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Repurposing the Dihydropyridine Calcium Channel Inhibitor Nicardipine as a Nav1.8 Inhibitor In Vivo for Pitt Hopkins Syndrome

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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 Nav1.8. This in turn results in increased after-hyperpolarization 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 patients or suggest the potential for use off label under compassionate use with their physician.

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ACKNOWLEDGMENTS AND DISCLOSURES

These studies were supported by a grant from the Pitt-Hopkins Research Foundation. Dr’s Patricia Cogram, Robert M.J. Deacon and Daniel Benitez are sincerely acknowledged for generating the data in this study under a contract with the Pitt-Hopkins Research Foundation. Special thanks are also due to Dr. Michael Tranfaglia for his intellectual support to Dr. Cogram and Dr. Deacon throughout the design and implementation of these experiments. The authors wish to thank Dr. Andrew J. Kennedy from the University of Alabama at Birmingham for kindly sending us the mice and the families of the Pitt-Hopkins Research Foundation for financial and moral support at the earliest stages of initiating these studies. SE acknowledges the support and discussions with Dr’s Aaron Gerlach, Aaron McMurtray and Kimberly Goodspeed. ACP kindly acknowledges funding from NIH/ NIAID 3R43NS107079-01S1. SE is CEO and Founder of Collaborations Pharmaceuticals, Inc., and has submitted a provisional patent and orphan drug designation on nicardipine for Pitt Hopkins Syndrome. AP is an employee at Collaborations Pharmaceuticals, Inc. AD is President of the Pitt Hopkins Research Foundation.

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Authors and Affiliations

  1. Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, North Carolina, 27606, USA

    Sean Ekins & Ana C. Puhl

  2. Pitt Hopkins Research Foundation, 13058 Bloomfield St., Studio City, California, 91604, USA

    Audrey Davidow

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  1. Sean Ekins
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Correspondence to Sean Ekins.

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Ekins, S., Puhl, A.C. & Davidow, A. Repurposing the Dihydropyridine Calcium Channel Inhibitor Nicardipine as a Nav1.8 Inhibitor In Vivo for Pitt Hopkins Syndrome. Pharm Res 37, 127 (2020). https://doi.org/10.1007/s11095-020-02853-5

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