PROJECT SUMMARY IPF is a terminal lung disease causing 40,000 deaths in the US each year, with a life expectancy of three to five years, and characterized by the formation of sporadic patches of fibrotic tissue scarring resulting in inevitable lung failure. Currently, there are only two palliative treatments available and lung transplant is a rare solution only 0.02% of patients can access. There is a growing interest in cell replacement therapy (CeRT) to restore organ function. Cellforma founders have demonstrated that CeRT is feasible and showed efficacy in an IPF mouse model. However, a scalable and cost-effective way to acquire the cells needed for IPF CeRT in patients is currently not yet achieved. Chemical reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) has recently been demonstrated but generating the IPF-relevant human lung cell types required has not been achieved. Cellforma is developing a data-driven, artificial intelligence/machine learning (AI/ML) platform to identify scalable and cost-effective chemical strategies to reprogram easy-to-acquire cells, such as human dermal fibroblasts (HDFs) from the skin, into hard or impossible-to-acquire lung cells. The company's graph- based AI/ML examines the complexity of cell behavior using chemical perturbation data to produce “reprogramming maps” that allow the generation of the desired cell types, faster protocol discovery times compared to current trial-and-error approaches, and without genetic engineering, viral vectors, or expensive growth factors. Cellforma will develop a mixture of reprogrammed human lung epithelial progenitor and supporting cells as a curative, first-in-class, CeRT for IPF patients. For this SBIR Phase I AIM 1 is to develop gene regulatory and chemical graph-based AI/ML to identify HDF-to-lung chemical reprogramming strategies. AIM 2 is to generate IPF-relevant lung cell types and experimentally assess their stability and functionality. HDFs or iPSCs will be reprogrammed into the desired lung AT2, and stromal fibroblast (SF) cell types. Cellforma aims to demonstrate that chemical reprogramming of HDFs to these relevant cells types can be performed at efficiencies higher than current standards. At the end of Phase I, Cellforma is expected to have established proprietary AI/ML to identify chemical protocols to transform HDFs into the lung AT2, and SFs required for CeRT in IPF patients with experimental validation of successful chemical cell reprogramming.