Developing a PPI inhibitor-based therapy for STXBP1 haploinsufficiency-associated epileptic disorders

Abstract

STXBP1 HAPLOINSUFFICIENCY IN EARLY ONSET EPILEPTIC ENCEPHALOPATHY Early onset epileptic encephalopathies that occur in very early childhood are rare but particularly catastrophic forms of epilepsy that are invariably associated with significant neurological morbidity (Nordli, 2012). Mutations in the Syntaxin Binding Protein 1 (STXBP1) gene have been linked with two distinct but related forms of the disorder including early onset epileptic encephalopathy with suppression-bursts (EESB) associated with Ohtahara syndrome, and more recently with infantile spasms (IS) associated with West syndrome (Barcia et al., 2013). Mutations in patients are not inherited but rather found to occur de novo in a single copy of the STXBP1 gene. Ohtahara syndrome is the earliest appearing age-related epileptic encephalopathy with seizures first presenting as early as the neonatal period and is diagnosed with a characteristic burstsuppression pattern on EEG (Yamatogi and Ohtahara, 2002). It is an extremely debilitating neurological disorder, involving intractable frequent daily seizures and severe intellectual disability. Patients often do not survive beyond early childhood. West syndrome can present with frequent daily IS-type seizures within the first few weeks but more typically within the first few months of life and is diagnosed by a characteristic hypsarrhythmia pattern on EEG (Wong and Trevethan, 2001). The majority of patients have some degree of developmental delay and go on to have mild to severe intellectual disability. Later in life, symptoms of Ohtahara syndrome patients can sometimes evolve into those usually associated with West syndrome, where the seizure-types become more reminiscent of IS and the burstsuppression pattern on EEG evolves into hypsarrhythmia. There is currently no cure for Ohtahara syndrome or West syndrome and current therapy, which consists of generic anticonvulsant medication, is largely unsatisfactory due to the refractory nature of the seizures. To date, STXBP1 mutations have been reported in 27 cases of EESB and 7 cases of IS not preceded by EESB/Ohtahara syndrome (Barcia et al., 2013). Whereas most genes associated with epileptic disorders encode ion channels or neurotransmitter receptor subunits, STXBP1 is the first epilepsy-associated gene with a direct role in the neurotransmitter release process (Poduri and Lowenstein, 2011). The presence of STXBP1 protein is necessary for neurotransmitter release in probably all neuron types in the brain (Verhage et al., 2000). However, it may be likely that impaired neurotransmitter release in inhibitory GABAergic interneurons throughout the brain results in uncontrolled synchronous firing of excitatory neurons in regions, resulting in epileptic foci. Indeed, a patient with an STXBP1 mutation was recently reported to have responded well to Vigabatrin (Romaniello et al., 2013), a drug which works specifically by inhibiting the gamma-aminobutyric acid transaminase enzyme responsible for the breakdown of GABA. In this article a potential route toward the development of a targeted anticonvulsant medication for STXBP1-associated epilepsy will be presented. The proposal is based on the refined model of neurotransmitter release suggested by recent findings in the Josep Rizo laboratory (Ma et al., 2013) and also the huge potential held in the field of protein-protein interaction (PPI) inhibitor therapeutic drug design.