ImmTOR nanoparticles enhance AAV transgene expression after initial and repeat dosing in a mouse model of methylmalonic acidemia
| العنوان: | ImmTOR nanoparticles enhance AAV transgene expression after initial and repeat dosing in a mouse model of methylmalonic acidemia |
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| المؤلفون: | Irini Manoli, Alicia M. Michaud, Takashi Kei Kishimoto, Teresa Capela, Lloyd Johnston, Aparajita C. Chowdhury, Stephanie L. Elkins, Sheldon S. Leung, Gina L. Rizzo, Christopher J. Roy, Randy J. Chandler, Charles P. Venditti, Luk H. Vandenberghe, Petr Ilyinskii, Lina Li, Eva Andres-Mateos |
| المصدر: | Molecular Therapy: Methods & Clinical Development, Vol 22, Iss, Pp 279-292 (2021) Molecular Therapy. Methods & Clinical Development |
| بيانات النشر: | Elsevier BV, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Genetic enhancement, Transgene, Methylmalonic acidemia, Methylmalonic acid, QH426-470, Virus, Transduction (genetics), chemistry.chemical_compound, Immune system, Genetics, medicine, ImmTOR rapamycin-encapsulated nanoparticles, Molecular Biology, immunogenicity mitigation, QH573-671, biology, Chemistry, medicine.disease, gene therapy, Molecular biology, biology.protein, Molecular Medicine, Original Article, re-dosing, Antibody, Cytology |
| الوصف: | A major barrier to adeno-associated virus (AAV) gene therapy is the inability to re-dose patients due to formation of vector-induced neutralizing antibodies (Nabs). Tolerogenic nanoparticles encapsulating rapamycin (ImmTOR) provide long-term and specific suppression of adaptive immune responses, allowing for vector re-dosing. Moreover, co-administration of hepatotropic AAV vectors and ImmTOR leads to an increase of transgene expression even after the first dose. ImmTOR and AAV Anc80 encoding the methylmalonyl-coenzyme A (CoA) mutase (MMUT) combination was tested in a mouse model of methylmalonic acidemia, a disease caused by mutations in the MMUT gene. Repeated co-administration of Anc80 and ImmTOR was well tolerated and led to nearly complete inhibition of immunoglobulin (Ig)G antibodies to the Anc80 capsid. A more profound decrease of plasma levels of the key toxic metabolite, plasma methylmalonic acid (pMMA), and disease biomarker, fibroblast growth factor 21 (FGF21), was observed after treatment with the ImmTOR and Anc80-MMUT combination. In addition, there were higher numbers of viral genomes per cell (vg/cell) and increased transgene expression when ImmTOR was co-administered with Anc80-MMUT. These effects were dose-dependent, with the higher doses of ImmTOR providing higher vg/cell and mRNA levels, and an improved biomarker response. Combining of ImmTOR and AAV can not only block the IgG response against capsid, but it also appears to potentiate transduction and enhance therapeutic transgene expression in the mouse model. Graphical abstract Kishimoto and colleagues extend their earlier findings showing that combining ImmTOR rapamycin-encapsulated nanoparticles with hepatotropic AAV vector leads to increased transduction, transgene expression, and suppression of IgG responses and therefore enables effective therapeutic AAV vector re-dosing in a mouse model of methylmalonic acidemia, an inborn metabolic disease. |
| تدمد: | 2329-0501 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::889a9ffee8669fa2cd9d4f735cfd13c4 https://doi.org/10.1016/j.omtm.2021.06.015 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....889a9ffee8669fa2cd9d4f735cfd13c4 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23290501 |
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