CRISPR Super-Repressor for Immune Evasion in Gene Therapy

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Solution Overview

Problem

Adeno-associated viral (AAV) vectors and CRISPR-Cas9 systems face challenges due to immune responses, including adaptive immune reactions and off-target effects, which compromise the effectiveness and safety of gene therapy applications.

Innovation Solution

A synthetic repression system is developed, comprising a guide RNA targeting MyD88, an aptamer site, and a multifunctional Cas nuclease, packaged in a DNA-based viral vector, to repress MyD88 expression and modulate immune responses, thereby reducing adverse immune reactions and improving the safety and efficacy of gene therapies.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If AAV vectors are used for gene delivery, then transgene expression efficiency is improved, but adaptive immune response increases

Engineering Contradiction:

Improvetransgene expression efficiencyVSAvoidadaptive immune response

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent applies preliminary anti-action by using a CRISPR-based repression system to suppress MyD88 expression before AAV vector administration. This pre-treatment reduces the host's adaptive immune response capacity, allowing subsequent AAV gene delivery to proceed with reduced antibody and T cell responses against the transgene and viral capsid, thereby resolving the contradiction between high expression efficiency and immune response

Inventive Principle:

Principle #9Preliminary anti-action

2Adaptability or versatility

If CRISPR-Cas9 system is used for gene editing, then gene modulation capability is improved, but immune response and off-target effects increase

Engineering Contradiction:

Improvegene modulation capabilityVSAvoidimmune response and off-target effects

Core Design Contradiction:

Adaptability or versatilityVSObject-affected harmful factors

Solution Approach 1:

The patent extracts and suppresses the specific immune response against Cas9 protein by using CRISPR repression to downregulate MyD88, a key adapter in immune signaling. This selective removal of the harmful immune response component allows the CRISPR-Cas9 gene modulation system to function with reduced pre-existing humoral and cellular immune responses, resolving the contradiction between gene modulation capability and immune response

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent implements preliminary action by temporarily suppressing MyD88 expression before CRISPR-Cas9 administration. This temporary repression creates a window of reduced immune responsiveness, allowing the CRISPR system to be administered and function with minimized off-target effects and immune-mediated clearance, thereby resolving the contradiction between gene modulation capability and harmful effects

Inventive Principle:

Principle #10Preliminary action

3Productivity

If Cas9 expression is prolonged, then gene editing efficiency is improved, but off-target activity increases

Engineering Contradiction:

Improvegene editing efficiencyVSAvoidoff-target activity

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The patent applies periodic action by using transient, controlled suppression of MyD88 expression rather than continuous repression. The temporary nature of the MyD88 suppression creates a defined time window for CRISPR-Cas9 activity with reduced off-target effects, while allowing normal immune function to resume afterward, thus resolving the contradiction between sustained gene editing efficiency and off-target activity

Inventive Principle:

Principle #19Periodic action

Data Source

PatentUS20240117364A1Synthetic immunomodulation with a crispr super-repressor in vivo

Publication Date: 2024.04.11 THE ARIZONA BOARD OF REGENTS ON BEHALF OF THE UNIV OF ARIZONA

AI summary

Provided herein are CRISPR-based synthetic repression systems as well as methods and compositions using the synthetic repression systems to treat septicemia, an adverse immune response in a subject and Waldenström macroglobulinemia.