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

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.

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Publication Details

Journal
Nature Communications
Published
2025-09-29
DOI
https://doi.org/10.1038/s41467-025-63619-4
Citations
1
Primary Topic
Neurofibromatosis and Schwannoma Cases
Type
article
Field-Weighted Citation Impact
1.39

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article

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

Zhihong Ren, Eduard Serra, Jaishri O. Blakeley, Hotae Lim et al.
1 citations
Nature Communications
Neurofibromatosis and Schwannoma Cases
1.39
article

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

Zhihong Ren, Eduard Serra, Jaishri O. Blakeley, Hotae Lim, Melissa L. Fishel, Yuqing Lu, Meritxell Carrió, Ren-Yuan Bai, Hua‐Zhen Xu, Christine A. Pratilas, Jingyi Shi, Verena Staedtke, Xiaojun Chen, Miaomiao Xu, Li Yang, Jianan Liu, Nihao Sun, Karis E. Weisgerber
article en
1 citations

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.

Nature CommunicationsVol. 16(1)
Indiana University Health (US), Kennedy Krieger Institute (US), Johns Hopkins University (US), Johns Hopkins Medicine (US), Indiana Cancer Consortium (US), Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES), Indiana University School of Medicine, Indiana University – Purdue University Indianapolis (US)
Johns Hopkins University, National Institutes of Health, National Cancer Institute, Congressionally Directed Medical Research Programs
Openalex Percentile: Top 15%
Neurofibromatosis and Schwannoma Cases
1.39
DOIOpen Access PDFOpenAlex
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