
In a significant stride for precision oncology, a collaborative team of researchers, including those from Johns Hopkins University School of Medicine and Kennedy Krieger Institute, has successfully engineered a novel adeno-associated virus (AAV) vector for gene replacement therapy, specifically targeting tumors associated with Neurofibromatosis Type 1 (NF1).
The groundbreaking work, detailed in a recent publication in Nature Communications, offers a path toward a disease-modifying treatment for NF1, a genetic disorder characterized by tumor growth along nerves. This achievement is the result of a multidisciplinary effort spanning the fields of gene therapy, molecular biology, and clinical oncology.
Overcoming the Size Challenge and Achieving Precision
NF1 is caused by mutations in the NF1 gene, which encodes the tumor suppressor protein neurofibromin. Loss of this protein is the underlying cause of tumor formation. A major hurdle has been the NF1 gene’s large size, which exceeds the conventional packaging capacity of AAV vectors.
The research team overcame this obstacle by designing an optimized AAV vector capable of efficiently delivering a functional NF1 gene fragment engineered to produce a viable and stable neurofibromin protein.
Crucially, the vector was modified for enhanced safety and specificity:
- Targeting: The AAV capsid was engineered to exhibit specific tropism for NF1-related tumor cells, including Schwann cells and tumor progenitor cells, ensuring therapeutic payloads reach their intended destinations.
- Safety Profile: The vector incorporated regulatory elements to ensure controlled gene expression and demonstrated an attenuated immunogenic profile in preclinical models, which is vital for enabling sustained gene expression.
Preclinical Data Shows Tumor Regression
Preclinical trials conducted in murine models of NF1 showed highly encouraging results. Upon intratumoral administration of the AAV vector, researchers observed significant tumor regression and a clear restoration of neurofibromin expression.
Mechanistically, the therapy successfully rescued key signaling pathways disrupted by NF1 loss, most notably the Ras-MAPK pathway. By reinstating neurofibromin’s GTPase-activating activity, the therapy normalized the aberrant signaling that drives uncontrolled cellular proliferation.
This pioneering AAV vector development, backed by institutions like Johns Hopkins, offers hope for NF1 patients who have long faced limited treatment options, heralding a major shift toward precision oncology by targeting tumorigenesis at its genetic core.
Source:
https://bioengineer.org/aav-vector-advances-gene-therapy-for-nf1-tumors/; https://www.nature.com/articles/s41467-025-63619-4
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