Children's Hospital of Philadelphia Researchers Develop Promising Tools to Enhance Gene Therapy Delivery for Hard-to-Treat Diseases

Two new studies demonstrate the use of adeno-associated viral vectors for brain gene therapies

PHILADELPHIA, May 20, 2025 /PRNewswire/ -- Adeno-associated viral (AAV) vectors are promising tools that can transport modified genetic material into the nuclei of cells in target tissues impacted by challenging diseases, offering the possibility of a one-time precision therapy to inherited diseases. Now, with two recently published preclinical studies, researchers at Children's Hospital of Philadelphia (CHOP) established a transformative advance in gene therapy, demonstrating how new generations of AAV vectors can target relevant brain cells and structures at much lower doses than current AAV based drugs. The findings were published by the journals Science Translational Medicine and Nature Communications. 

In these works from the laboratory of Professor Beverly Davidson, PhD, Director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at CHOP, the researchers used advanced AAV engineering to improve one-and-done treatments for a childhood onset neurodegenerative disorder known as Batten disease, and a more common neurodegenerative disease that affects children and adults, known as Huntington's disease.

The findings from both studies lay the groundwork for ongoing research aimed at translating these discoveries into future clinical trials in humans. The research could also potentially be applied to AAV engineering protocols for other cells and tissues in the periphery relevant to different inherited disorders.

For the Batten disease therapy, the team identified capsids that could provide for gene transfer to brain cells that would allow for lifelong enzyme replacement in the brain following the one-time therapy.  Notably, they discovered this could work with much lower doses than those currently used in clinical and preclinical studies.

"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," 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, published in Science Translational Medicine, Davidson and her colleagues performed a screen of millions of capsid variants of different AAV vectors to identify which can reach the target cells to provide for long term secretion of therapeutic proteins for lifelong enzyme replacement therapy. They identified the capsid AAV-Ep+, which was very effective in delivering therapeutic products to ventricular lining cells and cerebral neurons.

The researchers also showed that the newly engineered capsid was effective in a preclinical model of Batten disease as well as human neurons derived from induced pluripotent stem cells. The researchers believe that given the potency of the AAV capsid, this strategy could 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 paradigms as well.

In the second study, published in Nature Communications, the researchers used a similar screening method to identify the capsid AAV-DB-3 for targeting key deep brain and cortical structures. Notably, there was transduction of therapeutically relevant numbers of target brain cells in large animal models, at doses that when translated to patients would be orders of magnitude lower than in the clinic currently. And like AAV-Ep+, AAV-DB-3 transduced relevant mouse structures and human neurons derived from induced pluripotent stem cells, supporting its use in clinical translation.

"Innovations in gene therapy offer hope to patients and their families – potentially turning once-devastating diagnoses into manageable conditions," said Davidson.

Both studies were funded by the CHOP Research Institute and Latus Bio. Related intellectual property has been licensed by CHOP to Latus.

Dr. Davidson is 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.

Tecedor et al, "An AAV variant selected through NHP screens robustly transduces the brain and drives secreted protein expression in NHPs and mice." Sci Transl Med. Online May 14, 2025. DOI: 10.1126/scitranslmed.adr2531.

Leib et al, "Optimized AAV capsids for basal ganglia diseases show robust potency and distribution." Nat Commun. Online May 19, 2025. DOI: 10.1038/s41467-025-60000-3.

About Children's Hospital of Philadelphia: 
A non-profit, charitable organization, Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey. CHOP also operates the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia, the Behavioral Health and Crisis Center (including a 24/7 Crisis Response Center) and the Center for Advanced Behavioral Healthcare, a mental health outpatient facility. Its unique family-centered care and public service programs have brought Children's Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit https://www.chop.edu.

Contact: Karen Pasternack
Children's Hospital of Philadelphia
(917) 509-5834
[email protected]

SOURCE Children's Hospital of Philadelphia