Researchers at Children's Hospital of Philadelphia (CHOP) have developed new adeno-associated viral (AAV) vectors that can deliver gene therapies to the brain at significantly lower doses than current treatments, potentially revolutionizing treatment for neurodegenerative disorders. The findings, published in Science Translational Medicine and Nature Communications, demonstrate how these engineered vectors could improve safety and reduce costs for patients with conditions like Batten disease and Huntington's disease.
The research team, led by Professor Beverly Davidson, PhD, Director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at CHOP, engineered advanced AAV vectors that can precisely target relevant brain cells and structures while requiring substantially lower doses than current AAV-based therapies.
Solving Key Challenges in Gene Therapy
"One of the main issues plaguing gene therapies today is low potency. This results in high doses being required to reach therapeutic levels. High doses increase both patient safety issues and the cost of goods per patient," explained Davidson. "Our research has solved these problems, establishing the potential to create gene therapies that require lower doses and directly target cells needed for these disease indications."
AAV vectors serve as delivery vehicles that transport modified genetic material into the nuclei of cells in tissues affected by disease. They offer the possibility of one-time precision therapies for inherited diseases, but current approaches often require high doses that raise safety concerns and treatment costs.
Novel Capsids for Targeted Delivery
In the first study, published in Science Translational Medicine on May 14, 2025, Davidson's team screened millions of capsid variants to identify those capable of reaching target cells for long-term secretion of therapeutic proteins. They discovered the capsid AAV-Ep+, which proved highly effective in delivering therapeutic products to ventricular lining cells and cerebral neurons.
The researchers demonstrated that AAV-Ep+ was effective in a preclinical model of Batten disease, a childhood-onset neurodegenerative disorder, as well as in human neurons derived from induced pluripotent stem cells. This approach could potentially provide lifelong enzyme replacement in the brain following a single treatment.
The second study, published in Nature Communications on May 19, 2025, identified another capsid, AAV-DB-3, specifically designed for targeting key deep brain and cortical structures relevant to Huntington's disease treatment. The researchers observed transduction of therapeutically relevant numbers of target brain cells in large animal models at doses that would be orders of magnitude lower than those currently used in clinical settings.
Like AAV-Ep+, AAV-DB-3 successfully transduced relevant mouse structures and human neurons derived from induced pluripotent stem cells, supporting its potential for clinical translation.
Broader Applications and Future Directions
The findings from both studies establish a foundation for future clinical trials in humans. Beyond Batten and Huntington's diseases, the research could potentially be applied to AAV engineering protocols for other cells and tissues relevant to different inherited disorders.
"Innovations in gene therapy offer hope to patients and their families – potentially turning once-devastating diagnoses into manageable conditions," said Davidson.
The researchers believe their strategy could significantly reduce the doses and cost per patient of gene therapy required for potential treatments of lysosomal storage disorders and would be applicable to other protein replacement approaches as well.
Research Funding and Disclosures
Both studies were funded by the CHOP Research Institute and Latus Bio. The related intellectual property has been licensed by CHOP to Latus. Dr. Davidson serves as a paid consultant to Latus, sits on its Scientific Advisory Board, holds equity in the company, and is a named inventor on the intellectual property licensed by Latus.
The studies were published as Tecedor et al, "An AAV variant selected through NHP screens robustly transduces the brain and drives secreted protein expression in NHPs and mice" in Science Translational Medicine, and Leib et al, "Optimized AAV capsids for basal ganglia diseases show robust potency and distribution" in Nature Communications.
