Różne działanie leków blokujących kanały sodowe na mutacje SCN8A związane z padaczką wrażliwą lub oporną na leczenie
Differential effects of sodium channel blockers on SCN8A gain-of-function variants associated with drug-responsive or -resistant epilepsy
W skrócie
Naukowcy badali 173 pacjentów z mutacjami w genie SCN8A, które powodują padaczkę. Odkryli, że mutacje wpływające na aktywację kanału sodowego prowadzą do cięższych postaci choroby i słabiej reagują na standardowe leki, podczas gdy mutacje wpływające na wyłączanie kanału lepiej reagują na leczenie. Nowy lek PRAX-330 okazał się skuteczny dla obu grup pacjentów, co daje nadzieję na lepsze leczenie tego rodzaju padaczki, szczególnie u osób opornych na dotychczasowe terapie.
Oryginalny abstract (angielski)
Gain-of-function variants in SCN8A, which encodes the Na1.6 sodium channel, lead to epilepsy syndromes ranging from drug-responsive self-limited and intermediate epilepsy to drug-resistant developmental and epileptic encephalopathy (DEE). It is currently unclear why individuals with SCN8A gain-of-function variants show variable responses to sodium channel blockers (SCBs). Here, we compared the clinical characteristics of 173 individuals with 25 different SCN8A gain-of-function variants. We found that individuals with variants altering channel activation gating were more severely affected than those with variants altering inactivation properties: They had an earlier age at onset (3 vs. 5 months, P < 0.0001), higher prevalence of DEE (75% vs. 39%; P < 0.0001), and poorer response to SCBs (20% vs. 69% seizure free; P < 0.0001). We performed pharmacological studies on representative and recurrent variants from each group: two variants (F846S and M1760I) causing hyperpolarizing shifts of the voltage-dependent activation curves, and two variants (G1475R and N1877S) causing depolarizing shifts of the voltage-dependent fast inactivation curves. Phenytoin failed to suppress neuronal firing in neurons expressing activation-related variants, but showed good suppressing effects in neurons expressing inactivation-related variants. In contrast, PRAX-330, a new SCB, which showed much faster binding rates than phenytoin, was effective for both groups of variants by markedly reducing neuronal firing through rapidly and persistently stabilizing Na1.6 in the inactivated state. Our findings provide new pharmacogenetic insights into the mechanism of drug-resistance in SCN8A related epilepsy and support PRAX-330 and compounds with similar pharmacological properties as promising candidates for targeted therapies.