Researchers at Asan Medical Center in Seoul have newly identified the therapeutic potential of the drug ataluren for neurofibromatosis type 1.
According to Asan Medical Center on December 26, neurofibromatosis type 1 is a rare congenital disorder caused by genetic mutations that lead to abnormal development in the nervous system, bones, and skin. As patients age, symptoms worsen, resulting in a continuous decline in quality of life.
Professor Beomhee Lee and Researcher Soyoung Kim at the Medical Genetics Center of Asan Medical Center treated skin cells from neurofibromatosis type 1 patients with nonsense mutations using ataluren and monitored the outcomes.
Professor Beomhee Lee and Researcher Soyoung Kim, Medical Genetics Center, Asan Medical Center, Seoul.
As a result, they found that the function of tumor suppressor proteins was partially restored, blocking the signaling pathways that induce tumor formation, and consequently reducing tumor occurrence.
This study was supported by Humanscape (CEO Jang Minhoo), which provided data, analytical infrastructure, and research funding from its rare disease platform "Rare Note." This is the first study to demonstrate the therapeutic effect of ataluren in neurofibromatosis type 1 patients with nonsense mutations, offering significant evidence for the future development of personalized treatment strategies.
The results were published in the latest issue of the international journal "MedComm" (impact factor 10.7).
About 30% of patients with neurofibromatosis type 1 (NF1) have nonsense mutations. A nonsense mutation is a change in the DNA genetic code that introduces a premature stop signal before the protein is fully synthesized. In other words, neurofibromatosis type 1 with a nonsense mutation involves an early stop signal in the NF1 gene, preventing proper production of the neurofibromin protein.
When the function of neurofibromin is lost, the signaling pathway (RAS-MEK-ERK) that promotes cell growth and division becomes excessively activated, resulting in tumors developing in various organs.
Ataluren is originally known as a drug that restores 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 been directly demonstrated before.
The research team collected fibroblasts (cells that make up connective tissue such as skin, fascia, and tendons) from 22 Korean patients with neurofibromatosis type 1 and nonsense mutations and treated them with ataluren.
As a result, about 24% of all cells showed a reduction in abnormally hyperactivated signals (RAS and ERK). In other words, the function of the neurofibromin protein was partially restored in some cells.
The team further compared ataluren-responsive and non-responsive cells through transcriptome analysis. They observed that, when ataluren was effective, the levels of AMPD3 and TGFBR3 proteins in the patients' blood decreased. This indicates that these two proteins could serve as biomarkers for monitoring the efficacy of ataluren.
Notably, AMPD3 was further identified as a potential new therapeutic target for neurofibromatosis type 1. Inhibiting AMPD3 in the patients' Schwann cells (the main cellular component of neurofibromas) resulted in reduced ERK signaling, suppressed cell proliferation, and increased cell death. This suggests that AMPD3 could be a promising therapeutic target that selectively inhibits tumor cells associated with neurofibromatosis type 1.
Professor Beomhee 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 some patients with neurofibromatosis type 1. We expect that these findings will greatly contribute to providing personalized treatment for neurofibromatosis type 1 patients with nonsense mutations in the future."
© The Asia Business Daily(www.asiae.co.kr). All rights reserved.
