Secreted therapeutics: monitoring durability of microRNA-based gene therapies in the central nervous system


Posted: 2021-10-27 19:00:00
Brain Commun . 2021 Apr 1;3(2):fcab054. doi: 10.1093/braincomms/fcab054. eCollection 2021. Marina Sogorb-Gonzalez 1 2 , Carlos Vendrell-Tornero 1 , Jolanda Snapper 1 , Anouk Stam 1 , Sonay Keskin 1 , Jana Miniarikova 1 2 , Elisabeth A Spronck 1 , Martin de Haan 1 , Rienk Nieuwland 3 , Pavlina Konstantinova 1 , Sander J van Deventer 1 2 , Melvin M Evers 1 , Astrid Vallès 1 Affiliations Expand Affiliations 1 Department of Research and Development, uniQure Biopharma N.V., Amsterdam, 1105 BP, The Netherlands. 2 Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands. 3 Laboratory of Experimental Clinical Chemistry, and Vesicles Observation Center, Amsterdam UMC, University of Amsterdam, Amsterdam, 1105 AZ, The Netherlands. Item in Clipboard Marina Sogorb-Gonzalez et al. Brain Commun. 2021. Show details Display options Display options Format Brain Commun . 2021 Apr 1;3(2):fcab054. doi: 10.1093/braincomms/fcab054. eCollection 2021. Authors Marina Sogorb-Gonzalez 1 2 , Carlos Vendrell-Tornero 1 , Jolanda Snapper 1 , Anouk Stam 1 , Sonay Keskin 1 , Jana Miniarikova 1 2 , Elisabeth A Spronck 1 , Martin de Haan 1 , Rienk Nieuwland 3 , Pavlina Konstantinova 1 , Sander J van Deventer 1 2 , Melvin M Evers 1 , Astrid Vallès 1 Affiliations 1 Department of Research and Development, uniQure Biopharma N.V., Amsterdam, 1105 BP, The Netherlands. 2 Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands. 3 Laboratory of Experimental Clinical Chemistry, and Vesicles Observation Center, Amsterdam UMC, University of Amsterdam, Amsterdam, 1105 AZ, The Netherlands. Item in Clipboard CiteDisplay options Display options Format Abstract The preclinical development of microRNA-based gene therapies for inherited neurodegenerative diseases is accompanied by translational challenges. Due to the inaccessibility of the brain to periodically evaluate therapy effects, accessible and reliable biomarkers indicative of dosing, durability and therapeutic efficacy in the central nervous system are very much needed. This is particularly important for viral vector-based gene therapies, in which a one-time administration results in long-term expression of active therapeutic molecules in the brain. Recently, extracellular vesicles have been identified as carriers of RNA species, including microRNAs, and proteins in all biological fluids, whilst becoming potential sources of biomarkers for diagnosis. In this study, we investigated the secretion and potential use of circulating miRNAs associated with extracellular vesicles as suitable sources to monitor the expression and durability of gene therapies in the brain. Neuronal cells derived from induced pluripotent stem cells were treated with adeno-associated viral vector serotype 5 carrying an engineered microRNA targeting huntingtin or ataxin3 gene sequences, the diseases-causing genes of Huntington disease and spinocerebellar ataxia type 3, respectively. After treatment, the secretion of mature engineered microRNA molecules was confirmed, with extracellular microRNA levels correlating with viral dose and cellular microRNA expression in neurons. We further investigated the detection of engineered microRNAs over time in the CSF of non-human primates after a single intrastriatal injection of adeno-associated viral vector serotype 5 carrying a huntingtin-targeting engineered microRNA. Quantifiable engineered microRNA levels enriched in extracellular vesicles were detected in the CSF up to 2 years after brain infusion. Altogether, these results confirm the long-term expression of adeno-associated viral vector serotype 5-delivered microRNAs and support the use of extracellular vesicle-associated microRNAs as novel translational pharmacokinetic markers in ongoing clinical trials of gene therapies for neurodegenerative diseases. Keywords: Huntington disease; extracellular vesicles; gene therapy; microRNA; spinocerebellar ataxia. © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com. LinkOut - more resources Research Materials [x] Cite Copy Format: Send To [x]

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