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Updated: Jan 16, 2026
Author Spotlight: Optimizing Digital Droplet PCR Method for Accurate Adeno-Associated Viral Genome Quantification
Published on: October 11, 2024
Development of an adeno-associated virus vector for gene replacement therapy of NF1-related tumors
Ren-Yuan Bai1,2, Jingyi Shi3, Jianan Liu3
1Kennedy Krieger Institute, Baltimore, MD, USA. rbai1@jhmi.edu.
Abstract:
Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome caused by alterations in NF1 gene that lead to tumor growth throughout the nervous system, which can cause morbidity and mortality, and transform to malignancy. NF1 gene replacement therapy, though promising, is hindered by NF1 gene's large size and delivery challenges. We introduced a membrane-targeted, truncated neurofibromin comprising the GAP-related domain (GRD) fused to the KRAS4B C-terminal domain, which effectively inhibits the RAS signaling pathway and restores Schwann cell differentiation in an NF1 iPSC-derived model. For systemic application, we engineered an adeno-associated virus (AAV) vector using in vivo capsid evolution through sequential DNA shuffling and peptide library screening in a NF1 xenograft mouse model. This tailored vector, AAV-NF, exhibits greatly reduced liver uptake, enhanced tumor targeting across various NF1-related MPNST, neurofibromas and glioma models, and therapeutic efficacy in xenografts of MPNST. This study not only advances a viable AAV vector for NF1 treatment but also outlines a replicable strategy for vector and payload development in other monogenic and tumor-associated disease manifestations.
Insights
This study developed a novel adeno-associated virus (AAV) vector, AAV-NF, for treating Neurofibromatosis type 1 (NF1). The vector effectively targets tumors and shows therapeutic promise for NF1-related conditions.
Area of Science:
- Genetics and Molecular Biology
- Oncology
- Gene Therapy
Background:
- Neurofibromatosis type 1 (NF1) is a genetic disorder causing tumors in the nervous system.
- Current NF1 gene replacement therapy faces challenges due to the large gene size and delivery issues.
- Tumorigenesis in NF1 can lead to significant morbidity, mortality, and malignant transformation.
Purpose of the Study:
- To develop a targeted gene therapy approach for Neurofibromatosis type 1 (NF1).
- To engineer an adeno-associated virus (AAV) vector for efficient delivery of therapeutic payload to NF1-related tumors.
- To evaluate the efficacy of the engineered vector in preclinical NF1 models.
Main Methods:
- Developed a membrane-targeted, truncated neurofibromin for RAS signaling inhibition.
- Engineered an adeno-associated virus (AAV) vector using in vivo capsid evolution in an NF1 xenograft mouse model.
- Assessed vector tropism, liver uptake, tumor targeting, and therapeutic efficacy in various NF1 models.
Main Results:
- The engineered AAV-NF vector demonstrated reduced liver uptake and enhanced tumor targeting.
- AAV-NF showed therapeutic efficacy in preclinical models of malignant peripheral nerve sheath tumors (MPNST).
- The vector successfully restored Schwann cell differentiation in an NF1 induced pluripotent stem cell (iPSC) model.
Conclusions:
- This study presents a viable adeno-associated virus (AAV) vector, AAV-NF, for NF1 treatment.
- The developed vector strategy offers a replicable approach for gene therapy in monogenic and tumor-associated diseases.
- The findings advance potential therapeutic options for NF1 and related malignancies.
