Prostacyclin Analogue Pretreatment for Hematopoietic Stem Cell Engraftment

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Solution Overview

Problem

Current methods for hematopoietic stem cell engraftment in bone marrow transplantation are inefficient, requiring large numbers of stem cells and often resulting in prolonged bone marrow aplasia, due to the inability to effectively stimulate homing, engraftment, and retention of stem cells in the bone marrow niche.

Innovation Solution

The use of synthetic prostacyclin analogues such as Treprostinil, Iloprost, Beraprost, and Cicaprost to stimulate Gαs-signalling in hematopoietic stem cells through ex-vivo pretreatment, increasing cAMP levels and enhancing engraftment by incubating stem cells with these analogues and optionally combining with cAMP activators like forskolin.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If large numbers of stem cells are used for transplantation, then engraftment success is improved, but the complexity of cell collection and the duration of bone marrow aplasia worsen

Engineering Contradiction:

Improveengraftment successVSAvoidcell collection complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies parameter changes by modifying the chemical environment of stem cells through prostacyclin analogue treatment. This chemical parameter change enhances the cells' homing and engraftment capabilities, allowing successful transplantation with fewer cells rather than increasing cell quantity.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

Prostacyclin analogues serve as intermediary substances that mediate between the transplanted stem cells and the bone marrow niche. These compounds facilitate cell adhesion, migration, and engraftment by interacting with receptors on stem cells and components of the bone marrow microenvironment.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If large numbers of stem cells are used for transplantation, then engraftment success is improved, but the duration of bone marrow aplasia worsens

Engineering Contradiction:

Improveengraftment successVSAvoidduration of bone marrow aplasia

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The patent applies preliminary action by pretreating stem cells with prostacyclin analogues before transplantation. This pre-treatment prepares the cells for enhanced engraftment efficiency, so that when fewer cells are transplanted, they still achieve successful engraftment, thereby reducing the period of bone marrow aplasia.

Inventive Principle:

Principle #10Preliminary action

3Reliability

If cholera toxin is used to stimulate Gαs-signalling, then engraftment is improved, but harmful side effects worsen

Engineering Contradiction:

ImproveengraftmentVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent replaces the harmful cholera toxin with prostacyclin analogues that act as temporary, controllable stimulants. These analogues provide the necessary Gαs signalling activation only during the pretreatment phase, then are metabolized and eliminated, avoiding the persistent harmful effects of cholera toxin.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

Instead of using cholera toxin which causes harmful systemic effects, the patent employs prostacyclin analogues that selectively stimulate Gαs signalling in stem cells without the toxic side effects. This converts the approach from harmful to beneficial by achieving the same signalling effect through a safer mechanism.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

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 significantly increases the engraftment of stem cells in the bone marrow, reducing the number of stem cells needed for transplantation and shortening the duration of bone marrow aplasia, with Treprostinil being a stable and well-tolerated option that stimulates multiple Gs-coupled receptors without engaging inhibitory pathways.

Implementation Method 1

incubating said mixture for a period of time sufficient to stimulate G alphas-signalling in said cells

Methodology Applied

Scientific EffectGαs-signalling:

Implementation Method 2

Gαs is the guanine nucleotide binding α-subunit of the heterotrimeric G protein that stimulates all 9 isoforms of membrane-bound mammalian adenylyl cyclase

Methodology Applied

Scientific EffectcAMP production:

Data Source

PatentUS10213464B2Method for enhancing engraftment of haematopoetic stem cells

Publication Date: 2019.02.26 SCIPHARM SARL

AI summary

The present invention provides a novel method for enhancing engraftment of haematopoetic stem cells by an ex-vivo pretreatment comprising the steps of obtaining a sample containing haematopoetic stem cells and admixing a prostacyclin analog to obtain a mixture, incubating said mixture for a period of time sufficient to stimulate G alphas-signalling in said cells and optionally and isolating said stimulated cells. Further, a composition comprising a prostacyclin analog for use in the treatment of individuals undergoing haematopoetic stem cell transplantation is provided.