Engineered HSC Microglia Delivery Across the Blood-Brain Barrier

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Solution Overview

Problem

Current therapeutic strategies for treating neurological symptoms of genetic diseases fail to deliver therapeutic proteins across the blood-brain barrier, as standard intravenous delivery methods do not effectively address central nervous system defects.

Innovation Solution

Genetically modified hematopoietic stem cells (HSCs) are engineered to express therapeutic genes in microglial cells, allowing for the delivery of therapeutic proteins directly to the brain through homologous recombination and engraftment, enabling cross-correction of genetic defects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If intravenous delivery of therapeutic protein is used, then systemic delivery to body tissues is achieved, but delivery to the brain is insufficient due to blood-brain barrier

Engineering Contradiction:

Improvetherapeutic protein deliveryVSAvoidbrain delivery effectiveness

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent uses microglial cells as intermediary vehicles to transport therapeutic proteins across the blood-brain barrier. These cells are genetically modified to express the therapeutic protein and naturally traverse the barrier to deliver cargo directly to brain tissue, solving the delivery effectiveness problem while maintaining systemic administration capability

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The therapeutic protein is expressed directly within the microglial cells themselves rather than being secreted. This self-service approach ensures that the cells carrying the protein also produce it, guaranteeing both the transport function and the therapeutic function are fulfilled by the same cellular vehicle

Inventive Principle:

Principle #25Self-service

2Reliability

If hematopoietic stem cells are genetically modified with transgene integration, then therapeutic protein expression in microglial cells is achieved, but genetic modification complexity increases

Engineering Contradiction:

Improvetherapeutic protein expressionVSAvoidgenetic modification process

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The transgene is integrated into the hematopoietic stem cells before they differentiate into microglial cells. This preliminary genetic modification ensures that all subsequent microglial progeny inherit the therapeutic gene, guaranteeing reliable and sustained protein expression without requiring repeated modifications

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The genetic modification is performed on hematopoietic stem cells, which are multipotent progenitors that can differentiate into multiple lineages including microglial cells. This universal approach allows a single modification event to affect multiple cell types and ensure long-term, sustained therapeutic protein production

Inventive Principle:

Principle #6Universality (Multi-functionality)

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 enables systemic and local delivery of therapeutic proteins to the brain, effectively treating the neurological symptoms of genetic diseases by ensuring expression in microglial cells, thereby correcting genetic deficiencies.

Implementation Method 1

using programmable nucleases such as transcription activator-like effector nuclease (TALEN), zinc finger nuclease (ZFN), clustered regularly interspaced short palindromic repeats (CRISPR)-Cas, meganucleases and megaTAL (transcription activator-like (TAL) fused to a meganuclease) plus delivery of a repair template for that locus provided with recombinant adeno-associated virus (rAAV) to promote homology directed repair (HDR) of the locus

Methodology Applied

Scientific EffectHomologous recombination:

Implementation Method 2

delivery of a repair template for that locus provided with recombinant adeno-associated virus (rAAV) to promote homology directed repair (HDR) of the locus

Methodology Applied

Scientific EffectViral delivery:

Implementation Method 3

The modified cells can subsequently be returned to the patient through adoptive cell transfer or autologous HSC transplantation. This process will deliver the therapeutic gene product systemically to treat the body but also locally in the brain to treat the totality of the symptoms of the disease

Methodology Applied

Scientific EffectSecretion:

Data Source

PatentUS12534744B2Methods to genetically modify cells for delivery of therapeutic proteins

Publication Date: 2026.01.27 CELLECTIS SA

AI summary

The present disclosure provides methods to genetically modify cells by insertion of an artificial exon (ArtEx) for delivery of therapeutic proteins in specific cell types and more particularly engineered cells for expression of a transgene into the brain of a patient.