CasX:gNA System for HTT Gene Editing via Lipid Nanoparticle Delivery

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Solution Overview

Problem

Current treatments for Huntington's disease are primarily palliative, and there is a critical need for curative solutions to address the underlying genetic mutation causing the disease.

Innovation Solution

The use of modified Class 2, Type V CRISPR proteins and guide nucleic acids, specifically the CasX:gNA system, for editing the huntingtin (HTT) gene to correct or compensate for mutations, allowing for passive entry into cells and modifying target nucleic acid sequences to produce a functional huntingtin protein.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If traditional CRISPR delivery methods are used, then gene editing capability is achieved, but delivery efficiency into cells is limited

Engineering Contradiction:

Improvegene editing capabilityVSAvoiddelivery efficiency

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent modifies the chemical parameters of CRISPR components by incorporating lipid modifications and optimizing nucleic acid sequences to enhance cellular uptake efficiency while preserving gene editing functionality

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite delivery systems by combining CRISPR-Cas proteins with lipid nanoparticles and modified nucleic acids, forming multifunctional complexes that improve both delivery efficiency and editing capability

Inventive Principle:

Principle #40Composite materials

2Productivity

If viral vectors are used for CRISPR delivery, then delivery efficiency is improved, but immune response and safety concerns increase

Engineering Contradiction:

Improvedelivery efficiencyVSAvoidimmune response

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent uses lipid nanoparticles as intermediary carriers to deliver CRISPR components, replacing viral vectors and thereby eliminating immune response while maintaining efficient delivery through the lipid-mediated entry mechanism

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent employs non-integrating, transient lipid nanoparticle carriers that are cleared from the body after delivery, avoiding the long-term safety concerns and immune responses associated with viral vector integration

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

3Adaptability or versatility

If CRISPR components are delivered as separate molecules, then flexibility is maintained, but cellular uptake efficiency decreases

Engineering Contradiction:

ImproveflexibilityVSAvoidcellular uptake efficiency

Core Design Contradiction:

Adaptability or versatilityVSProductivity

Solution Approach 1:

The patent merges CRISPR-Cas proteins, guide RNAs, and lipid components into pre-formed ribonucleoprotein complexes that are then encapsulated in lipid nanoparticles, combining the flexibility of separate components with the uptake efficiency of unified structures

Inventive Principle:

Principle #5Merging (Combining)

Data Source

PatentUS20230032369A1Compositions and methods for the targeting of htt

Publication Date: 2023.02.02 SCRIBE THERAPEUTICS INC

AI summary

Provided herein are CRISPR:guide systems comprising Class 2 Type V polypeptides (e.g. CasX:gNA systems comprising CasX polypeptides), guide nucleic acids (gNA), and optionally donor template nucleic acids useful in the modification of a HTT gene. The systems are also useful for introduction into cells, for example eukaryotic cells having mutations in the huntingtin protein. Also provided are methods of using such systems to modify cells having such mutations and utility in methods of treatment of a subject with a HTT-related disease, such as Huntington's disease.