Gene Therapy for Epilepsy

(GenTLE Trial)

Recruiting at 18 trial locations

Overseen By uniQure

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: UniQure Biopharma B.V.

Must be taking: Anti seizure drugs

Must not be taking: Antipsychotics, Antivirals

Disqualifiers: Psychogenic seizures, Contralateral seizures, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 1 year

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy, AMT-260, to determine if it can safely reduce seizures in adults with a specific type of epilepsy affecting one side of the brain. The study explores different doses to find the best balance between safety and effectiveness. Individuals who frequently experience seizures despite taking up to four anti-seizure medications might be suitable candidates. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications, but you must be on a stable dose of up to 4 approved anti-seizure drugs for at least 6 months before joining. Some medications that could interfere with the study might need to be stopped.

Is there any evidence suggesting that AMT-260 is likely to be safe for humans?

Research has shown that AMT-260 was safe in earlier studies. In one study, a participant who received AMT-260 experienced only two seizures over five months, with no other major problems reported, suggesting the treatment was well-tolerated.

Additionally, lab tests conducted before human trials demonstrated its safety, allowing progression to human trials.

As a Phase 1/2 trial, the primary goal is to ensure the treatment's safety for people, indicating that earlier tests showed enough promise to warrant testing with more participants. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for epilepsy, which often involve medications like anti-seizure drugs targeting neurotransmitter activity, AMT-260 represents a groundbreaking approach by employing gene therapy. Researchers are excited about this treatment because it targets the underlying genetic causes of epilepsy rather than just managing symptoms. By delivering a modified gene directly to the brain, AMT-260 aims to provide a more precise and potentially long-lasting solution, which could reduce the frequency and severity of seizures significantly. This innovative mechanism has the potential to transform epilepsy treatment by addressing the root cause rather than just alleviating symptoms.

What evidence suggests that AMT-260 might be an effective treatment for epilepsy?

Research has shown that AMT-260, the investigational treatment in this trial, might help reduce seizures in people with unilateral mesial temporal lobe epilepsy. One study reported that a participant who received AMT-260 experienced only two seizures over five months and even had a seizure-free period. Early lab research found that AMT-260 reduced seizure activity and improved health in test models. This treatment uses a special virus to deliver tiny molecules called microRNAs, which target and lower the activity of a specific brain receptor linked to epilepsy. These findings suggest that AMT-260 could potentially lower the number of seizures. ^{1 2 3 4 5}

Who Is on the Research Team?

Clinical Development Lead

Principal Investigator

uniQure France SAS

Are You a Good Fit for This Trial?

Adults aged 18-65 with unilateral refractory mesial temporal lobe epilepsy, having at least 2 seizures per month and on stable anti-seizure drugs. They must have normal cognitive function, no major unrelated neurosurgery history, and agree to use birth control. MRI-compatible devices are okay if implanted over 3 months ago.

Inclusion Criteria

For WOCBP only: Negative pregnancy test

I have been diagnosed with hard-to-treat epilepsy in one side of my brain for over a year.

I have been on up to 4 stable autism drugs for at least 3 months.

Exclusion Criteria

I have had seizures not caused by epilepsy in the past year.

I do not have any implants that prevent me from having an MRI, or any MRI-compatible devices were implanted over 3 months ago.

I have no health issues preventing me from undergoing general anesthesia or surgery.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AMT-260 via MRI-guided Convection-enhanced Delivery (CED) in two dosing cohorts to assess safety, tolerability, and first signs of efficacy

1 year

Multiple visits for dosing and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including adverse events and changes in seizure frequency

1 year

Regular visits for monitoring and sample collection

What Are the Treatments Tested in This Trial?

Interventions

• AMT-260

Trial Overview The trial tests AMT-260 gene therapy for safety and effectiveness in reducing seizures in adults with MTLE. It involves injecting the treatment directly into the brain using MRI-guided techniques while monitoring patients' responses.

How Is the Trial Designed?

Group I: AMT-260 Experimental Treatment 1 Intervention

Cohort 1: AMT-260 starting dose (1.0x 10E12 gc/mL). Cohort 2: AMT-260 adapted dose (6.0x 10E11 gc/mL or 3.0x 10E12 gc/mL).

Who Is Running the Clinical Trial?

UniQure Biopharma B.V.

Lead Sponsor

Trials

12

Recruited

260+

uniQure France SAS

Lead Sponsor

Trials

1

Recruited

10+

Published Research Related to This Trial

Gene therapy using a recombinant adeno-associated viral vector expressing the neuropeptide Y (NPY) gene significantly reduced the progression of seizures in a rat model of temporal lobe epilepsy, indicating its potential as a treatment alternative to surgery.

In 40% of the treated rats, spontaneous seizure frequency decreased compared to their baseline levels, demonstrating the efficacy of this gene therapy approach in managing intractable epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuropeptide Y gene therapy decreases chronic spontaneous seizures in a rat model of temporal lobe epilepsy. Noè, F., Pool, AH., Nissinen, J., et al.[2021]

Gene therapy using a single vector for neuropeptide Y and Y2 receptor showed promising results in reducing seizure frequency in a rat model of chronic epilepsy, with a 31% responder rate and a 13% seizure-freedom rate.

The treatment significantly prolonged the intervals between seizures and reduced the duration of seizures, indicating its potential as an effective alternative for patients with focal epilepsy who do not respond to traditional medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disease Modification by Combinatorial Single Vector Gene Therapy: A Preclinical Translational Study in Epilepsy. Melin, E., Nanobashvili, A., Avdic, U., et al.[2020]

The study successfully demonstrated that an adeno-associated viral (AAV) vector can effectively transduce human neuronal cells to secrete Neuropeptide Y (NPY), which has anticonvulsant properties, indicating potential for gene therapy in treating pharmacoresistant epilepsy.

This research lays the groundwork for future clinical trials, as it shows that AAV-NPY can produce significantly higher levels of NPY compared to control vectors, suggesting a promising approach for patients who do not respond to traditional epilepsy medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A clinical-grade gene therapy vector for pharmacoresistant epilepsy successfully overexpresses NPY in a human neuronal cell line. Patrício, MI., Barnard, AR., Green, AL., et al.[2019]

Gene therapy using recombinant adeno-associated viral (AAV) vectors shows promise in treating epilepsy, particularly in patients who do not respond to traditional anti-epileptic drugs, with preclinical studies demonstrating significant reductions in seizures.

Specifically, the over-expression of neuropeptide Y (NPY) in the rat hippocampus led to long-lasting anticonvulsant effects, including reduced seizure generalization and delayed epileptogenesis, indicating the potential efficacy of this approach, though further research is needed to assess safety and side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuropeptide Y overexpression using recombinant adeno-associated viral vectors. Noé, F., Frasca, A., Balducci, C., et al.[2021]

In a study using a rat model of epilepsy, the AAV1 vector carrying the neuropeptide Y (NPY) and its receptor Y2 showed the highest efficacy in suppressing seizures compared to other AAV serotypes and transgene sequences, indicating its potential as a strong candidate for gene therapy.

The AAV1-NPY-IRES-Y2 vector not only effectively reduced seizure activity but also decreased glutamate release in human hippocampal tissue from patients with drug-resistant epilepsy, supporting its therapeutic potential for treating focal epilepsies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combinatorial gene therapy for epilepsy: Gene sequence positioning and AAV serotype influence expression and inhibitory effect on seizures. Melin, E., Andersson, M., Gøtzsche, CR., et al.[2023]

Gene therapy using recombinant adeno-associated viral (AAV) vectors to deliver neuropeptide Y (NPY) in the rat hippocampus has shown significant anticonvulsant effects, reducing seizure generalization and providing neuroprotection in experimental models.

This approach represents a promising alternative for treating epilepsy in patients resistant to conventional drugs, although further research is needed to assess its safety and efficacy in chronic seizure models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy in epilepsy: the focus on NPY. Noe', F., Nissinen, J., Pitkänen, A., et al.[2022]

The study demonstrated that an adeno-associated virus (AAV) vector can successfully transfer and express a gene in human brain slices, specifically targeting neurons without causing cytotoxicity, which is crucial for potential therapies in neurological diseases like epilepsy.

Expression of the lacZ marker gene was observed as early as 5 hours after injection and remained functional as long as the brain slices were viable, indicating the AAV vector's effectiveness for localized genetic interventions in the human central nervous system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Direct gene transfer into human epileptogenic hippocampal tissue with an adeno-associated virus vector: implications for a gene therapy approach to epilepsy. Freese, A., Kaplitt, MG., O'Connor, WM., et al.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06063850

NCT06063850 | AMT-260 Gene Therapy Study in Adults ... The main goals of this clinical study are to learn if AMT-260 is safe and tolerable and works to reduce the frequency of seizures in adults with unilateral ...

2. uniqure.gcs-web.com uniqure.gcs-web.com/news-releases/news-release-details/uniqure-presents-clinical-case-study-first-patient-dosed-amt-260

uniQure Presents Clinical Case Study of First Patient Dosed ... Since receiving AMT-260, the participant has reported two seizures during the five-month follow-up period, with no seizures reported during the ...

3. neurology.org neurology.org/doi/10.1212/WNL.0000000000203971

Preclinical Proof-of-concept of a Novel AAV9-microRNA ... Results: AMT-260 showed a dose-dependent decrease in electrical seizures and hyperlocomotion and improved health. A full biological effect was observed at 5.0E+ ...

4. uniqure.com uniqure.com/programs-pipeline/phase-i-iia-clinical-trial-of-amt-260

Phase I/IIa Clinical Trial of AMT-260 | Programs & Pipeline The GenTLE Phase I/IIa study is designed to investigate the safety, tolerability and efficacy of AMT-260 in adults with unilateral mesial temporal lobe epilepsy ...

5. aesnet.org aesnet.org/abstractslisting/preclinical-efficacy-and-safety-assessment-of-amt-260-a-novel-aav9-dual-microrna-based-vector-targeting-grik2-for-the-treatment-of-temporal-lobe-epilepsy

preclinical efficacy and safety assessment of amt-260, a novel ... The work presented here summarizes the preclinical efficacy and safety of AMT-260, an AAV9 vector coding for two microRNAs capable to knockdown GluK2 ...