Human Lentiviral Gene Therapy Restores the Cellular Phenotype of Autosomal Recessive Complete IFN-γR1 Deficiency
| Autor: | Liart Pollmann, Nico Lachmann, Katharina Hahn, Miriam Hetzel, Ulrich Baumann, Juliette Nowak, Anna-Lena Neehus, Jacinta Bustamante, Ariane Hai Ha Nguyen, Ansgar Schulz, Jean-Laurent Casanova, Frank Pessler, Kathrin Haake, Syed F. Hassnain Waqas, Mania Ackermann |
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| Přispěvatelé: | TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany. |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
lcsh:QH426-470 Transgene medicine.medical_treatment Genetic enhancement Cell Hematopoietic stem cell transplantation Article 03 medical and health sciences Transduction (genetics) 0302 clinical medicine Interferon Immunity Lentiviral Vectors Genetics medicine lcsh:QH573-671 IFN-γR1 deficiency Molecular Biology lcsh:Cytology business.industry Gene Therapy 3. Good health MSMD lcsh:Genetics Haematopoiesis 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research Molecular Medicine business medicine.drug |
| Zdroj: | Molecular therapy. Methods & clinical development United States Molecular Therapy-Methods & Clinical Development Molecular Therapy: Methods & Clinical Development, Vol 17, Iss, Pp 785-795 (2020) Molecular Therapy. Methods & Clinical Development |
| ISSN: | 2329-0501 |
| Popis: | 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. Graphical Abstract Current therapeutic options for IFNγR1-deficient Mendelian susceptibility to mycobacterial disease (MSMD) are limited to allogenic bone marrow transplantation. This study highlights lentiviral vectors to correct the cellular phenotype of IFNγR1-deficient HeLa cells and primary patient cells, paving the way for gene therapy strategies. |
| Databáze: | OpenAIRE |
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