Inhibiting GSK-3 Beta Protein Slowed Disease Progression, Improved Lung Function in PF Mice

Inhibiting GSK-3 Beta Protein Slowed Disease Progression, Improved Lung Function in PF Mice

By blocking activity of the protein GSK-3 beta, the investigational therapy 9-ING-41 slowed disease progression and improved lung function in mice with pulmonary fibrosis (PF), a study found.

The study, “Glycogen Synthase Kinase-3β Inhibition with 9-ING-41 Attenuates the Progression of Pulmonary Fibrosis,” was published in the journal Nature Scientific Reports.

Although the mechanisms responsible for the onset and progression of PF are unknown, disease progression is associated with a series of cellular alterations. These include the destruction of epithelial cells forming the alveoli (the air sacs of the lungs) and the abnormal expansion of myofibroblasts (a type of cell that promotes tissue scarring, or fibrosis, by producing large amounts of a protein called collagen.

A protein called GSK-3 beta regulates the mechanisms leading to collagen production, as well as the activity of several transcription factors, which determine the proteins produced by a given cell. Abnormal GSK-3 beta activity has been linked to several medical conditions, including Alzheimer’s disease, diabetes, and cancer.

9-ING-41, a specific inhibitor of GSK-3 beta developed by Actuate Therapeutics, is currently being tested in clinical trials for advanced cancers, such as glioblastoma, lymphoma, neuroblastoma, and pancreatic cancer.

Now, researchers from the University of Texas Health Science Center at Tyler, together with colleagues at Actuate Therapeutics, investigated the role of GSK-3 beta in a mouse model of bleomycin-induced PF. They assessed if inhibiting this protein using 9-ING-41 could have relevant therapeutic effects.

They found that GSK-3 beta levels were higher in the lungs of PF mice than in the lungs of saline-treated mice (control group). Additionally, the protein was found mostly within myofibroblasts at lung injuries in PF mice, suggesting that it could play a role in disease progression.

Treatment with 9-ING-41 blocked the differentiation of fibroblasts into myofibroblasts (a key process in fibrosis), and also reduced the production of collagen by myofibroblasts.

Treating PF mice with 9-ING-41 slowed disease progression, and improved lung function and lung volume. The lungs of mice treated with the inhibitor also showed less fibrotic tissue, less collagen deposition, and reduced epithelial cell death than those of untreated mice.

Overall, “these findings strongly support our hypothesis that the therapeutic targeting of GSK-3β with the novel inhibitor, 9-ING-41, reduces myofibroblast differentiation, collagen deposition, and subsequent PF,” the researchers wrote.

The team also noted that the inhibitor was well-tolerated, and the animals showed no signs of treatment toxicity.

Notably, the dosages used in the study were not enough to completely stop PF progression. Mice treated with 9-ING-41 had more scar tissue and worse lung function compared to non-PF mice. For this reason, according to the team, additional studies with longer courses of treatment may be required to achieve such improvements.

“Pharmacologic targeting of GSK-3β in vivo is effective and generally well tolerated. Our findings also provide a strong rationale for the advancement of 9-ING-41 as a candidate new therapeutic for the treatment of patients with PF,” the team concluded.

Alejandra has a PhD in Genetics from São Paulo State University (UNESP) and is currently working as a scientific writer, editor, and translator. As a writer for BioNews, she is fulfilling her passion for making scientific data easily available and understandable to the general public. Aside from her work with BioNews, she also works as a language editor for non-English speaking authors and is an author of science books for kids.
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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.
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Alejandra has a PhD in Genetics from São Paulo State University (UNESP) and is currently working as a scientific writer, editor, and translator. As a writer for BioNews, she is fulfilling her passion for making scientific data easily available and understandable to the general public. Aside from her work with BioNews, she also works as a language editor for non-English speaking authors and is an author of science books for kids.
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