Human Lentiviral Gene Therapy Restores the Cellular Phenotype of Autosomal Recessive Complete IFN-γR1 Deficiency

Abstract

Autosomal recessive (AR) complete interferon-g receptor 1 (IFN-gR1) 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-gR-downstream signaling cascade. In our study, we developed lentiviral vectors constitutively expressing the human IFN-gR1 and demonstrate stable transgene expression without interference with cell viability and proliferation in transduced human hematopoietic cells. Using an IFN-gR1-deficient HeLa cell model, we show stable receptor reconstitution and restored IFN-gR1 signaling without adverse effect on cell functionality. Transduction of both SV40-immortalized and primary fibroblasts derived from IFN-gR1-deficient MSMD patients was able to recover IFN-gR1 expression and restore type II IFN signaling upon stimulation with IFN-g. In summary, we highlight lentiviral vectors to correct the IFN-g mediated immunity and present the first gene therapy approach for patients suffering from AR complete IFN-gR1 deficiency.

Diagnosis and Management of Infections in Patients with Mendelian Susceptibility to Mycobacterial Disease

“…The self-inactivating lentiviral vector, which targets primitive hematopoetic stem cells, has led to a better safety profile and efficacy [ 93 ]. A recent study described a lenti-viral-based gene therapy approach to correct cellular phenotypes in AR patients with complete IFNγR1 deficiency [ 94 ]. A mouse model with complete IFNGR1 deficiency was transplanted using lentiviral-based gene therapy [ 95 ].…”

An Updated Review on MSMD Research Globally and A Literature Review on the Molecular Findings, Clinical Manifestations, and Treatment Approaches in China

“…A recent study presented the first gene therapy approach for patients suffering from AR complete IFN-γR1 deficiency. Lentiviral vectors were used to correct defective IFN-γ-mediated immunity without generating GVHD ( 124 ), and we expect HSCGT to become an increasingly effective method to cure PID patients in the future.…”

Pediatric immune deficiencies: current treatment approaches

“…The experience with XL-CGD and WAS continues to be immature but so far it has been shown partial correction of the disease [63][64][65][66]. Autologous gene-corrected T-cell therapy may resolve the defect in IEIs with restricted defects to the T cells, so far, this approach has been investigated in preclinical models [67][68][69][70][71][72].…”