Inositol signaling molecules (ISMs) have been linked to regulation of ion channels. Evidence indicates that an lnsP4, myo-inositol 3,4,5,6-tetrakisphosphate [lns(3,4,5,6)P4] and its analogs regulate CI- channels in multiple epithelia. While inositol polyphosphates are highly charged, making them unlikely to cross membranes, we have developed membrane permeant forms that enable intracellular delivery recapitulating the activity of endogenous inositol polyphosphates. These activities suggest that derivatives of inositol polyphosphates may be therapeutic in cystic fibrosis (CF) and other diseases characterized by abnormal ion flux. In contrast to extracellularly acting agents directed against the extracellular domain of ion channel pores, membrane-permeant inositol polyphosphate analogs modulate ion channel activities from inside the cell. We have identified an lnsP4 derivative, INO-4995, as a potential treatment for CF and have initiated development toward the filing of an IND. INO-4995 is selective for CF epithelial tissue as compared to non-CF tissue. The goal of the current study is to predict how INO-4995 functions in CF tissue and in different genetic backgrounds. This will aid in identifying and treating an optimal patient population most likely to benefit from the compound's therapeutic effects.
The specific aims i nclude:
Aim 1 : Assess the in-vitro cellular metabolism and the in-vivo pharmacokinetics of radiolabeled INO-4995.
Aim 2 : Assess the bioavailability and safety of INO-4995 using an epithelial airway tissue culture system.
Aim 3 : Determine the effects of INO-4995 on nasal transepithelial voltage of CF and non-CF mice under a variety of conditions, including genetic background, age, and gender. To date, work has been performed with tissue from deltaF508 homozygous CF patients. We will extend this work to assess the electrophysiological effects of the compound on tissue with other mutations or in tissue that is heterozygous for deltaF508. We will also compare the effect of the compound in deltaF508 homozygous mice on different genetic backgrounds. The broader aim of this study is to further characterize the biological responses to INO-4995, and in conjunction with the ongoing preclinical and clinical development program for CF, would offer further validation for the therapeutic utility of an inositol polyphosphate signaling molecule derivative. This work will help delineate the mechanism of action of INO-4995, will assess the bioavailability and safety, and will help define dosing/regimen protocols, and could expedite regulatory and clinical planning during the development process.
| Traynor-Kaplan, Alexis E; Moody, Mark; Nur, Magda et al. (2010) INO-4995 therapeutic efficacy is enhanced with repeat dosing in cystic fibrosis knockout mice and human epithelia. Am J Respir Cell Mol Biol 42:105-12 |
