A team of researchers at Waseda University in Japan has identified a gene called Nwd1 that plays a key role in the development of metabolic dysfunction-associated steatohepatitis (MASH). This discovery could lead to new therapeutic strategies, potentially reshaping the treatment landscape for liver disease.
illustration of the liver
A team of researchers at Waseda University in Japan have identified a gene, known as Nwd1, that plays a crucial role in the development of metabolic dysfunction-associated steatohepatitis (MASH). Their findings, published in Communications Biology, suggest that Nwd1 and the molecules it interacts with could serve as potential targets for new MASH therapies.
The role of Nwd1 in liver function
The research team previously determined that Nwd1 (NACHT and WD repeat domain-containing protein 1) is primarily produced in the brain and liver. While its role in brain development was established, its liver function remained uncertain. To investigate this, the researchers employed CRISPR gene-editing technology to render the Nwd1 gene non-functional in mice. The results showed that the liver cells in the modified mice became swollen with fat molecules, and scar tissue formed in the liver, closely mimicking the effects of MASH in humans.
crispr graphic
While Nwd1 (NACHT and WD repeat domain-containing protein 1) role in brain development was established, its liver function remained uncertain, to investigate this, the researchers employed CRISPR gene-editing technology to render the Nwd1 gene non-functional in mice.
The link between Nwd1 and SERCA2 ATPase
Further analysis revealed that the loss of Nwd1 disrupted the activity of a protein called SERCA2 ATPase, which led to reduced calcium levels in the cells’ endoplasmic reticula (ER). The ER is a vital organelle responsible for protein folding and lipid transfer, and dysfunction in its activity has been linked to MASH. This finding underscores SERCA2’s potential as a therapeutic target for the disease.
According to the authors, unravelling the function of Nwd1 could provide deeper insights into the mechanisms of MASH pathogenesis and aid in the development of new treatment strategies, particularly those addressing ER stress.
Challenges in MASH drug development
Developing effective treatments for MASH has been a significant challenge in the pharmaceutical industry. Many companies, including major players like Pfizer and Bristol Myers Squibb, as well as smaller biotech firms such as Genfit and NGM Biopharmaceuticals, have attempted but failed to bring MASH drugs to market. However, a breakthrough came in March 2024 with the FDA approval of Madrigal Pharmaceuticals’ Rezdiffra (resmetirom), the first successful drug for treating MASH.
A growing market for MASH therapies
The demand for MASH treatments is expected to rise significantly in the coming years. A study published in January projected that the number of MASH cases in the US will increase from 14.9 million adults in 2020 to 23.2 million by 2050.
Rezdiffra has already demonstrated strong market performance, generating $180 million in sales within its first nine months. Given the growing prevalence of MASH and the newly discovered role of Nwd1 in its development, further research into this gene could pave the way for additional therapeutic options in the future.