STTR Phase I: Autologous Hematopoietic Stem Cell Production to End Graft-Versus-Host Disease

The broader impact of this Small Business Technology Transfer (STTR) Phase I project is the potential elimination of Graft-Versus-Host Disease (GVHD). GVHD is a devastating illness that afflicts transplant recipients who are recovering from chemotherapy and who suffer from suppression of their bone marrow function and immune system. GVHD associated illnesses lead to a very high rate of premature death in these patients. This project focuses on the development of a novel biocomputational platform to generate patient-derived stem cells to be subsequently reintroduced to the same cancer patient. This completely bypasses third-party bone marrow and blood donations, decreasing, and potentially eliminating, lethal GVHD and drastically improving outcomes. The use of cells derived directly from the same patient (e.g. skin cells) to reconstitute the blood system is considered one of the highest and most challenging goals of blood system regenerative biology research. This will advance bioinformatics and cell therapy research and will advance the state-of-the-art in cancer treatment and personalized medicine. The proposed project will use a high-fidelity prototype computational tool to generate transcription factor recipes for cellular transdifferentiation, test those predicted recipes through systematic and high-throughput wetlab validations, and demonstrate proof of concept for the autologous production of persistent HSCs that maintain long-term multilineage engraftment and self-renewal, potentially enabling recapitulation of the entire blood lineage. The project scope includes an effort to survey, identify, and procure appropriate initial cell types; determine cell type-specific predictions for reprogramming into HSCs; prioritize the most promising recipes and carry out appropriate viral transductions; create an in vitro analog of target HSCs and determine alignment with the human HSC phenotype; and perform reprogramming experiments for the top transcription factor recipes. Data analysis will include key comparisons of reprogrammed HSCs, in vitro analog HSCs, primary human HSCs, and data from prior published efforts to produce HSCs. HSCs are fundamentally different from the differentiated cell types previously targeted with the computational tool, as they retain proliferative potential and are therefore very difficult to generate. Proof of concept in this challenging system will not only address GVHD, but also further prove the efficacy of the overall biocomputational platform for use in numerous other biological systems and potential cures. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.