Prototype of drug expected to treat lung diseases

A reagent known as NZ-97 has shown promise in treating lung diseases by stimulating the growth of new stem cells and repairing damaged tissue, based on data from a new proof-of-concept study.

In many lung diseases, a lack of stem cells leads to progressive damage, but researchers have developed small, lung-targeted drug-like molecules that stimulate the proliferation of lung stem cells. data Published in Proceedings of the National Academy of Sciences.

Michael J. Boron, Ph.D., associate professor in the Department of Chemistry at the Scripps Research Institute in San Diego, California, and colleagues. reframea drug repurposing library created by the Caliber Skaggs Institute for Innovative Medicines (Drug Discovery Division of the Scripps Research Institute) to test existing drugs as a basis for promoting stem cell growth and repair in the lungs. and database.

“Currently, there are no drugs that promote regenerative repair in the lungs,” Boron said in an interview. “This is especially important idiopathic pulmonary fibrosis“The disease is caused by a failure of the lower respiratory tract stem cell population, alveolar type 2 cells (AEC2), to proliferate and regenerate the gas exchange epithelium,” he said.

Researchers have identified dipeptidyl peptidase 4 (DPP4) inhibitors as a potential tool to promote the production of stem cells in the lower airways called AEC2. The researchers noted in their study that AEC2 dysfunction appears to play an important role in the development of idiopathic pulmonary fibrosis. They developed a new highly soluble DPP4 inhibitor known as NZ-97 that can be administered by intratracheal injection.

In a mouse model of lung disease, NZ-97 induced proliferation of AEC2 cells and improved damaged lung tissue. “Importantly, NZ-97 was well tolerated when administered intratracheally daily to naive animals,” the researchers wrote in the study.

Furthermore, 1 month of treatment with NZ-97 at 0.5 mg/kg every 4 days showed no detectable changes in alveolar structure, increased inflammation, or cellular hyperplasia.

The current study “identified a novel mechanism that promotes alveolar repair” and revealed that it could treat not only idiopathic pulmonary fibrosis (IPF), but also potentially other lung diseases, including: Chronic obstructive pulmonary diseasesaid Boron.

“Here we report the drug prototype NZ-97, a locally delivered and lung-retained molecule that inhibits DPP4 in the lung lumen,” Boron explained. Boron said NZ-97's prototype drug is chemically similar to Caliber Skaggs researchers' new clinical drug candidate, CMR316, which is scheduled to begin Phase 1 clinical trials in late summer 2024.

CMR316 is designed to be delivered in a mist via a nebulizer once a week. “If CMR316 proves effective in improving IPF, it could provide a new means of regenerating the lungs and could be added to standard-of-care anti-fibrotic drugs to slow disease progression or In some cases, it may even be possible to reverse it,” Boron said. Medscape Medical News.

“A key challenge is to understand whether the identified regenerative mechanisms show improvement in clinical trials,” Boron said. “While we have shown efficacy in animal models and in patient-derived cells, the extent and duration of improvement in patients will ultimately be determined in the clinic.”

Looking to the future, CMR316's Phase 1 clinical trial is designed to assess safety and target engagement, Boron said. Medscape Medical News. Boron's lab also continues to work with Caliber to develop other regenerative approaches to treat diseases in other organs, he said.

Responding to regenerative treatment needs

Dharani K. Narendra, MD, of Baylor College of Medicine in Houston, Texas, said in an interview that the current study and ongoing research on NZ-97 addresses the need for regenerative therapies in lung disease.

“The identification of DPP4 inhibitors, particularly NZ-97, as potential agents to proliferate alveolar epithelial cell type 2 (AEC2) represents a promising therapeutic strategy to stimulate regeneration of damaged alveolar epithelium.” she said. “AEC2 plays a critical role in lung repair, and targeting it has the potential to improve a variety of lung diseases for which there are currently no effective treatments,” she explained.

“DPP4 inhibitors are well established in diabetes management and have known biological effects. However, the success and efficacy of repurposing NZ-97 in promoting lung repair is somewhat surprising.” said Narendra. “This surprise stems from the drug's novel use and efficacy in the pulmonary setting, where traditional DPP4 inhibitors required larger and potentially unsafe doses to achieve similar effects. “It shows great potential in this case,” she said.

If the study is successful, NZ-97 could have substantial clinical benefits in the treatment of lung diseases such as IPF and other conditions involving alveolar damage. By promoting AEC2 proliferation, NZ-97 reduces lung injury and improves patient outcomes by promoting regenerative repair, possibly reducing reliance on more invasive treatments such as There is a possibility. lung transplant.

Further research on NZ-97 is needed to identify potential barriers to its use, Narendra said. Medscape Medical News.

“Further research is needed to assess the long-term effects of NZ-97, understand its mechanisms in human lung tissue, and determine its safety and efficacy in clinical practice,” Narendra said. Stated.

Narendra had no financial disputes to disclose, but he served on the editorial board of the Journal of Chest Physicians.