A novel AAV9-dual microRNA-vector targeting GRIK2 in the hippocampus as a treatment for mesial temporal lobe epilepsy.
Molecular Therapy - Methods & Clinical Development. 2024-12-01; 32(4): 101342
DOI: 10.1016/j.omtm.2024.101342
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Baudouin SJ(1), Giles AR(2), Pearson N(1), Deforges S(3), He C(1), Boileau C(4),
Partouche N(1), Borta A(1), Gautron J(3), Wartel M(5), Bočkaj I(5), Scavarda
D(6), Bartolomei F(7), Penchet G(8), Aupy J(8), Sims J(9), Smith J(2), Mercer
A(2), Danos O(2), Mulle C(3), Crépel V(4), Porter R(1).
Author information:
(1)uniQure (Corlieve Therapeutics AG), 4052 Basel, Switzerland.
(2)REGENXBIO Inc., Rockville, MD 20850, USA.
(3)Institute for Neuroscience, 33000 Bordeaux, France.
(4)INSERM, INMED, Aix-Marseille University, 13009 Marseille, France.
(5)uniQure biopharma B.V., 1105BP Amsterdam, the Netherlands.
(6)APHM, INSERM, Aix-Marseille University, Timone Hospital, Pediatric
Neurosurgery, 13005 Marseille, France.
(7)APHM, INSERM, Aix-Marseille University, INS, Timone Hospital, Epileptology
Department, 13005 Marseille, France.
(8)Pellegrin Hospital, Neurosurgery Department, CHU, 33000 Bordeaux, France.
(9)Integrated Biologix GmbH, 4051 Basel, Switzerland.
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 GRIK2 mRNA. Intra-hippocampal delivery of this vector in a mouse
model of mTLE significantly reduced GRIK2 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 GRIK2 mRNA expression.
These data suggest that the intra-hippocampal delivery of a GMP-grade AAV9
encoding a synthetic miRNAs targeting GRIK2 is a promising treatment strategy
for mTLE.
© 2024 uniQure biopharma B.V.
DOI: 10.1016/j.omtm.2024.101342
PMCID: PMC11489344
PMID: 39429724
Conflict of interest statement: A patent application has been filed relating to
this work. S.J.B., N.Pearson, C.H., N.Partouche, J.G., and R.P. declare an
association with uniQure/Corlieve Therapeutics. M.W. and I.B. declare an
association with uniQure B.V. A.G., J.S., A.M., and O.D. declare association
with Regenxbio Inc.