Summary
This project aims to improve the success of in utero hematopoietic stem cell transplantation (IUTx) for genetic disorders, particularly sickle cell disease (SCD), by understanding and overcoming engraftment barriers and validating a sheep model for therapeutic testing.
What they want
The project proposes three aims: (1) define and overcome barriers to engraftment using non-genotoxic conditioning in fetal sheep to understand the roles of niche availability, host HSC competition, and fetal immunity; (2) determine the impact of donor HSC phenotype and functionality on engraftment levels after IUTx; and (3) validate a CRISPR/Cas-edited sheep model for SCD by monitoring animals, identifying stressors for crises, defining complications, and testing the therapeutic efficacy of IUTx for SCD.
Deliverables
- Identification of mechanisms involved in resistance to HSC engraftment
- Achievement of a minimum target of 20-25% HSC engraftment
- Validation of a highly clinically relevant sheep SCD model
- Testing of the therapeutic efficacy of IUTx for treating/curing SCD
Technical requirements
- Use of fetal sheep as a model
- Non-genotoxic conditioning
- CRISPR/Cas editing
- Somatic cell nuclear transfer
- Hb electrophoresis
- Monitoring animals over time
