Repurposing the Dihydropyridine Calcium Channel Inhibitor Nicardipine as a Na v 1.8 Inhibitor In Vivo for Pitt Hopkins S
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RESEARCH PAPER
Repurposing the Dihydropyridine Calcium Channel Inhibitor Nicardipine as a Nav1.8 Inhibitor In Vivo for Pitt Hopkins Syndrome Sean Ekins 1
&
Ana C. Puhl 1 & Audrey Davidow 2
Received: 9 November 2019 / Accepted: 5 June 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT Purpose 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 v 1.8. This in turn results in increased afterhyperpolarization as well as altered firing properties. We have recently identified through a drug repurposing screen an FDA approved dihydropyridine calcium antagonist nicardipine used to treat angina, which inhibited Nav1.8. Methods 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. Results Nicardipine returned this spectrum of behavioral deficits in the Tcf4(± ) PTHS mouse model to WT levels and resulted in statistically significant results. Conclusions 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
* Sean Ekins [email protected]
1
Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, North Carolina 27606, USA
2
Pitt Hopkins Research Foundation, 13058 Bloomfield St., Studio City, California 91604, USA
patients or suggest the potential for use off label under compassionate use with their physician.
KEY WORDS drug discovery . drug repurposing . nicardipine . Pitt Hopkins syndrome . rare diseases INTRODUCTION It is suggested that there are well over 7000 rare diseases, while only a fraction have current treatments approved there is increasing interest in developing treatments for many more and there are several government provided incentives for doing this (1). One approach to potentially bring treatments to rare disease patients faster is by repurposing or repositioning existing FDA approved drugs for new applications and there are several ways to do this experimentally or computationally (2–6). 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. While PTHS was initially described by D. Pitt and I. Hopkins (7), t
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