Project Details
Description
The epilepsies affect over 60 million people worldwide. Even with optimal medication, >30% of people with epilepsy continue to have seizures. Past 30 years, newly introduced antiseizure medicines (ASM) have had little impact on drug-resistant epilepsy but rather have improved tolerability. These drugs affect whole brain, resulting in adverse effects. People suffering from drug-resistant epilepsy are further affected by co-morbidities, such as cognitive impairment, depression, and sudden unexpected death in epilepsy (SUDEP). The annual cost of epilepsy in Europe is estimated at 15 B€. The major unmet need is defined as inability to control seizures in drug-resistant population. Drug-resistant epilepsy is often focal, including Temporal lobe epilepsy (TLE).
More research in this direction is highly warranted, since there is no cure. In this regard, gene therapy, including optogenetics and chemogenetics, has emerged as one of the most promising alternative treatment modalities. However, CNS gene therapy is lagging behind. In epilepsy, several gene therapy alternatives are at late preclinical stage, and their advance towards clinical trials is expected in the nearest future.
In this proposal, we will investigate a new generation of precise gene therapies based on targeting novel optogenetic and chemogenetic tools to strengthen seizure-suppressant effect and improve seizure freedom outcome in drug-resistant models of epilepsy. There are several novel aspects in the proposed project including: simultaneous Jaws and ChrimsonSA opsin activation by less invasive single red light spectrum, which will allow for deeper penetration into the brain parenchyma though the scull bone; Novel PSAM/PSEM approach in chemogenetics based on chloride channels; Novel BLINK2 and PAC-K, opsins based on potassium channels as an alternative to chloride-dependent silencing; validation in human drug-resistant epileptic tissue resected from patients.
Taken together, these innovative approaches will lead to discovery of novel gene therapy targets and modalities, facilitating preclinical investigations, which in the long-run will benefit drug-resistant population of patients with epilepsy.
More research in this direction is highly warranted, since there is no cure. In this regard, gene therapy, including optogenetics and chemogenetics, has emerged as one of the most promising alternative treatment modalities. However, CNS gene therapy is lagging behind. In epilepsy, several gene therapy alternatives are at late preclinical stage, and their advance towards clinical trials is expected in the nearest future.
In this proposal, we will investigate a new generation of precise gene therapies based on targeting novel optogenetic and chemogenetic tools to strengthen seizure-suppressant effect and improve seizure freedom outcome in drug-resistant models of epilepsy. There are several novel aspects in the proposed project including: simultaneous Jaws and ChrimsonSA opsin activation by less invasive single red light spectrum, which will allow for deeper penetration into the brain parenchyma though the scull bone; Novel PSAM/PSEM approach in chemogenetics based on chloride channels; Novel BLINK2 and PAC-K, opsins based on potassium channels as an alternative to chloride-dependent silencing; validation in human drug-resistant epileptic tissue resected from patients.
Taken together, these innovative approaches will lead to discovery of novel gene therapy targets and modalities, facilitating preclinical investigations, which in the long-run will benefit drug-resistant population of patients with epilepsy.
| Status | Active |
|---|---|
| Effective start/end date | 2023/07/01 → 2025/12/31 |
Funding
- Hjärnfonden
