Gene Therapy for Epilepsy

(GenTLE Trial)

Recruiting in Palo Alto (17 mi)

+11 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

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

Trial Summary

What is the purpose of this trial?

This trial is testing a new treatment called AMT-260 for adults with a type of epilepsy that doesn't respond to usual treatments. The treatment is delivered directly to the affected part of the brain using MRI guidance. The goal is to see if this method can better control seizures and improve safety and tolerability.

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.

What data supports the effectiveness of the treatment AMT-260 for epilepsy?

Research shows that gene therapy using adeno-associated viral (AAV) vectors to deliver neuropeptide Y (NPY) can reduce seizures in animal models of epilepsy. This approach has demonstrated significant anticonvulsant effects, including reduced seizure frequency and progression, suggesting its potential as a promising treatment for epilepsy. ^{1 2 3 4 5}

Is gene therapy for epilepsy safe for humans?

The safety of gene therapy for epilepsy in humans is not fully established yet. While studies in animals show promising results in reducing seizures, more research is needed to understand potential side effects and safety concerns in humans. ^{1 2 4 5 6}

What makes the treatment AMT-260 unique for epilepsy?

AMT-260 is a gene therapy that uses an adeno-associated virus (AAV) vector to deliver genetic material directly into brain cells, aiming to modify the disease by overexpressing neuropeptide Y (NPY), which has anticonvulsant properties. This approach is novel because it targets the underlying causes of seizures in pharmacoresistant epilepsy, rather than just managing symptoms like traditional medications. ^{1 2 4 6 7}

Research Team

Andreas Borta

Principal Investigator

uniQure France SAS

Eligibility Criteria

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 am between 18 and 65 years old and can make my own medical decisions.

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

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.

Trial Timeline

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

Treatment Details

Interventions

• AMT-260 (Gene Therapy)

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

A clinical-grade gene therapy vector for pharmacoresistant epilepsy successfully overexpresses NPY in a human neuronal cell line. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Combinatorial gene therapy for epilepsy: Gene sequence positioning and AAV serotype influence expression and inhibitory effect on seizures. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Neuropeptide Y gene therapy decreases chronic spontaneous seizures in a rat model of temporal lobe epilepsy. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Disease Modification by Combinatorial Single Vector Gene Therapy: A Preclinical Translational Study in Epilepsy. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Gene therapy in epilepsy: the focus on NPY. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Neuropeptide Y overexpression using recombinant adeno-associated viral vectors. [2021]

7. United States 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. [2019]