CRISPR Nanoparticles for LSEC Targeted Gene Editing

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Solution Overview

Problem

Current treatments for hemophilia A, such as recombinant Factor VIII administration, are limited by high costs, frequent injections, and the formation of Factor VIII-inactivating antibodies, necessitating the development of alternative therapies to effectively increase functional Factor VIII expression.

Innovation Solution

The use of gene-editing technologies, specifically CRISPR/Cas9 systems combined with nanoparticles targeting liver sinusoidal endothelial cells, to deliver guide RNAs and nucleases for precise correction of mutant Factor VIII genes, thereby increasing functional Factor VIII expression.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If recombinant Factor VIII administration is used to treat hemophilia A, then Factor VIII activity is restored, but treatment cost increases and frequent injections are required

Engineering Contradiction:

ImproveFactor VIII activityVSAvoidtreatment frequency

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent applies preliminary action by using CRISPR/Cas9 gene editing to permanently correct the mutant F8 gene in liver sinusoidal endothelial cells before any Factor VIII deficiency occurs. The gene correction is established in advance, enabling the patient's own cells to continuously produce functional Factor VIII without requiring repeated administrations of recombinant Factor VIII.

Inventive Principle:

Principle #10Preliminary action

2Reliability

If recombinant Factor VIII administration is used to treat hemophilia A, then Factor VIII activity is restored, but antibody formation increases

Engineering Contradiction:

ImproveFactor VIII activityVSAvoidantibody formation

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies self-service by enabling the patient's own liver sinusoidal endothelial cells to produce functional Factor VIII through gene correction. The corrected cells continuously synthesize endogenous Factor VIII that is structurally identical to natural human Factor VIII, eliminating the immune system's recognition of it as foreign and preventing antibody formation that occurs with recombinant Factor VIII administration.

Inventive Principle:

Principle #25Self-service

3Reliability

If gene-editing components are delivered systemically, then gene correction may occur, but off-target effects increase

Engineering Contradiction:

Improvegene correctionVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies the intermediary principle by using nanoparticles as a delivery vehicle that specifically targets and accumulates in liver sinusoidal endothelial cells. These nanoparticles act as intermediaries that transport CRISPR/Cas9 gene-editing components to the intended target cells while minimizing distribution to other tissues, thereby enhancing gene correction efficiency in LSECs and reducing off-target effects in non-target organs.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20240279649A1Gene editing for expression of functional factor viii for the treatment of hemophilia

Publication Date: 2024.08.22 SEATTLE CHILDRENS HOSPITAL (DBA SEATTLE CHILDRENS RES INST)

AI summary

Gene-editing to allow for expression of functional factor VIII for the treatment of hemophilia A is described. The disclosure further provides nanoparticles to deliver gene-editing components to liver sinusoidal endothelial cells (LSEC) to correct mutant factor VIII genes.