Gene therapy of inherited diseases has provided convincing evidence of therapeutic benefits for many treated patients. In particular, treatment of primary severe congenital immunodeficiencies by gene transfer into hematopoietic stem cells ( HSCs ) has proven in some cases to be as beneficial as allogeneic stem cell transplantation, the treatment of choice for these diseases if HLA-matched donors are available.
Researchers have conducted a phase I clinical trial aimed at the correction of X-CGD, a rare inherited immunodeficiency characterized by severe and life threatening bacterial and fungal infections as well as widespread tissue granuloma formation.
Phagocytic cells of CGD patients fail to kill ingested microbes due to a defect in the nicotinamide dinucleotide phosphate ( NADPH ) oxidase complex resulting in compromised antimicrobial activity.
In this clinical trial researchers used a gammaretroviral vector with strong enhancer-promoter sequences in the long terminal repeats ( LTRs ) to genetically modify CD34 + cells in two X-CGD patients.
After successful reconstitution of phagocytic functions, both patients experienced a clonal outgrowth of gene marked cells caused by vector-mediated insertional activation of proto-oncogenes leading to the development of myeloid malignancies.
Moreover, functional correction of gene transduced cells decreased with time, due to epigenetic inactivation of the vector promoter within the LTR, resulting in the accumulation of non-functional gene transduced cells.
The understanding of the molecular basis of insertional mutagenesis has motivated the development of advanced integrating vectors with equal therapeutic potency but reduced genotoxicity.
In particular, the deletion of the enhancer elements within the viral LTR U3 regions has significantly contributed to the reduction of genotoxic effects associated with LTR-driven gammaretroviral vectors.
Moreover, the use of tissue specific promoters, which are inactive in stem/progenitor cells but active in terminally differentiated cells, should further increase the safety level of SIN vectors.
Based on the aforementioned advancements, researchers developed SIN gammaretroviral and lentiviral vectors for the safe and effective gene therapy of X-linked CGD.
They combined the SIN configuration with an internal promoter, with preferential expression in myeloid cells. ( Xagena )
Grez M, Human Gene Therapy, 2013