Bioengineering strategies for exogenic organ production

The overall goal for this revised Phase 1 grant proposal is to significantly enhance the efficiency of generating human vasculature in a pig. This product will provide an unlimited number of organs (such as hearts) for xenotransplantation and will be associated with decreased immunological barriers. Problem: The only curative therapy for endstage diseases such as heart failure is solid organ transplantation. Millions of patients (worldwide) could benefit from such therapy but are not eligible for transplantation due to limited donor organ availability. Therefore, there is an urgent need to develop alternative organ sources for transplantation. Our early stage prototype, using somatic cell nuclear transfer technology (SCNT; cloning) and blastocyst complementation provides proof of concept for the feasibility of our platform and patented technology whereby we have successfully engineered viable and normal intraspecies porcine chimeras and have further generated human vasculature in early staged porcine embryos. While our publications and patents indicate the importance and feasibility of this platform approach, the process of SCNT is inherently inefficient. Solution: Therefore, in order to transform the field and maximally increase the efficiency of engineering vasculature in a gene edited pig, we will compare our proven (and published) approach using SCNT with in vitro fertilization/zygote gene editing/blastocyst complementation. In this Phase I grant application, we predict that zygote editing and blastocyst complementation will provide a more efficient and economical platform for the production of human vasculature and these human-porcine chimeras will serve as an unlimited source of organs (such as hearts) for exogenic organ transplantation. As outlined in this Phase I proposal, we will pursue our specific aims, achieve our five milestones and produce four products. The successful completion of the Phase I studies will provide a platform to exponentially increase the production exogenic organs for research and therapies to fulfill an unmet and urgent need. Live, fully functional interspecies chimeras that have either a completely nonhuman primate (macaque) or humanized vasculature in a gene edited pig will be produced in the future Phase II proposal. Project Number: 1R41HL174447-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Daniel Garry | Institution: NORTHSTAR GENOMICS, LLC, EAGAN, MN | Award Amount: $279,750 | Activity Code: R41 | Study Section: Special Emphasis Panel[ZRG1 MCST-G (15)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R41HL17444701A1