Development of an adeno-associated virus vector for gene replacement therapy of NF1-related tumors

Ren-Yuan Bai (), Jingyi Shi, Jianan Liu, Nihao Sun, Yuqing Lu, Xiaojun Chen, Manzhu Xu, Hotae Lim, Yang Li, Huazhen Xu, Karis Weisgerber, Zhihong Ren, Christine A. Pratilas, Jaishri O. Blakeley, Melissa L. Fishel, Meritxell Carrió, Eduard Serra and Verena Staedtke
Additional contact information
Ren-Yuan Bai: Kennedy Krieger Institute
Jingyi Shi: Kennedy Krieger Institute
Jianan Liu: Kennedy Krieger Institute
Nihao Sun: Kennedy Krieger Institute
Yuqing Lu: Kennedy Krieger Institute
Xiaojun Chen: Kennedy Krieger Institute
Manzhu Xu: Johns Hopkins University School of Medicine
Hotae Lim: Johns Hopkins University School of Medicine
Yang Li: Kennedy Krieger Institute
Huazhen Xu: Kennedy Krieger Institute
Karis Weisgerber: Kennedy Krieger Institute
Zhihong Ren: Johns Hopkins University School of Medicine
Christine A. Pratilas: Johns Hopkins University School of Medicine
Jaishri O. Blakeley: Johns Hopkins University School of Medicine
Melissa L. Fishel: Indiana University School of Medicine
Meritxell Carrió: Badalona
Eduard Serra: Badalona
Verena Staedtke: Kennedy Krieger Institute

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63619-4

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