Channel modulators
Inventors
Green, Colin Richard • KIM, Yeri • Phillips, Anthony • Duft, Bradford James
Assignees
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Publication Number
US-11401516-B2
Publication Date
2022-08-02
Expiration Date
Abstract
The inventions relate to compositions and articles of manufacture comprising connexin modulators, pannexin modulators, gap junction modulators, hemichannel modulators, and pannexin channel modulators and their use, alone or in combination, in treating ocular and other disorders.
Core Innovation
The invention provides methods for modulating inflammasome activity by administering a connexin 43 hemichannel modulator according to Formula I or Formula II in an amount effective to modulate inflammasome activity. In particular, tonabersat is disclosed as the connexin 43 hemichannel modulator, and the goal is to inhibit inflammasome activity in a subject or a human subject.
The document characterizes the inhibition as preventing inflammasome-driven activation of an inflammatory cascade, with dependent refinements narrowing the target to the NLRP3 inflammasome, including NLRP3 inflammasome activation and NLRP3-mediated inflammatory cascade activation. It further describes connexin 43 (Cx43) hemichannel and gap junction modulation associated with peptide-based and tonabersat-related agents.
The document describes connexin 43 (Cx43) hemichannel modulation linked to reduction of vascular leakage and improved retinal ganglion cell survival after ischemia-reperfusion. It also describes ocular delivery formulations and devices for connexin modulators, including sustained ocular delivery concepts, ocular implant structures, microneedle-based ocular administration to posterior ocular segments, and co-administration or kit concepts with additional ocular agents such as rho-kinase inhibitors and VEGF antagonists.
Claims Coverage
The independent claims cover two method approaches to inhibiting inflammasome activity: one using a connexin 43 hemichannel modulator defined by Formula I or Formula II, and another using tonabersat in a human subject. Across the independent claims, the key inventive features are the inflammasome inhibition objective, the specific channel modulator class or compound, and modulation of inflammasome activity, with dependent claims further narrowing to NLRP3 and inflammatory cascade activation.
Inflammasome modulation by connexin 43 hemichannel modulator
A method for inhibiting inflammasome activity in a subject comprising administering to the subject a connexin 43 hemichannel modulator according to Formula I or Formula II in an amount effective to modulate inflammasome activity.
Inflammasome modulation in humans by tonabersat
A method for inhibiting inflammasome activity in a human subject comprising administering a tonabersat compound to the human subject in an amount effective to modulate inflammasome activity.
The independent claim set covers administering a connexin 43 hemichannel modulator defined by Formula I or Formula II to inhibit inflammasome activity and separately covers administering tonabersat to a human subject for the same purpose. Dependent claims further specify NLRP3 inflammasome activation, inhibition of inflammatory cascade activation, and specific compound forms and delivery routes.
Stated Advantages
Inhibits or modulates inflammasome activity in a subject or human subject.
Prevents inflammasome-driven activation of an inflammatory cascade.
Tonabersat is stated to be non-toxic in cell viability assays.
Tonabersat does not affect Cx43 mRNA transcription/translation.
Reduction of vascular leakage and improved retinal ganglion cell survival after ischemia-reperfusion.
Documented Applications
Treatment or use directed to ocular disorders, including glaucoma, age-related macular degeneration, diabetic macular edema, and diabetic retinopathy.
Use in conditions described as injury, inflammation, fibrosis, and vascular leak.
Combination therapy including ocular agents such as VEGF modulators and PDGF modulators.
Retinal ischemia protection with preservation of retinal ganglion cells.
Ocular delivery formulations and devices for connexin modulators and pannexin modulators.
Sustained ocular delivery concepts and ocular implant structures.
Microneedle-based ocular administration to posterior ocular segments, including suprachoroidal delivery.
Co-administration or kit concepts combining connexin/pannexin modulators with rho-kinase inhibitors and VEGF antagonists.
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