Immunosuppression overcomes insulin- and vector-specific immune responses that limit efficacy of AAV2/8-mediated insulin gene therapy in NOD mice
| Autor: | Asha Recino, Nick Holmes, Rob Foale, Shu Uin Gan, Fiona M. Gribble, Kian Chuan Sia, Yvonne Sawyer, Anne Cooke, Maja Wallberg, Roy Y Calne, Kok Onn Lee, Frank Reimann, Amit C. Nathwani, Jenny Trendell, Maria Notaridou, Richard Kay, Andrew M. L. Lever |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Genetic enhancement medicine.medical_treatment T-Lymphocytes Adaptive immunity Autoimmunity Nod Mice SCID Biology Article Diabetes Mellitus Experimental 03 medical and health sciences Mice 0302 clinical medicine Immune system Mice Inbred NOD Genetics medicine Animals Humans Insulin Molecular Biology Immunological disorders Proinsulin NOD mice Immunosuppression Therapy Immunosuppression Genetic Therapy Dependovirus Acquired immune system 3. Good health Mice Inbred C57BL 030104 developmental biology HEK293 Cells Liver 030220 oncology & carcinogenesis Immunology CD4 Antigens Molecular Medicine |
| Zdroj: | Gene Therapy |
| ISSN: | 1476-5462 0969-7128 |
| Popis: | We report the restoration of euglycaemia in chemically induced diabetic C57BL/6 mice and spontaneously diabetic Non Obese Diabetic (NOD) mice by intravenous systemic administration of a single-stranded adeno-associated virus (ssAAV2/8) codon optimised (co) vector encoding furin cleavable human proinsulin under a liver-specific promoter. There were no immunological barriers to efficacy of insulin gene therapy in chemically induced C57BL/6 mice, which enjoyed long-lasting correction of hyperglycaemia after therapy, up to 250 days. Euglycaemia was also restored in spontaneously diabetic NOD mice, although these mice required a 7–10-fold higher dose of vector to achieve similar efficacy as the C57BL/6 mice and the immunodeficient NODscid mice. We detected CD8+ T cell reactivity to insulin and mild inflammatory infiltration in the livers of gene therapy recipient NOD mice, neither of which were observed in the treated C57BL/6 mice. Efficacy of the gene therapy in NOD mice was partially improved by targeting the immune system with anti-CD4 antibody treatment, while transfer of NOD mouse AAV2/8-reactive serum to recipients prevented successful restoration of euglycaemia in AAV2/8-HLP-hINSco-treated NODscid mice. Our data indicate that both immune cells and antibodies form a barrier to successful restoration of euglycaemia in autoimmune diabetic recipient mice with insulin gene therapy, but that this barrier can be overcome by increasing the dose of vector and by suppressing immune responses. |
| Databáze: | OpenAIRE |
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