Researchers at Children’s Hospital of Philadelphia have made significant strides in gene therapy through the use of adeno-associated viral (AAV) vectors, which have the potential to transport modified genetic material directly into the nuclei of target cells. These advancements offer hope for a one-time precision therapy aimed at inherited diseases, particularly in challenging conditions.
Recent studies, published in the journals Science Translational Medicine and Nature Communications, highlight innovative techniques developed by a research team led by Professor Beverly Davidson, PhD. Davidson serves as the Director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at CHOP.
Their work focuses on gene therapies for Batten disease, a rare childhood neurodegenerative disorder, and Huntington’s disease, a more common condition that affects both children and adults. The researchers have engineered new generations of AAV vectors that can effectively target relevant brain cells and structures using significantly lower doses than currently used in AAV-based treatments.
These breakthroughs are poised to facilitate clinical trials and may open avenues for applying AAV engineering strategies to other inherited disorders affecting different cells and tissues throughout the body.
For the Batten disease therapy, the research team successfully identified specific capsids that enable gene transfer to brain cells, allowing for lifelong enzyme replacement following a single treatment. Importantly, these newly identified capsids can achieve therapeutic effects at much lower doses than those required in existing clinical and preclinical studies.
“One of the main issues plaguing gene therapies today is low potency,” Davidson stated. “This results in high doses being required to reach therapeutic levels, which increase both patient safety issues and the cost of goods per patient.”
In their first study, published in Science Translational Medicine, Davidson and her colleagues screened millions of capsid variants from various AAV vectors to identify those that can effectively reach target cells for long-term secretion of therapeutic proteins. Notably, they discovered the capsid AAV-Ep+, which proved highly effective in delivering therapeutic products to both ventricular lining cells and cerebral neurons.
The researchers conducted successful tests using AAV-Ep+ in a preclinical model of Batten disease, as well as with human neurons derived from induced pluripotent stem cells. Given the substantial potency of this engineered AAV capsid, the researchers anticipate that this approach could lower both the doses and costs involved in treating lysosomal storage disorders. Additionally, they believe it can be adapted to other protein replacement therapy strategies.
The second study, published in Nature Communications, utilized a similar screening methodology to pinpoint the capsid AAV-DB-3, which effectively targets crucial structures in the deep brain and cortex. Impressively, this capsid was able to transduce therapeutically relevant numbers of target brain cells in large animal models, employing doses that would be orders of magnitude lower than those currently utilized in clinical settings.
AAV-DB-3 also demonstrated promising results in relevant mouse structures and human neurons derived from induced pluripotent stem cells, further supporting its potential for clinical application.
“Innovations in gene therapy offer hope to patients and their families – potentially turning once-devastating diagnoses into manageable conditions,” Davidson commented. This latest research marks a significant step forward in the field of gene therapy, aiming to enhance treatment efficacy and accessibility for patients dealing with neurodegenerative diseases.
image source from：https://pennwatch.org/childrens-hospital-of-philadelphia-researchers-develop-tools-to-enhance-gene-therapy-delivery-for-hard-to-treat-diseases/
