Htt Repressors With AAV9 Delivery for Mutant Allele Suppression

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Solution Overview

Problem

Current diagnostic and treatment options for Huntington's Disease (HD) are limited, particularly in quantifying low-abundance mutant Huntingtin (mHTT) levels in the patient CNS, which hinders understanding of neuropathobiology and effectiveness of HTT-lowering drugs, and existing gene therapies lack widespread delivery to the brain.

Innovation Solution

Development of engineered zinc finger proteins, TALE proteins, and CRISPR/Cas systems that modulate Htt gene expression, utilizing AAV9 for widespread delivery and axonal transport to treat HD by repressing mutant Htt alleles, including fusion proteins with transcriptional repression domains and nuclease domains for targeted gene modification.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If current diagnostic methods are used, then existing technology can be maintained, but quantification of low-abundance mutant Htt levels in patient CNS is hindered

Engineering Contradiction:

Improvequantification of mutant Htt levelsVSAvoiddetection of low-abundance mutant Htt

Core Design Contradiction:

Measurement precisionVSDifficulty of detecting and measuring

Solution Approach 1:

The patent employs sensitive detection methods that change the measurement parameters to detect low-abundance mutant Htt levels. By using advanced quantification techniques, the system can measure trace amounts of mutant protein that were previously undetectable, thereby improving measurement precision without requiring changes to the biological sample.

Inventive Principle:

Principle #35Parameter changes

2Productivity

If existing gene therapies are used, then gene modification can be achieved, but widespread delivery to the brain is lacking

Engineering Contradiction:

Improvedelivery efficiency to brainVSAvoidcoverage area in brain

Core Design Contradiction:

ProductivityVSArea of stationary object

Solution Approach 1:

The patent utilizes adeno-associated virus (AAV) vectors as intermediary carriers to deliver gene therapy components throughout the brain. These viral vectors act as mediators that can cross the blood-brain barrier and distribute therapeutic genes to multiple brain regions, thereby achieving widespread delivery without requiring direct injection into each target area.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The gene therapy system is designed with universal delivery capabilities that can target multiple brain regions simultaneously. The AAV vectors are engineered to have broad tropism, allowing a single administration to achieve therapeutic coverage across diverse neural tissues, thus improving delivery efficiency and coverage area without requiring region-specific protocols.

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Reliability

If mutant Htt expression is not repressed, then normal Htt function is maintained, but cell death and motor deficits progress

Engineering Contradiction:

Improvecell survival and motor functionVSAvoidtoxicity from mutant Htt

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent employs allele-specific repression strategies that selectively target mutant Htt expression while preserving wild-type Htt function. By designing repressors that recognize specific mutations in the Htt gene, the system achieves localized suppression of toxic alleles without affecting the beneficial wild-type allele, thereby maintaining cell survival and motor function while eliminating harmful effects.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS12551575B2Htt repressors and uses thereof

Publication Date: 2026.02.17 SANGAMO THERAPEUTICS INC

AI summary

Disclosed herein are Htt repressors and methods and compositions for use of these Htt repressors.