PHILADELPHIA, Pa. — Researchers at Children’s Hospital of Philadelphia (CHOP) have developed advanced generations of adeno-associated viral (AAV) vectors capable of targeting key brain cells at significantly lower doses, a breakthrough with potential to improve safety, efficacy and cost in gene therapy for inherited neurological disorders.
The findings, published in Science Translational Medicine and Nature Communications, represent a major step forward in developing one-time treatments for diseases such as Batten disease and Huntington’s disease. Both studies were led by the laboratory of Beverly Davidson, PhD, Director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at CHOP.
“One of the main issues plaguing gene therapies today is low potency. This results in high doses being required to reach therapeutic levels,” Davidson said. “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.”
In the first study, researchers screened millions of AAV capsid variants to find those capable of targeting brain ventricular lining cells and cerebral neurons for enzyme replacement in Batten disease. They identified a vector, AAV-Ep+, which showed high efficiency in delivering genetic material to both mouse models and human neurons derived from induced pluripotent stem cells.
The lower-dose effectiveness of AAV-Ep+ may reduce patient risk and manufacturing costs associated with gene therapies currently requiring higher vector volumes. It also opens new possibilities for treating lysosomal storage disorders and similar genetic conditions requiring protein replacement.
Second vector targets deeper brain regions at low doses
In the second study, published in Nature Communications, Davidson’s team applied a similar method to identify another capsid, AAV-DB-3, capable of targeting deep brain and cortical structures affected in Huntington’s disease. In preclinical models, the vector successfully reached therapeutic cell populations in both rodents and large animals, again at doses substantially lower than current clinical norms.
Like AAV-Ep+, the AAV-DB-3 vector showed promising results in human neuron models, suggesting its readiness for future clinical translation. Both engineered capsids may be adaptable for other gene therapy applications targeting central nervous system diseases.
Funding for both studies was provided by the CHOP Research Institute and Latus Bio. The underlying intellectual property has been licensed by CHOP to Latus. Davidson is a paid consultant to the company, serves on its Scientific Advisory Board, and holds equity and inventor rights related to the licensed technology.