Tumor Development Suppression Observed in Neurofibromatosis Type 1 Patients with Nonsense Mutations

Professor Beom Hee Lee’s Team at Asan Medical Center: “Findings Will Serve as Important Evidence for Developing Patient Tailored Treatment Strategies”

▲ Professor Beom Hee Lee of the Medical Genetics Center at Asan Medical Center and Researcher So Young Kim 

Neurofibromatosis type 1 is a congenital rare disease caused by genetic mutations that lead to developmental abnormalities affecting the nervous system, bones, and skin. As symptoms tend to worsen with age, patients experience a continuous decline in quality of life. Recently, a Korean research team has confirmed the therapeutic potential of the drug ataluren in a subset of patients with neurofibromatosis type 1.

Professor Beom Hee Lee of the Medical Genetics Center at Asan Medical Center and Researcher So Young Kim treated skin cells from patients with neurofibromatosis type 1 carrying nonsense mutations with ataluren and observed the outcomes over time.

As a result, partial restoration of the tumor suppressor protein function was observed, leading to the blockade of signaling pathways that drive tumor formation and ultimately a reduction in tumor development.

This study was conducted with support from Humanscape, led by CEO Minhoo Chang, which provided data from its rare disease platform RareNote, along with analytical infrastructure and research funding. As the first study to demonstrate the therapeutic effects of ataluren in patients with neurofibromatosis type 1 carrying nonsense mutations, the findings are considered highly significant in that they offer important evidence for the future development of patient tailored treatment strategies.

The findings were published in the latest issue of the international journal MedComm (impact factor 10.7).

Approximately 30 percent of patients with neurofibromatosis type 1 (NF1) carry nonsense mutations. A nonsense mutation refers to a genetic alteration in which a premature stop signal appears within the DNA code, causing protein synthesis to terminate before the protein is fully formed. In neurofibromatosis type 1 with nonsense mutations, an early termination signal occurs in the NF1 gene, preventing the proper production of the tumor suppressor protein neurofibromin.

When the function of neurofibromin is lost, the signaling pathway that promotes cell growth and proliferation, the RAS, MEK, and ERK pathway, becomes excessively activated, ultimately leading to tumor development in multiple organs.

Ataluren is a drug originally known to restore protein synthesis in diseases caused by nonsense mutations, such as muscular dystrophy. However, its therapeutic effect in neurofibromatosis type 1 with nonsense mutations had not previously been directly demonstrated.

The research team obtained fibroblasts, cells that make up connective tissues such as skin, fascia, and tendons, from 22 Korean patients with neurofibromatosis type 1 carrying nonsense mutations and treated the cells with ataluren.

As a result, approximately 24 percent of the cells showed a reduction in abnormally overactivated signaling, including RAS and ERK. This indicates that the function of the neurofibromin protein was partially restored in a subset of the cells.

The research team further conducted transcriptomic analysis to compare cells that responded to ataluren with those that did not. When ataluren was effective, reduced levels of the proteins AMPD3 and TGFBR3 were observed in patients’ blood. This finding suggests that these two proteins may serve as biomarkers for monitoring the therapeutic efficacy of ataluren.

In particular, AMPD3 was further validated as a potential new therapeutic target for neurofibromatosis type 1. When AMPD3 was inhibited, ERK signaling associated with cell growth decreased in patients’ Schwann cells, the primary cellular component of neurofibromas, resulting in suppressed cell proliferation and increased cell death. These findings suggest that AMPD3 may serve as a promising therapeutic target that selectively suppresses tumor cells associated with neurofibromatosis type 1.

Professor Beom Hee Lee of the Medical Genetics Center at Asan Medical Center stated, “Through this study, we were able to confirm for the first time the therapeutic potential of ataluren in a subset of patients with neurofibromatosis type 1. We expect these findings to provide a strong foundation for delivering patient tailored treatments to individuals with neurofibromatosis type 1 carrying nonsense mutations in the future.”