extracting and analyzing vectors from these regions. Through rigorous testing, they identified several vectors that demonstrated improved brain delivery and minimized liver targeting.
“Engineering gene therapy vectors has been done for years, promising results with the potential to treat disorders that affect the entire brain,” Szablowski said. “This work is the first time to combine engineered vectors and focused ultrasound delivery.”
The new method presents a non-invasive way to deliver genes to specific areas of the brain, making it particularly suitable for treating disorders that occur in specific areas of the brain, such as psychiatric disorders. The team’s research showed that combining ultrasound with the engineered vectors improved the specificity of brain versus liver delivery by about 1,000-fold compared to clinically used AAVs without focused ultrasound treatment.
“This is an important improvement because higher liver transduction may limit toxicity,” Szablowski said. “And the improved efficiency of brain delivery means that lower doses of vectors are needed, potentially lowering the cost of gene therapy.”
The research team includes Rice bioengineering graduate student Manwal Harb; former Rice research assistant James S. Trippett; Ph.D. candidates in biology at the California Institute of Technology Hongyi R. Li and John E. Heath; and Mikhail G. Shapiro, professor of chemical and medical engineering at Caltech.
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