< Terug naar vorige pagina

Publicatie

A Novel Platform for Immune Tolerance Induction in Hemophilia A Mice

Tijdschriftbijdrage - Tijdschriftartikel

Hemophilia A (HA) is an X-linked bleeding disease caused by factor VIII (FVIII) deficiency. We previously demonstrated that FVIII is produced specifically in liver sinusoid endothelial cells (LSECs) and to some degree in myeloid cells, and thus, in the present work, we seek to restrict the expression of FVIII transgene to these cells using cell-specific promoters. With this approach, we aim to limit immune response in a mouse model by lentiviral vector (LV)-mediated gene therapy encoding FVIII. To increase the target specificity of FVIII expression, we included miRNA target sequences (miRTs) (i.e., miRT-142.3p, miRT-126, and miRT-122) to silence expression in hematopoietic cells, endothelial cells, and hepatocytes, respectively. Notably, we report, for the first time, therapeutic levels of FVIII transgene expression at its natural site of production, which occurred without the formation of neutralizing antibodies (inhibitors). Moreover, inhibitors were eradicated in FVIII pre-immune mice through a regulatory T cell-dependent mechanism. In conclusion, targeting FVIII expression to LSECs and myeloid cells by using LVs with cell-specific promoter minimized off-target expression and immune responses. Therefore, at least for some transgenes, expression at the physiologic site of synthesis can enhance efficacy and safety, resulting in long-term correction of genetic diseases such as HA.

Tijdschrift: Molecular Therapy : The Journal of the American Society of Gene Therapy
ISSN: 1525-0016
Issue: 8
Volume: 25
Pagina's: 1815-1830
Jaar van publicatie:2017
Trefwoorden:Animals, CD11b Antigen/genetics, Disease Models, Animal, Endothelial Cells/metabolism, Factor VIII/genetics, Gene Expression, Genes, Reporter, Genetic Vectors/genetics, Hemophilia A/genetics, Immune Tolerance/genetics, Immunization, Immunosuppression/methods, Isoantibodies/blood, Lentivirus/genetics, Male, Mice, Mice, 129 Strain, Mice, Inbred BALB C, Mice, Inbred C57BL, Organ Specificity/genetics, Promoter Regions, Genetic, T-Lymphocytes, Regulatory/immunology, Transduction, Genetic, Transgenes, Whole Blood Coagulation Time
Auteurs:International
Toegankelijkheid:Open