SharePoint
Aide
IRSN, Institut de radioprotection et de sûreté nucléaire

Search our site :

ok

Contact us :

ok
En Fr

Enhancing Nuclear Safety


Research

Research programs

The GIPSIS project

 

​Last update on November 2018

 


The GIPSIS project aims to develop an innovative therapeutic strategy for hematopoietic syndrome (the partial or complete destruction of blood stem cells) in patients with acute radiation syndrome (ARS), by generating hematopoietic stem cells (which give rise to blood cells) from induced pluripotent stem1 (iPS) cells. The three-year project was launched in 2013 with the University of the Sorbonne. The project aimed to define the conditions for a treatment protocol for the injection of hematopoietic stem cells obtained by reprogramming skin cells.

 

Schema_therapie_GIPSIS-EN.jpg 

Figure 1: Principle of the treatment proposed by GIPSIS © IRSN

 

 

Background and objectives

 

Acute Radiation Syndrome (ARS) occurs following the exposure of a large part of the body to a single high dose of ionizing radiation. This syndrome can particularly affect professionals involved in irradiation accidents or criticality events at nuclear installations. It affected victims of the bombings of Nagasaki and Hiroshima, and may involve victims of malicious acts involving a source of radioactivity. The hematopoietic form of this syndrome affects the bone marrow, and results in the partial or total destruction of hematopoietic stem cells (which give rise to blood cells) and lymphocytes (cells of the immune system). This destruction causes a fall in immunity and defects in blood clotting, leading to serious and potentially life-threatening infections and internal bleeding.

 

An international protocol already exists for the medical management of accidental irradiation, METROPOL (Medical Treatment Protocols for radiation accident victims), and for the hematopoietic form in particular, there is a European consensus with a protocol for the therapeutic management of accidents involving mass irradiation incidents. As accidental irradiation exposure is often heterogeneous, in certain cases areas of the bone marrow that have not been irradiated may restore hematopoietic production. The European consensus recommends first-line treatment with cytokines to stimulate the production of blood cells. If the bone marrow dysfunction (in this case, aplasia) persists for more than 14 days, the patient is referred for hematopoietic stem cell transplant. However, the emergency treatment of the population in the event of an accident or malicious act, or the treatment of soldiers during a nuclear conflict, would require the availability of a ready-to-use frozen product, allowing the treatment of a large number of people.

 

The GIPSIS project aims to use cell therapy science to find a solution to this problem. It relies on the use of so-called induced pluripotent stem (iPS) cells to treat the syndrome. These cells were first obtained in 2006 by researchers at Kyoto University, reprogramming differentiated adult cells to return them to an embryonic cell state, capable of differentiating into any other cell. This reprogramming is effected by introducing genes essential for maintaining the properties of embryonic cells. In the GIPSIS project, these genes were introduced using an episome (circular DNA) which is eliminated as the iPS cells divide in culture. The iPS cells then make it possible to obtain pluripotent adult hematopoietic stem cells (able to differentiate only into blood cells or immune cells). Since iPS cells can be obtained from any tissue taken from the patient, they are 100% compatible, with no chance of the graft-versus-host diseases that can occur when the donor's cells are not sufficiently compatible with those of the patient (recipient), and the newly produced immune system cells attack the patient's body.


Shema_iPS_GIPSIS.jpg 

Figure 2: Reprogramming skin cells to become iPS cells © IRSN

 

The next phase of the GIPSIS project involves the use of iPS cells from universal banks. These have the advantage of providing "medicinal" iPS stem cells, of clinical grade. These banks are currently under development for future clinical trials. They will make it possible to use iPS cells as a source of stem cells for cell therapy for large numbers of people, starting from a very limited number of cells derived from "universal" donors.

 

 

Progress of the project


The project is proceeding in three experimental phases, coordinated by the IRSN:

  • the first phase (under the responsibility of the University of the Sorbonne) consists of demonstrating that hematopoietic stem cells generated from healthy donor iPS cells are able to reconstitute the hematopoietic process (production of blood and immune cells) in an immunocompromised organism. The feasibility of the protocol has been established (tests carried out on cell cultures in the laboratory) and (tests of the treatment in a living organism) taking as a model the irradiated and immunocompromised mouse.

 

Schéma_Gipsis_etape_projet_1.jpg 

Figure 3: Protocol for the differentiation of iPS cells into hematopoietic stem cells © IRSN

 

  • the second phase (under the responsibility of the University of the Sorbonne in collaboration with the hematology department of the Saint Antoine Hospital) aims to establish that iPS cells from patients with hematological disease have the same capabilities as cells derived from a healthy donor, using the methods developed in the first phase. The principle challenge in this second phase is to verify that there are no genetic abnormalities in the cells produced.
  • the third phase aims to define the characteristics of the final injectable product for the treatment of ARS. The goal is to produce the purest hematopoietic stem cells possible for the purpose of treating an adult patient. The protocol used respects the good manufacturing practices established in France and in Europe regarding the quality of pharmaceutical products.

 

 

Early results and perspectives

 

The GIPSIS project team is the first in the world to produce functional hematopoietic grafts from human iPS cells, capable of renewal and hematopoietic reconstitution in immunocompromised mice. The next step in validating the use of these iPS cells is to go to clinical trials. Currently, European and international efforts are in progress to develop clinical-grade iPS cell banks from universal donors. In France, GAIT (the Global Alliance for iPSC Therapies), a British initiative, will be established in 2019 at the Evry site. These banks will provide research teams with clinical grade iPS cells.

 

Continuing the GIPSIS project, the research team plans to demonstrate the feasibility of producing and differentiating iPS cells, in order to obtain blood stem cell grafts of sufficient size to treat a human patient (3000 times greater than that necessary for the mouse). This new project, IPS-clinique, focuses on the industrialization of the process developed in the GIPSIS project, in collaboration with I-Stem, for the production of iPs cells and a cell therapy platform at the French Blood Establishment (Etablissement français du sang - EFS) for their differentiation into hematopoietic stem cells. This study will comply with the biosafety standards of the ANSM (National Agency for Safety of Medicines and Health Products) in the field of advanced therapeutic medicinal products, in order to obtain authorization to conduct clinical trials thereafter. These criteria imply production in the most secure environment possible:

  • Absence of contaminant in the cells (bacteria, viruses etc.)
  • Elimination of all products of animal origin
  • Extremely strict control of the cells at each step, to verify that they are functional, that they have no genetic abnormalities or contamination and so on.
  • Production of a graft of sufficient size to treat a human

 

Subject to success in these tests, the therapy proposed by the GIPSIS project has great potential for the creation of a patient-specific treatment of the hematopoietic form of ARS, as well as other hematological diseases. It also paves the way for the use of iPS cells for other medical applications, including building more complex organs, such as the liver or kidney. The desirability of establishing a bank of iPS cells from universal donors is thus very clear.

 

1. A stem cell is an undifferentiated cell, capable of self-renewal, differentiation into other cell types, and proliferation in culture. Stem cells originate either in the embryo or the fetus, or from adult tissues with or without transformation. Their properties allow them to be used to regenerate or recreate destroyed tissues (called "cell therapy").

Send Print

Characteristics

​Dates: 2013-2017

Funding: Directorate General of Armaments (ASTRID/ANR program (ANR-13-

ASTR-0009)), Etablissement Français du Sang (EFS) (APR 2013 & Fighting Leukemia)

Partners: University of the Sorbonne, Etablissement Français du Sang (EFS), INSERM

Involved IRSN laboratory

Further informations

Contact


Close

Send to a friend

The information you provide in this page are single use only and will not be saved.
* Required fields

Recipient's email:*  

Sign with your name:* 

Type your email address:*   

Add a message :

Do you want to receive a copy of this email?

Send

Cancel

Close

WP_IMPRIMER_TITLE

WP_IMPRIMER_MESSAGE

Back

Ok