TABLE 3.

Steps of hematopoietic stem cell gene therapy and main advantages over Allo-HSCT in IEM with neurological involvement.

Steps of HSC-GT
1. Collection of autologous HSC
2. Ex vivo transduction of HSC with gene vectors encoding supraphysiological levels of the enzyme of interest
3. Busulfan-based conditioning regimen
4. Infusion of transduced HSC
5. Transduced HSC cross the BBB and engraft in the brain as microglia/macrophages
6. Microglial function is restored
7. Supraphysiological levels of the lacking enzyme are deployed into the brain (“Trojan Horse”)
Main advantages over Allo-HSCT
No need for a compatible donor
Shorter diagnosis-to-transplant time
Potential eligibility of patients with more advanced disease
Less intensive conditioning regimen
No need for GvHD prophylaxis
Absent risk of GvHD or graft rejection

HSC-GT, hematopoietic stem cell gene therapy; HSC, hematopoietic stem cells; BBB, blood-brain barrier; Allo-HSCT, allogeneic hematopoietic stem cell transplantation; GvHD, graft vs. host disease.