Dosage Thresholds and Influence of Transgene Cassette in Adeno-Associated Virus–Related Toxicity
| Autor: | Hanen Khabou, Deniz Dalkara, Laure Pacot, Sylvain Fisson, Chloé Cordeau |
|---|---|
| Přispěvatelé: | Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Généthon, Genethon - Inserm UMR_S951, Immunologie moléculaire et biothérapies innovantes (IMBI), GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Généthon, Association française contre les myopathies (AFM-Téléthon)-Association française contre les myopathies (AFM-Téléthon) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Retinal Disorder MESH: gene therapy retina AAV GFP toxicity promoter Transgene Genetic enhancement viruses Genetic Vectors Green Fluorescent Proteins Gene Dosage medicine.disease_cause Virus Green fluorescent protein 03 medical and health sciences Capsid 0302 clinical medicine Genetics medicine Animals Transgenes Molecular Biology Adeno-associated virus Retina [SDV.GEN]Life Sciences [q-bio]/Genetics business.industry Immunity Genetic Therapy Dependovirus Virology 3. Good health Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure [SDV.TOX]Life Sciences [q-bio]/Toxicology Toxicity Molecular Medicine business 030217 neurology & neurosurgery |
| Zdroj: | Human Gene Therapy Human Gene Therapy, Mary Ann Liebert, 2018, ⟨10.1089/hum.2018.144⟩ Human Gene Therapy, Mary Ann Liebert, 2018, 0, ⟨10.1089/hum.2018.144⟩ |
| ISSN: | 1043-0342 |
| DOI: | 10.1089/hum.2018.144⟩ |
| Popis: | International audience; Today, there are >500 published studies and 40 clinical trials to treat retinal disorders using gene therapy. The great majority of them rely on the use of adeno-associated virus vectors (AAV) for therapeutic gene delivery. Thus far, AAVs have an excellent safety profile in the clinic. Nevertheless, it is known that AAV-mediated gene delivery leads to toxicity at higher input doses in experimental gene therapy. This study reveals the factors that contribute to retinal toxicity after subretinal administration of AAV vectors in wild-type mice. The study shows that alongside the input dose, the nature of the transgene and the cells mediating the expression determine the extent of toxicity. Importantly, the study shows that AAV vectors encoding green fluorescent protein (GFP) used as controls in experimental gene therapy are toxic at doses as low as 5 × 109 vg, confounding the observed therapeutic effect in gene therapy paradigms. Altogether, the data show the importance of reducing input doses while increasing transgene expression levels via the use of more efficient capsids and promoters in order to avoid side effects in AAV-mediated gene therapy. Furthermore, the toxicity observed with AAV-GFP vectors imply a reinterpretation of previous gene therapy studies where the therapeutic effect was measured in relation to this control. |
| Databáze: | OpenAIRE |
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