Authors :
Presenting Author: Stephane Baudouin, PhD – Corlieve Therapeutics, SAS, France, a wholly-owned subsidiary of uniQure N.V.
Nick Pearson, PhD – Corlieve Therapeutics, SAS, France, a wholly-owned subsidiary of uniQure N.V.; Nicolas Partouche, PhD – Research – Corlieve Therapeutics, SAS, France, a wholly-owned subsidiary of uniQure N.V.; Morgane Wartel, PhD – Research – Corlieve Therapeutics, SAS, France, a wholly-owned subsidiary of uniQure N.V.; Sonay Keskin, MSc – Research – Corlieve Therapeutics, SAS, France, a wholly-owned subsidiary of uniQure N.V.; Christophe Mulle, PhD – Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, F-33000 Bordeaux, France; Valerie Crepel, PhD – Aix-Marseille Univ. INSERM, INMED, Marseille, France; Andreas Borta, PhD, MD – Clinical Development & Translational Sciences – Corlieve Therapeutics, SAS, France, a wholly-owned subsidiary of uniQure N.V.; Richard Porter, PhD – Corlieve Therapeutics, SAS, France, a wholly-owned subsidiary of uniQure N.V.
Rationale:
Temporal Lobe Epilepsy (TLE) is the most common form of focal epilepsy characterized by recurrent seizures generated in the hippocampus. Patients with TLE are often resistant to anti-seizure medications. Mossy fiber sprouting from dentate granule cells (DGCs) is a consistent anatomical hallmark of TLE, leading to synaptic reorganization in an aberrant excitatory network. In TLE, the DGCs operate via aberrant ectopic expression of GluK2/GluK5 kainate type receptors and GluK2/GluK5 was demonstrated to play a central role in the generation of seizure activity. However, the pharmacological potential of GluK2/GluK5 as a target for the treatment of TLE remained to be demonstrated. The work presented here summarizes the preclinical efficacy and safety of AMT-260, an AAV9 vector coding for two microRNAs capable to knockdown GluK2 expression, providing a novel therapeutic option for refractory TLE patients.
Methods:
We administered the AAV9-vector carrying two small interfering RNAs targeting GRIK2 (AMT-260) bilaterally into the hippocampus of a mouse model for TLE (pilocarpine) and into non-human primates (NHP). The efficacy of AMT-260 was measured in the mouse model using electroencephalogram (EEG) and behavior as readouts. Molecular analyses on mouse hippocampus were conducted one, three, and six months after administration to evaluate the stability of microRNA and GluK2 expression. The safety and biodistribution of AMT-260 was assessed in exploratory and IND-enabling GLP NHP studies after one, three, and six months of treatment following bilateral convection-enhanced, MRI guided intrahippocampal delivery, similar to the route proposed for clinical administration.
Results:
Injection of increasing doses of AMT-260 into the hippocampus of mice treated with pilocarpine showed a dose-dependent decrease in the number of electrical seizures per day and improved general health. A full biological effect was observed at 5.0E+09 vg per hippocampus in pilocarpine mice. Expression of Gluk2 was significantly knocked down, and stable, up to 6 months after administration.
In the pivotal GLP NHP study, at doses ranging from 1.2E+10 to 1.2E+12 vg/hippocampus of AMT-260, vector DNA was concentrated in the hippocampus and adjacent entorhinal cortex with little or no distribution outside the CNS. High neuronal expression of the microRNA in the hippocampus was associated with substantial knockdown of GRIK2 mRNA ( > 90%) at six months after administration. All doses were pre-clinically well tolerated and showed the potential for a good benefit to risk ratio for TLE patients.
Conclusions:
With the preclinical efficacy in pharmacology models and a good safety profile, AMT-260 will proceed into clinical testing for the treatment of patients with refractory mesial temporal lobe epilepsy.
Funding:
This research has been funded by uniQure Biopharma B.V.