Base Editor System for KLKB1 Polynucleotide Modification

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Solution Overview

Problem

Hereditary angioedema is a rare and potentially life-threatening condition with severe swelling episodes that can be difficult to diagnose and treat, requiring improved therapeutic methods to manage its frequency and severity.

Innovation Solution

The use of a base editor system comprising a fusion protein or complex with a nucleic acid programmable DNA binding protein and a deaminase domain to modify the kallikrein B1 (KLKB1) polynucleotide, reducing its expression and activity, thereby treating hereditary angioedema.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional treatments are used for hereditary angioedema, then the condition can be managed, but the frequency and severity of attacks remain high and treatment options are limited

Engineering Contradiction:

Improveeffectiveness of treatmentVSAvoidtreatment options

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies parameter changes by modifying the KLKB1 polynucleotide sequence through base editing (changing nucleobases) or double-strand cutting, thereby altering the expression and activity of the KLKB1 polypeptide. This molecular-level parameter modification reduces the frequency and severity of angioedema attacks, providing a more effective and versatile treatment approach compared to conventional therapies.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If the KLKB1 polynucleotide is modified to reduce expression and activity, then angioedema attacks are reduced, but the complexity of the treatment method increases

Engineering Contradiction:

Improvereduction of attack frequency and severityVSAvoidcomplexity of treatment method

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent replaces complex mechanical or pharmacological intervention systems with a molecular biology-based approach using base editors and guide polynucleotides to directly modify the KLKB1 polynucleotide. This substitution simplifies the treatment mechanism at a fundamental level by targeting the genetic code itself, thereby reducing attack frequency and severity through precise molecular modification rather than complex external interventions.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

3Manufacturing precision

If base editing is used to alter the KLKB1 polynucleotide, then targeted therapeutic effect is achieved, but the precision and control of the modification must be maintained

Engineering Contradiction:

Improveprecision of polynucleotide modificationVSAvoidcontrol of expression reduction

Core Design Contradiction:

Manufacturing precisionVSReliability

Solution Approach 1:

The patent applies local quality by using guide polynucleotides to target specific locations within the KLKB1 polynucleotide for base editing or double-strand cutting. This localized modification approach ensures that the precision and control of expression reduction are achieved at the specific genetic locus, thereby maintaining high manufacturing precision while ensuring reliable therapeutic effect through targeted rather than global modification.

Inventive Principle:

Principle #3Local quality

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

This approach effectively reduces the frequency and severity of angioedema attacks by altering the KLKB1 polynucleotide, providing a targeted therapeutic method for managing the condition.

Implementation Method 1

the modification is associated with reduced expression, and/or reduced activity of the KLKB1 polypeptide encoded by the polynucleotide. Non-limiting examples of alterations include base edits and/or double-strand cuts

Methodology Applied

Scientific EffectBase editing:

Implementation Method 2

a base editor containing a fusion protein or a protein complex containing a nucleic acid programmable DNA binding protein (napDNAbp) domain and a deaminase domain

Methodology Applied

Scientific EffectDeamination:

Implementation Method 3

The guide polynucleotide targets the base editor to effect an alteration of the nucleobase of the KLKB1 polynucleotide

Methodology Applied

Scientific EffectGuide RNA binding:

Implementation Method 4

a nucleic acid programmable DNA binding protein (napDNAbp) domain

Methodology Applied

Scientific EffectProgrammable DNA binding:

Data Source

PatentUS20240360433A1Compositions and methods for the treatment of hereditary angioedema (HAE)

Publication Date: 2024.10.31 BEAM THERAPEUTICS INC

AI summary

The invention of the disclosure features compositions and methods for treating hereditary angioedema by introducing one or more alterations to a kallikrein B1 (KLKB1) polynucleotide in a cell. In particular embodiments, the invention provides a base editor system (e.g., a fusion protein or complex comprising a programmable DNA binding protein, a nucleobase editor, and gRNA) for modifying a KLKB1 polynucleotide, where the modification is associated with reduced expression and/or reduced activity of the KLKB1 polypeptide encoded by the polynucleotide.