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Considerations and developed strategies why to test NRP2945 in typical absence epilepsy

Genetic generalized epilepsy (GGE) is common and accounts for approximately 20% of epilepsy diagnoses (Jallon et al., 2005). A number of seizure types are seen in GGE. These include absence seizures (AS), myoclonic seizures (MS) and generalized tonic-clonic seizures (GTCS) as classified by the International League Against Epilepsy (ILAE) Commission on Classification in 1981 and mentioned in a commentary in 2017 again (Scheffer et al., 2017).

Electrophysiological different biomarkers (SWD frequency: 1.5-2.5 Hz versus 2.5-4.5 Hz) differentiate atypical from typical AS, respectively. Although both types of AS are considered separately by ILAE there is evidence that there could be a continuum in development of these seizures (Holmes et al., 1987; Carney & Jackson, 2014). The typical AS occurring in children, adolescents and adults are normally effectively treatable by AEDs while the atypical form has a poorer outcome while often being more drug-resistant. However, there is also a substantial adult population showing typical absence seizures that are resistant to valproate, phenytoin and /or lamotrigine.
Typical AS are correlated to thalamo-cortical network dysfunctions. Under physiological conditions there is a fine balance between excitatory thalamo-cortical and cortico-thalamic pathways. These projection neurons receives inhibitory input from the Nucleus reticularis in the thalamus (Steriade et al., 2005). If especially the inhibitory circuits of this fine-tuned thalamo-cortical network get interrupted by diminished GABA availability or through dysregulations of the GABA A receptor protein subunits, the propensity for the generation of absence seizures is increasing. Absence Epilepsy

CuroNZ has specifically shown that NRP2945 is capable of actively regenerating inhibitory calbindin, calretinin and parvalbumin expressing neurons (Landgraf et al., 2005; Gorba et al., 2006). Absence seizures represent one of the hallmarks of the electrophysiological profile of children diagnosed with Lennox-Gastaut Syndrome (Stefan et al., 2008). 

In regard to the mechanism of action of NRP2945 which is ultimately leading within an hour after injection to upregulation of the ligand GABA, and specific proteinsubunits within the GABA A receptor. This circumstance allows for a fast deactivation profile and lower de-sensitization response at the GABA A receptor and hitherto increasing the phasic inhibitory response in GABA A receptor transfected HEK cells (Hinkle & MacDonald, 2003). NRP2945 has been shown to downregulate typical absence seizures in adult GAERS rats by more than 50% when administered acutely or in chronic fashion with a persistent disease-modifying effect (Dezsi et al., 2017).

Therefore, the intended proof-of-concept for NRP2945 to be trialled in drug-resistant adult absence epilepsy patients is sound and it is hypothesized that NRP2945 will decrease the cumulative typical absence seizure frequency in the subjects.

Very recently, the group around Prof Patrick Kwan discovered a novel electrophysiological biomarker for drug-resistant GGE with high incidence rates during sleeping patterns. This biomarker is named generalized polyspike train (Sun et al., 2018, in press). Although our clinical absence epilepsy study with NRP2945 will not be analysing EEG profiles during night time, this particular EEG biomarker will guide us for the screening procedure for the absence epilepsy study with NRP2945.

References

  • Carney PW and Jackson, GD (2014). Insights into the mechanisms of absence seizure generation provided by EEG and functional MRI. Frontiers of Neurology 5 (162): 1-13.
  • Dezsi G, Sieg F, Thomas M, O’Brien TJ, van der Hart M, Jones NC (2017). Disease-modifying effects of Neural Regeneration Peptide 2945 in the GAERS model of absence epilepsy. Neurochemical Research 42(7); 2055-2064.
  • Gorba T, Bradoo P, Antonic A, Marvin K, Liu DX, P. Lobie P, Reymann KG, Gluckman P and Sieg F (2006). Neural regeneration protein is a novel chemoattractive and neuronal survival-promoting factor. Exp Cell Research, 312: 3060-3074.
  • Hinkle DJ and Macdonald RL (2003). Subunit Phosphorylation Selectively Increases Fast Desensitization and Prolongs Deactivation of α1β1γ2L and α1β3γ2L GABAA Receptor Currents. J Neurosci 23(37): 11698 –11710.
  • Holmes GL, McKeever M and Adamson M (1987). Absence seizures in children:  clinical and encephalographic features. Ann Neurol 21: 268-273.
  • Jallon P and Latour P (2005). Epidemiology of idiopathic generalized seizures. Epilepsia, 46 (Suppl. 9): 10–14.
  • Landgraf P, Sieg F, Meyer G, Wahle P, Pape H-C and Kreutz MR (2005) A maternal blood-borne factor promotes survival of the developing thalamus. FASEB J. 19: 225-227.
  • Scheffer I et al. (2017). ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology. Epilepsia, 58(4):512–521.
  • Stefan H, Snead OCIII, Eeg-Olofsson O (2008). Typical and atypical absence seizures, myoclonic absences, and eyelid myoclonia. 2nd edition in: Engel J, Pedley TA, editors. Epilepsy: A comprehensive textbook, Philadelphia, PA Lippincott, Williams and Wilkins (2008): 573-584.
  • Steriade M (2005). Sleep, epilepsy and thalamic reticular inhibitory neurons. Trends Neurosci 28: 317-324.
    Sun Y, Seneviratne U, Perucca P, Chen Z, Tan KM, O’Brien TJ, D’Souza W and Kwan P (2018). Generalized polyspike train: an EEG biomarker of drug-resistant idiopathic generalized epilepsy. Neurology, in press.

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