Human Lentiviral Gene Therapy Restores the Cellular Phenotype of Autosomal Recessive Complete IFN-?R1 Deficiency.

ABSTRACT: Autosomal recessive (AR) complete interferon-? receptor 1 (IFN-?R1) deficiency, also known as one genetic etiology of Mendelian susceptibility to mycobacterial disease (MSMD), is a life-threatening congenital disease leading to premature death. Affected patients present a pathognomonic predisposition to recurrent and severe infections with environmental mycobacteria or the Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine. Current therapeutic options are limited to antibiotic treatment and hematopoietic stem cell transplantation, however with poor outcome. Given the clinical success of gene therapy, we introduce the first lentiviral-based gene therapy approach to restore expression and function of the human IFN-?R-downstream signaling cascade. In our study, we developed lentiviral vectors constitutively expressing the human IFN-?R1 and demonstrate stable transgene expression without interference with cell viability and proliferation in transduced human hematopoietic cells. Using an IFN-?R1-deficient HeLa cell model, we show stable receptor reconstitution and restored IFN-?R1 signaling without adverse effect on cell functionality. Transduction of both SV40-immortalized and primary fibroblasts derived from IFN-?R1-deficient MSMD patients was able to recover IFN-?R1 expression and restore type II IFN signaling upon stimulation with IFN-?. In summary, we highlight lentiviral vectors to correct the IFN-? mediated immunity and present the first gene therapy approach for patients suffering from AR complete IFN-?R1 deficiency.

SUBMITTER: Hahn K 

PROVIDER: S-EPMC7184269 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature