About Lennox-Gastaut Syndrome (LGS)
Lennox-Gastaut Syndrome is a refractory childhood epilepsy which falls under the disease category ultra-orphan drug destination. Less than 20,000 children in the US are diagnosed for this severe form of epilepsy. Read more about orphan drug indications....
- Currently, there is no monotherapy currently approved and patients require often hospital care.
- There is strong unmet need for memory improving drugs because the majority of affected children are not able to finish secondary school.
- A strong neuroprotective drug candidate with memory enhancing capabilities and a high safety profile is needed for future clinical trials.
What is the rationale why NRP2945 will work for Lennox-Gastaut Syndrome patients?
For long time it has been hypothesized that the GABAergic system which sets the inhibitory tonus in the brain is impaired within various neurodegenerative diseases.
CuroNZ has chosen a preclinical proof-of-concept animal model where GABAergic impairment has already been validated to be involved in the disease typical pathogenesis process. Namely, administration of pentylenetetrazol (PTZ) provokes acute convulsive seizure activity in the brain and downregulates GABAergic receptor systems.
More recently, the EpiK4 consortium has identified de novo mutations (only in patients not in parents) in Lennox-Gastaut Syndrome and infantile spasm patients with the highest frequency of patients for the beta 3 subunit of the GABA A receptor (GABRB3 gene). Furthermore, the consortium identified that mutations in the GABRA1 gene (GABA A receptor alpha 1 subunit) are named to be “mutation intolerant” and can be therefore considered to provoke a pathogenic disease course for Lennox-Gastaut Syndrome.
Why does this genetic finding have direct implications for the therapeutic effect of NRP2945?
CuroNZ has shown that NRP2945 has the capacity to prevent convulsive seizures in PTZ-dosed rats completely.
- In an acute rat PTZ study we have shown that NRP2945 is able to upregulate the GABA A receptor beta-subunit by approximately 80% at protein level at 120 minutes after NRP2945 exposure within the hippocampal CA1-region and by 30% within the somatosensory cortex.
- We found significant GABA receptor alpha-subunit upregulation in CA1 region and neocortex after NRP2945 exposure.
- Furthermore, we found a significant increase of the GAD-65 protein – the enzyme that is crucial for converting glutamate into the inhibitory transmitter GABA in all tested brain regions after NRP2945 administration.
In conclusion, NRP2945 is restoring the GABAergic system after chemically induced injury (PTZ) and is “setting” a strong inhibitory tonus in the brain circuits.
CuroNZ intends to also evaluate NRP2945 for thalamocortical driven absence seizures and myoclonic seizures in 2015. After that we want to initiate trials in young patients who have been diagnosed with Lennox-Gastaut Syndrome (LGS) in late 2016.