AMT-260 miRNA Gene Therapy Displays Preclinical Promise Ahead of First-in-Human Trial


uniQure’s AAV9-vector therapy carrying 2 small interfering RNAs targeting GRIK2 was well-tolerated, with a hopeful risk-benefit ratio. A phase 1/2 is set to begin recruitment in late 2023.

Stephane Baudouin, PhD, the senior director and head of in vivo Pharmacology at uniQure’s French subsidiary, Corlieve Therapeutics

Stephane Baudouin, PhD

In a recently conducted preclinical good laboratory practice, nonhuman primate and mouse model study, the investigational adeno-associated virus (AAV) vector-based miRNA gene therapy AMT-260 has shown promise as a potential genetic medicine for the treatment of temporal lobe epilepsy (TLE).1 The work suggested signals of efficacy and safety the uniQure product, which was cleared for a US-based clinical trial (NCT06063850) in September 2023.2

“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,” first author Stephane Baudouin, PhD, the senior director and head of in vivo Pharmacology at uniQure’s French subsidiary, Corlieve Therapeutics, and colleagues wrote. Baudouin et al presented the data in a poster at the 2023 American Epilepsy Society Annual Meeting, held December 1-5, in Orlando, Florida.

All told, AMT-260 was assessed at doses that ranged from 1.2 × 1010 vg/hippocampus to 1.2 × 1012 vg/hippocampus in a mouse model for TLE (mice treated with pilocarpine) and in nonhuman primates. Notably, all doses were well tolerated preclinically and showed the potential for a good risk-benefit ratio for patients with TLE.

The injection of increasing doses resulted in a dose-dependent decrease in the rate of electrical seizures experienced per day and improved the overall general health of the models. A full effect biologically was reported in pilocarpine-treated mice at a dose of 5.0 × 109 vg/hippocampus, while Baudouin et al reported significant knockdowns on the expression of Gluk2, which remained stable up to 6 months post administration of AMT-260.

READ MORE: uniQure Expanding Clinical Pipeline to Fabry Disease

“TLE is the most common form of focal epilepsy characterized by recurrent seizures generated in the hippocampus [and] patients with TLE are often resistant to antiseizure medications,” Baudouin and colleagues wrote. “In TLE, the [dentate granule cells] 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.” They added that “AMT-260 includes an AAV9 vector coding for 2 microRNAs capable [of knocking down] GluK2 expression, providing a novel therapeutic option for refractory TLE patients.”

Key Takeways

  1. The miRNA gene therapy from uniQure, AMT-260, demonstrated efficacy and safety in preclinical studies, supporting its upcoming clinical trial for refractory mesial temporal lobe epilepsy.
  2. AMT-260 showed a dose-dependent reduction in daily seizures and a significant knockdown of GluK2 expression in temporal lobe epilepsy models.
  3. uniQure, with FDA clearance, is executing a phase 1/2a trial (NCT06063850) for AMT-260, addressing refractory mesial temporal lobe epilepsy, marking a significant step in gene therapy development.

Molecular analyses on the mouse models were conducted at 1, 3, and 6 post treatment to evaluate the stability of microRNA and GluK2 expression. Overall, the vector DNA was shown to be concentrated in the hippocampus and the adjacent entorhinal cortex without much dissemination outside the central nervous system, and evidence of high neuronal expression of the microRNA was linked with a substantial knockdown of GRIK2 mRNA exceeding 90% at the 6-month time point.

In light of its’ September investigational new drug application clearance, uniQure noted that it intends to carry out the aforementioned phase 1/2a clinical trial, with screening of potential participants with refractory mesial TLE anticipated to begin in the last 3 months of 2023. This first-in-human study is planned to include an initial multicenter, open-label phase during which 2 cohorts of 6 patients each will be treated at 2 different doses, followed by a randomized, controlled portion that will seek to demonstrate proof-of-concept for AMT-260.

“The clearance of the IND for AMT-260 is an important achievement in advancing our pipeline and is our next program to enter clinical development in an area of high unmet medical need,” Walid Abi-Saab, the chief medical officer of uniQure, said in a statement in Setpember.2 “There are few treatment options for patients who have refractory MTLE, and we are pleased to soon begin the clinical investigation of this 1-time administered gene therapy approach as a potential new treatment.”

1. Baudouin S, Pearson N, Partouche N, et al. Preclinical Efficacy and Safety Assessment of AMT-260, a Novel AAV9-Dual MicroRNA-Based Vector Targeting GRIK2 for the Treatment of Temporal Lobe Epilepsy. Presented at: AES Annual Meeting; December 1-5, 2023; Orlando, FL. Poster 3.259
2. uniQure announces FDA clearance of investigational new drug application for AMT-260 gene therapy for refractory mesial temporal lobe epilepsy. News release. uniQure N.V. September 5, 2023. Accessed December 1, 2023.
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