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Human Lentiviral Gene Therapy Restores the Cellular Phenotype of Autosomal Recessive Complete IFN-γR1 Deficiency.
Hahn, Katharina Pollmann, Liart Nowak, Juliette Nguyen, Ariane Hai Ha Haake, Kathrin Neehus, Anna-Lena Waqas, Syed F Hassnain Pessler, Frank Baumann, Ulrich Hetzel, Miriam
Hahn, Katharina
Pollmann, Liart
Nowak, Juliette
Nguyen, Ariane Hai Ha
Haake, Kathrin
Neehus, Anna-Lena
Waqas, Syed F Hassnain
Pessler, Frank
Baumann, Ulrich
Hetzel, Miriam
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2020-04-11
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2020-05-12
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Abstract
Autosomal recessive (AR) complete interferon-γ receptor 1 (IFN-γR1) 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-γR-downstream signaling cascade. In our study, we developed lentiviral vectors constitutively expressing the human IFN-γR1 and demonstrate stable transgene expression without interference with cell viability and proliferation in transduced human hematopoietic cells. Using an IFN-γR1-deficient HeLa cell model, we show stable receptor reconstitution and restored IFN-γR1 signaling without adverse effect on cell functionality. Transduction of both SV40-immortalized and primary fibroblasts derived from IFN-γR1-deficient MSMD patients was able to recover IFN-γR1 expression and restore type II IFN signaling upon stimulation with IFN-γ. In summary, we highlight lentiviral vectors to correct the IFN-γ mediated immunity and present the first gene therapy approach for patients suffering from AR complete IFN-γR1 deficiency.
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Mol Ther Methods Clin Dev. 2020 Apr 11;17:785-795. doi: 10.1016/j.omtm.2020.04.002. eCollection 2020 Jun 12.
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Article
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en
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2329-0501
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Attribution-NonCommercial-ShareAlike 4.0 International