A novel AAV9-dual microRNA-vector targeting GRIK2 in the hippocampus as a treatment for mesial temporal lobe epilepsy
Mesial temporal lobe epilepsy (mTLE) is the most prevalent type of epilepsy in adults. First and subsequent generations of anti-epileptic therapy regimens fail to decrease seizures in a large number of patients suffering from mTLE, leaving surgical ablation of part of the hippocampus as the only therapeutic option to potentially reach seizure freedom. GluK2 has recently been identified as a promising target for the treatment of mTLE using gene therapy. Here, we engineered an adeno-associated virus serotype 9 vector expressing a cluster of two synthetic microRNAs (miRNAs), expressed from the human synapsin promoter, that target <i>GRIK2</i> mRNA. Intra-hippocampal delivery of this vector in a mouse model of mTLE significantly reduced <i>GRIK2</i> expression and daily seizure frequency. This treatment also improved the animals' health, reduced their anxiety, and restored working memory. Focal administration of the vector to the hippocampus of cynomolgus monkeys in GLP toxicology studies led to the selective transduction of hippocampal neurons with little exposure elsewhere in the brain and no transduction outside the central nervous system. Expression of miRNAs in hippocampal neurons resulted in substantially decreased <i>GRIK2</i> mRNA expression. These data suggest that the intra-hippocampal delivery of a GMP-grade AAV9 encoding a synthetic miRNAs targeting <i>GRIK2</i> is a promising treatment strategy for mTLE.
Authors
- Morgane Wartel (ORCID: https://orcid.org/0000-0002-4955-7972)
- Nick Pearson
- Valérie Crépel (ORCID: https://orcid.org/0000-0003-0408-3766)
- Andreas Borta
- Justine Gautron
- Céline Boileau (ORCID: https://orcid.org/0000-0002-8078-2545)
- April R. Giles
- Stéphane J. Baudouin (ORCID: https://orcid.org/0000-0001-6902-6071)
- Irena Bočkaj (ORCID: https://orcid.org/0000-0001-5824-2414)
- Jared B. Smith (ORCID: https://orcid.org/0000-0002-0273-4898)
- Nicolas Partouche (ORCID: https://orcid.org/0000-0002-2092-6017)
- Séverine Deforges (ORCID: https://orcid.org/0000-0001-7450-6897)
- Didier Scavarda (ORCID: https://orcid.org/0000-0001-9344-8071)
- Jérôme Aupy (ORCID: https://orcid.org/0000-0001-7268-7479)
- Christophe Mulle (ORCID: https://orcid.org/0000-0003-2709-6615)
- Andrew C. Mercer (ORCID: https://orcid.org/0000-0002-9873-1519)
- Fabrice Bartoloméi (ORCID: https://orcid.org/0000-0002-1678-0297)
- Olivier Danos (ORCID: https://orcid.org/0000-0003-2202-4540)
- Chenxia He
- Richard H. Porter
- Jennifer Sims
- Guillaume Penchet
Institutions
- Inserm (FR)
- Aix-Marseille Université (FR)
- TiGenix (Spain) (ES)
- Assistance Publique Hôpitaux de Marseille (FR)
- Regenxbio (United States) (US)
- Institut de Neurosciences des Systèmes (FR)
- Hôpital Pellegrin (FR)
- Institut de Neurobiologie de la Méditerranée (FR)
- UniQure (Netherlands) (NL)
- Institut Interdisciplinaire de Neuroscience (FR)
- PIQUR Therapeutics (Switzerland) (CH)
- Hôpital de la Timone (FR)
Publication Details
- Journal
- Molecular Therapy — Methods & Clinical Development
- Published
- 2024-09-16
- DOI
- https://doi.org/10.1016/j.omtm.2024.101342
- Citations
- 12
- Primary Topic
- Genetics and Neurodevelopmental Disorders
- Type
- article
- Field-Weighted Citation Impact
- 6.60
Funders
- Aix-Marseille Université
- Bpifrance
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Centre National de la Recherche Scientifique
- Inserm Transfert