In vivo cell engineering using a bone marrow organoid

PROJECT SUMMARY/ABSTRACT This project tests a bioinstructive material capable of forming bone and bone marrow in a localized, easily accessible subcutaneous site as a delivery portal for anti-HIV genetic engineering constructs. The larger goal is to enable genetic engineering of blood progenitor and stem cells without requiring hematopoietic stem cell transplantation and without incurring the liabilities of systemically delivered gene modifying vectors. By enabling easy access to a subcutaneous bone marrow organoid, small concentrations of gene engineering vectors can be locally administered reducing the cost of goods and likelihood of modifying other organs. The organoid will be tuned to produce specific subsets of cells appropriate for the varying anti-HIV constructs in Projects 1 and 2. The ability of this strategy to generate HIV-1 resistant stem and progenitor cells will be tested in humanized mice and non-human primates in close collaboration with investigators in this project and the larger program.