Idiopathic pulmonary fibrosis (IPF), a progressive and incurable disease characterized by irreversible scarring of the lungs, may have a new therapeutic avenue. Researchers at Scripps Research have identified a class of drugs that can restore the regenerative capacity of lung stem cells, specifically type 2 alveolar epithelial cells (AEC2s), which are crucial for repairing damaged lung tissue. This discovery has led to the development of CMR316, an optimized compound currently undergoing Phase 1 clinical trials.
The Role of AEC2s in Lung Regeneration
AEC2s function as stem cells in the lung, regenerating lung epithelial tissue after injury from toxic air pollutants or infections. However, with aging or in diseases like IPF, AEC2s lose their ability to differentiate and repopulate the lower airway, leading to the buildup of scar tissue. Michael Bollong, a chemical biologist at Scripps Research, sought a way to reverse this process and restore the regenerative ability of AEC2s.
Identifying DPP4 Inhibitors
Through a phenotypic screen of the ReFRAME drug repurposing library, Bollong and his team identified dipeptidyl peptidase-4 (DPP4) inhibitors as a class of drugs that could restore AEC2s’ ability to regenerate. The ReFRAME library, a unique asset of Scripps Research and Calibr, contains approximately 13,000 molecules that have been in Phase 1 clinical trials.
Mechanism of Action
DPP4 is an extracellular protease known for degrading incretin hormones, but it also degrades several signaling molecules. It is strongly expressed in AEC2s and epithelial cells lining the lung lumen. Researchers found that DPP4 inhibitors work by blocking the degradation of growth factors such as IGF-1 and IL-6, which are essential for expanding and differentiating AEC2s.
Development of CMR316
While commercial oral DPP4 inhibitors were initially considered, they were found to be ineffective in the lung due to their high membrane permeability. To address this, the researchers chemically modified the drug to have low membrane permeability, ensuring it remains in the lung lumen to engage DPP4. This modified drug, CMR316, is delivered directly to the lung as a nebulized solution.
Clinical Trial and Future Prospects
CMR316 has now entered a Phase 1 clinical trial. According to Bollong, it is incredibly rewarding to see an idea progress to being tested in patients, especially as the project was conducted internally at Scripps Research in collaboration with Peter Schultz's group and Calibr, without external pharma sponsorship.
