Compositions and methods for using engineered deubiquitinases for probing ubiquitin-dependent cellular processes
Inventors
Colecraft, Henry M. • Kanner, Scott
Assignees
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Publication Number
US-12559739-B2
Publication Date
2026-02-24
Expiration Date
Abstract
The present disclosure provides, inter alia, a recombinant engineered deubiquitinase (DUB) and methods for treating or ameliorating an inherited ion channelopathy, such as long QT syndrome, Brugada syndrome, or cystic fibrosis, in a subject. Further provided are methods for screening mutations causing such inherited ion channelopathies for a trafficking-deficient mutation that is treatable by the recombinant engineered DUB disclosed herein.
Core Innovation
The invention relates to a method of treating or ameliorating the effects of an inherited ion channelopathy in a human subject by administering a recombinant engineered deubiquitinase (DUB), or nanoDUB. The engineered DUB is composed of a catalytic unit comprising the catalytic domain of a deubiquitinase, a protein binder that specifically binds a target substrate protein for deubiquitination, and a variable linker between the catalytic unit and the protein binder.
The protein binder is an antibody or an antigen binding fragment thereof, including binder formats such as a nanobody (vhh4) and other antigen-binding constructs. The catalytic unit is based on deubiquitinase catalytic domains and may be constrained by deubiquitinase family membership such as USP, OTU, UCH, Josephin, MINDY, or JAMM, or by specific named catalytic domains including Cezanne, OTUD1, OTUD4, TRABID, or OTULIN.
The engineered DUB is used to treat inherited ion channelopathies including long QT syndrome, Brugada syndrome, and cystic fibrosis by administering nucleic acids encoding the engineered DUB. The document also describes a mutation-screening workflow to identify trafficking-deficient mutations that are rescueable by selecting an engineered DUB based on the mutant channel’s ubiquitination status, including evaluation across LQT1/LQT2 mutation contexts and HERG regulation pathways.
Claims Coverage
The independent claim covers treating or ameliorating an inherited ion channelopathy by administering a recombinant engineered DUB with three structural features: a catalytic domain unit, a target-binding protein binder, and a variable linker. Dependent claims refine the engineered DUB by specifying the inherited ion channelopathy, binder formats, deubiquitinase family or named catalytic domains, and linkage-type selectivity.
Recombinant engineered DUB for treating inherited ion channelopathies
A method of treating or ameliorating the effects of an inherited ion channelopathy in a human subject by administering a recombinant engineered deubiquitinase (DUB) comprising a catalytic unit with the catalytic domain of a deubiquitinase, a protein binder that specifically binds a target substrate protein for deubiquitination, and a variable linker between the catalytic unit and the protein binder.
Inherited ion channelopathy disease set
The inherited ion channelopathy comprises epilepsy, migraine, neuropathic pain, cardiac arrhythmias, long QT syndrome, Brugada syndrome, cystic fibrosis, hyperinsulinemic hypoglycemia, or Bartter syndrome.
Protein binder as antibody or antigen-binding fragment formats
The antibody is a nanobody, scFv, (scFv)2, Fab, Fab′, F(ab′)2, Fv, diabody, or a DARPin.
Catalytic-unit family members of deubiquitinases
The catalytic unit includes the catalytic domain of a deubiquitinase from USP, OTU, UCH, Josephin, MINDY, or JAMM families.
Catalytic-unit catalytic domains selected from named enzymes
The catalytic unit includes the catalytic domain of Cezanne, OTUD1, OTUD4, TRABID, or OTULIN.
Linkage-type selectivity of catalytic unit
The catalytic unit is selective for a particular ubiquitin linkage type.
The claims cover administration of a recombinant engineered DUB assembled from a deubiquitinase catalytic domain, an antibody-based protein binder that targets a substrate protein for deubiquitination, and a variable linker, with further claim coverage directed to specific ion channelopathy indications, binder formats, catalytic domain families or named enzymes, and linkage-type selectivity.
Stated Advantages
Treat or ameliorate the effects of an inherited ion channelopathy in a human subject.
Documented Applications
Treating inherited ion channelopathies, including long QT syndrome, Brugada syndrome, and cystic fibrosis, by administering nucleic acids encoding the engineered DUB.
Mutation screening to identify trafficking-deficient mutations that are rescueable by selecting an engineered DUB based on the mutant channel’s ubiquitination status, including evaluation across LQT1/LQT2 mutations and HERG regulation pathways.
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