A team led by Johns Hopkins and Kennedy Kreiger Institute researchers has developed a new gene therapy strategy that may overcome longstanding barriers to treating neurofibromatosis type 1 (NF1) as well as other conditions related to a single gene alteration. 

The experimental therapy combines a miniaturized version of the NF1 gene with a uniquely engineered adeno-associated virus (AAV) vector that efficiently targets tumor tissue while limiting uptake in the liver and other healthy organs. This is an important development, as nontargeted uptake is a significant limitation of naturally occurring (nonengineered) AAV products.

Published Sept. 29 in Nature Communications, the study demonstrates that when the vector — named AAV-NF (K55) — is paired with the payload GRD-C24, it suppresses tumor growth in xenograft mouse models of NF1-related cancers. The findings establish a foundation for advancing toward larger-animal safety studies, leading to a first-in-human clinical trial.

NF1 is one of the most common single gene disorders worldwide. It stems from mutations in the NF1 gene that produce neurofibromin, a protein that normally regulates RAS and its signaling pathway. When the gene is disrupted, the pathway becomes overactive, driving tumor formation throughout the body. Up to 15% of these tumors turn into treatment-resistant and aggressive cancers, such as the sarcoma called malignant peripheral nerve sheath tumor and brain cancers like glioblastoma. Because NF1 tumors are driven by a single genetic defect, researchers see a unique opportunity for gene-based therapy to address them at their source.

“When the NF1 gene mutates, it leaves the RAS pathway hyperactivated, and cells — especially Schwann cells — proliferate without control,” says Renyuan Bai, associate professor of neurological surgery at the Johns Hopkins University School of Medicine. “That’s what leads to the formation of neurofibromas, which can progress to the dangerous sarcoma, malignant peripheral nerve sheath tumors.”

The NF1 gene is more than twice the size an AAV can carry. To overcome that logistical hurdle, the team created a “mini-NF1” construct, retaining the core enzyme region responsible for turning off RAS hyperactivity. They fused it with a short cell membrane-binding sequence from RAS so the hybrid protein could locate precisely where growth control occurs inside the cell.

Using capsid evolution, the team engineered a tumor-targeted AAV vector, AAV-NF. Libraries of modified capsids were injected into mice bearing human NF1 tumors, and variants that most effectively reached tumor cells were enriched. After multiple rounds, AAV-K55 emerged, delivering the mini-NF1 payload efficiently while minimizing liver uptake. In animal models, it significantly slowed growth of NF1 tumors, including MPNST, supporting translation to human studies.

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