Bioengineered AAV Capsids with Combined High Human Liver Transduction In Vivo and Unique Humoral Seroreactivity
| Autor: | Andrew M. Davidoff, Nicole K. Paulk, Sean Nygaard, Feijie Zhang, Amit C. Nathwani, Annelise Haft, Bin Li, Katja Pekrun, Marcus B. Valentine, Kirk Chu, Mark A. Kay, Markus Grompe, Erhua Zhu, Jianpeng Xu, Christopher L. Morton, Ian E. Alexander, Allison P Dane, Yue Zhang, Federico Mingozzi, Leszek Lisowski, Christian Leborgne |
|---|---|
| Přispěvatelé: | Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-GENETHON 3-École pratique des hautes études (EPHE), Centre de Physique des Particules de Marseille (CPPM), Aix Marseille Université (AMU)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Tongji University, UR 1268 Biopolymères Interactions Assemblages, Institut National de la Recherche Agronomique (INRA), University of Manchester [Manchester], NASA Goddard Space Flight Center (GSFC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, École Pratique des Hautes Études (EPHE) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Models Molecular Protein Conformation Genetic enhancement viruses [SDV]Life Sciences [q-bio] Genetic Vectors Biology Virus Neutralization law.invention 03 medical and health sciences Transduction (genetics) Mice law In vivo Transduction Genetic Drug Discovery Genetics medicine Animals Humans Molecular Biology Pharmacology Gene Transfer Techniques Dependovirus Virology 3. Good health 030104 developmental biology medicine.anatomical_structure Capsid Liver Hepatocyte Recombinant DNA Hepatocytes Molecular Medicine Heterografts Original Article Capsid Proteins Female Genetic Engineering |
| Zdroj: | Molecular Therapy Molecular Therapy, Nature Publishing Group, 2018, 26, pp.289-303. ⟨10.1016/j.ymthe.2017.09.021⟩ Molecular Therapy, Cell Press, 2018, 26, pp.289-303. ⟨10.1016/j.ymthe.2017.09.021⟩ Molecular Therapy, 2018, 26, pp.289-303. ⟨10.1016/j.ymthe.2017.09.021⟩ |
| ISSN: | 1525-0016 1525-0024 |
| DOI: | 10.1016/j.ymthe.2017.09.021⟩ |
| Popis: | International audience; Existing recombinant adeno-associated virus (rAAV) serotypes for delivering in vivo gene therapy treatments for human liver diseases have not yielded combined high-level human hepatocyte transduction and favorable humoral neutralization properties in diverse patient groups. Yet, these combined properties are important for therapeutic efficacy. To bioengineer capsids that exhibit both unique seroreactivity profiles and functionally transduce human hepatocytes at therapeutically relevant levels, we performed multiplexed sequential directed evolution screens using diverse capsid libraries in both primary human hepatocytes in vivo and with pooled human sera from thousands of patients. AAV libraries were subjected to five rounds of in vivo selection in xenografted mice with human livers to isolate an enriched human-hepatotropic library that was then used as input for a sequential on-bead screen against pooled human immunoglobulins. Evolved variants were vectorized and validated against existing hepatotropic serotypes. Two of the evolved AAV serotypes, NP40 and NP59, exhibited dramatically improved functional human hepatocyte transduction in vivo in xenografted mice with human livers, along with favorable human seroreactivity profiles, compared with existing serotypes. These novel capsids represent enhanced vector delivery systems for future human liver gene therapy applications. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|