Engineered Deubiquitinases for Ion Channel Trafficking Rescue

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Solution Overview

Problem

Current technologies lack effective methods for high-throughput screening of mutations causing inherited ion channelopathies and viral infections that result in trafficking defects, and there is a need for personalized treatment strategies and therapeutic interventions targeting ubiquitin-dependent processes.

Innovation Solution

Development of recombinant engineered deubiquitinases (DUBs) comprising a catalytic unit, protein binder, and variable linker, which are administered to subjects via nucleic acids to treat or ameliorate ion channelopathies and viral infections by regulating ubiquitination status and enhancing membrane protein trafficking.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If current screening technologies are used, then screening can be performed, but high-throughput screening of mutations causing inherited ion channelopathies and viral infections is ineffective

Engineering Contradiction:

Improvescreening throughputVSAvoidscreening effectiveness

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent introduces an engineered deubiquitinase as an intermediary tool that specifically targets and removes ubiquitin chains from ion channels. This intermediary enzyme enables high-throughput screening by providing a controllable, specific, and efficient mechanism to study ubiquitin-dependent trafficking defects that current technologies cannot effectively detect

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention changes the parameter of ubiquitin chain status by using engineered deubiquitinases to selectively remove ubiquitin modifications from ion channels. This parameter change enables the detection and screening of trafficking defects that are dependent on ubiquitination status, thereby improving both throughput and reliability of screening for inherited ion channelopathies

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If general treatment approaches are used, then treatment can be provided, but personalized treatment strategies for ubiquitin-dependent processes are unavailable

Engineering Contradiction:

Improvepersonalization capabilityVSAvoidtreatment implementation complexity

Core Design Contradiction:

Adaptability or versatilityVSEase of manufacture

Solution Approach 1:

The patent segments the treatment approach by developing specific engineered deubiquitinases tailored to target particular ion channels and ubiquitin chain types. This segmentation enables personalized treatment strategies where the specific deubiquitinase can be selected and optimized for each patient's unique mutation profile, making personalized medicine feasible for ubiquitin-dependent processes

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The engineered deubiquitinases are designed to autonomously perform their function of removing ubiquitin chains from target ion channels without requiring complex external intervention. This self-service capability simplifies treatment implementation, as the therapeutic agent can be administered and will automatically target and correct the specific trafficking defect based on its engineered specificity

Inventive Principle:

Principle #25Self-service

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The engineered DUBs effectively rescue trafficking-deficient mutations in ion channels, improving membrane protein expression and function, and provide a modular approach to combat viral infections by targeting ubiquitin-dependent processes.

Implementation Method 1

engineered deubiquitinases (DUBs)... regulating ubiquitination status... effectively rescue trafficking-deficient mutations

Methodology Applied

Scientific EffectDeubiquitination: Hydrolysis

Data Source

PatentUS20260002144A1Compositions and methods for using engineered deubiquitinases for probing ubiquitin-dependent cellular processes

Publication Date: 2026.01.01 THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK

AI summary

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.