Cerebral organoids

Autor: Pavlina Konstantinova, Lance A. Mulder, Katja C. Wolthers, Marina Sogorb-Gonzalez, Josse A. Depla, Melvin M. Evers, Dasja Pajkrt, Vivi M. Heine, Adithya Sridhar, Sander J. H. van Deventer
Přispěvatelé: AII - Infectious diseases, Graduate School, Medical Microbiology and Infection Prevention, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Human genetics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), Complex Trait Genetics
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Depla, J A, Sogorb-Gonzalez, M, Mulder, L A, Heine, V M, Konstantinova, P, van Deventer, S J, Wolthers, K C, Pajkrt, D, Sridhar, A & Evers, M M 2020, ' Cerebral Organoids : A Human Model for AAV Capsid Selection and Therapeutic Transgene Efficacy in the Brain ', Molecular Therapy-Methods and Clinical Development, vol. 18, pp. 167-175 . https://doi.org/10.1016/j.omtm.2020.05.028
Molecular therapy. Methods & clinical development, 18, 167-175. Nature Publishing Group
Molecular Therapy-Methods and Clinical Development, 18, 167-175. Cell Press
Molecular Therapy-Methods and Clinical Development, 18, 167-175. CELL PRESS
Molecular Therapy: Methods & Clinical Development, Vol 18, Iss, Pp 167-175 (2020)
Molecular Therapy-Methods and Clinical Development
Molecular Therapy. Methods & Clinical Development
Molecular Therapy-Methods & Clinical Development
ISSN: 2329-0501
Popis: The development of gene therapies for central nervous system disorders is challenging because it is difficult to translate preclinical data from current in vitro and in vivo models to the clinic. Therefore, we developed induced pluripotent stem cell (iPSC)-derived cerebral organoids as a model for recombinant adeno-associated virus (rAAV) capsid selection and for testing efficacy of AAV-based gene therapy in a human context. Cerebral organoids are physiological 3D structures that better recapitulate the human brain compared with 2D cell lines. To validate the model, we compared the transduction efficiency and distribution of two commonly used AAV serotypes (rAAV5 and rAAV9). In cerebral organoids, transduction with rAAV5 led to higher levels of vector DNA, transgenic mRNA, and protein expression as compared with rAAV9. The superior transduction of rAAV5 was replicated in iPSC-derived neuronal cells. Furthermore, rAAV5-mediated delivery of a human sequence-specific engineered microRNA to cerebral organoids led to a lower expression of its target ataxin-3. Our studies provide a new tool for selecting and deselecting AAV serotypes, and for demonstrating therapeutic efficacy of transgenes in a human context. Implementing cerebral organoids during gene therapy development could reduce the usage of animal models and improve translation to the clinic.
Graphical Abstract
Induced pluripotent stem cell-derived cerebral organoids are an innovative human model of the brain that could improve translation of gene therapy to the clinic. Depla et al. demonstrate the application of cerebral organoids as a preclinical model for AAV capsid selection and testing efficacy of therapeutic transgenes.
Databáze: OpenAIRE
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