dihydropyridines and Facies

Individuals with the rare genetic disorder Pitt Hopkins Syndrome (PTHS) do not have sufficient expression of the transcription factor 4 (TCF4) which is located on chromosome 18. TCF4 is a basic helix-loop-helix E protein that is critical for the normal development of the nervous system and the brain in humans. PTHS patients lacking sufficient TCF4 frequently display gastrointestinal issues, intellectual disability and breathing problems. PTHS patients also commonly do not speak and display distinctive facial features and seizures. Recent research has proposed that decreased TCF4 expression can lead to the increased translation of the sodium channel Na. We have now performed behavioral testing in groups of 10 male Tcf4(± ) PTHS mice dosing by oral gavage at 3 mg/kg once a day for 3 weeks using standard methods to assess sociability, nesting, fear conditioning, self-grooming, open field and test of force.. Nicardipine returned this spectrum of behavioral deficits in the Tcf4(± ) PTHS mouse model to WT levels and resulted in statistically significant results.. These in vivo results in the well characterized Tcf4(± ) PTHS mice may suggest the potential to test this already approved drug further in a clinical study with PTHS patients or suggest the potential for use off label under compassionate use with their physician.

Topics: Animals; Behavior Control; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Disease Models, Animal; Drug Discovery; Drug Repositioning; Facies; Fear; Gene Expression Regulation; Humans; Hyperventilation; Intellectual Disability; Male; Mice; NAV1.8 Voltage-Gated Sodium Channel; Nicardipine; Phenotype; Social Skills; Transcription Factor 4

Pitt Hopkins Syndrome (PTHS) is a rare genetic disorder caused by mutations of a specific gene, transcription factor 4 (TCF4), located on chromosome 18. PTHS results in individuals that have moderate to severe intellectual disability, with most exhibiting psychomotor delay. PTHS also exhibits features of autistic spectrum disorders, which are characterized by the impaired ability to communicate and socialize. PTHS is comorbid with a higher prevalence of epileptic seizures which can be present from birth or which commonly develop in childhood. Attenuated or absent TCF4 expression results in increased translation of peripheral ion channels K. We now describe a high throughput screen (HTS) of 1280 approved drugs and machine learning models developed from this data. The ion channels were expressed in either CHO (K. The HTS delivered 55 inhibitors of K. This work could lead to the potential repurposing of nicardipine or other dihydropyridine calcium channel antagonists as potential treatments for PTHS acting via Na

Topics: Animals; Bayes Theorem; CHO Cells; Cricetulus; Dihydropyridines; Drug Repositioning; Facies; HEK293 Cells; Humans; Hyperventilation; Intellectual Disability; KCNQ1 Potassium Channel; Machine Learning; NAV1.8 Voltage-Gated Sodium Channel; Potassium Channel Blockers; Small Molecule Libraries; Sodium Channel Blockers; Structure-Activity Relationship; Voltage-Gated Sodium Channel Blockers