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Steps towards the use of adult stem cells for gene therapy

This research, published on Oct. 12 on the Nature review website, provides evidence of a major concept could pave the way for the future use of these stem cells to treat humans, through perspective gene therapies. For several years now, scientists have been able to produce cells with stem cell properties, by using specialized and mature cells from our body, such as skin cells. These 'iPS' stem cells are said to be "pluripotent': they can provide specialized cells, upon demand, with the same gene pool as the original cells. iPS cells represent a potential basis for the exploration of several therapeutic areas, particularly transplants or gene therapy. However, to date research conducted on these cells had not provided proof of their potential in vivo efficiency for the aforementioned types of use.

For the first time, researchers from the Sanger Institute and the University of Cambridge (United Kingdom), with collaboration from an Institut Pasteur/Inserm team in France, have demonstrated that the cells derived from iPS stem cells may be used within the framework of gene therapy to help counter pathological effects in a mice model with liver failure.

The researchers focussed on a rare genetic disease affecting the liver. It is caused by a point mutation in the a1-antitrypsin gene, which is essential for hepatic cells to function correctly. Children display varying degrees of mild symptoms (jaundice, abdomen distension, etc.), but, in adulthood, these symptoms may progressively develop into a pulmonary emphysema and cirrhosis, where the only hope of a cure is a liver transplant.

Researchers from the University of Cambridge, directed by Ludovic Vallier and David Lomas, and from the Sanger Institute, coordinated by Allan Bradley, began by sampling patients' skin cells, which were then cultured in vitro for "differentiation" before applying the properties of the pluripotent stem cells: this is the "iPS cells" stage. Through genetic engineering, scientists were then able to correct the mutation responsible for the disease. They then engaged the now "healthy" stem cells in the maturation process, leading them to differentiate to liver cells.

Scientists from the Institut Pasteur and Inserm, led by Hélène Strick-Marchand in the mixed Institut Pasteur/Inserm Innate Immunity unit (directed by James Di Santo), then tested new human hepatic cells thus produced on an animal model afflicted with liver failure. Their research showed that the cells were entirely functional and suited to integration in existing tissue and that they may contribute to liver regeneration in the mice treated.

This groundbreaking work, published in Nature, thus strengthened hopes in scientific and medical communities regarding the use of iPS cells to treat humans.


Illustration: human iPS cell differentiation to hepatocytes (in red) in a section of a mouse liver. The cell cores are visible in blue. © Institut Pasteur


Targeted gene correction of a1-antitrypsin deficiency in induced pluripotent stem cells, Nature, en ligne le 12 octobre 2011.

Kosuke Yusa (1)*, S. Tamir Rashid (2,3)*, Helene Strick-Marchand (4), Ignacio Varela (5), Pei-Qi Liu6, David E. Paschon (6), Elena Miranda (3,7), Adriana Ordóñez (3), Nick Hannan (2), Foad Rouhani (1), Sylvie Darche (4), Graeme Alexander (3), Stefan J. Marciniak (3), Mamoru Hasegawa (8), Noemi Fusaki (8), Michael C. Holmes (6), James P. Di Santo (4), David A. Lomas (3) §, Allan Bradley (1) § and Ludovic Vallier (2) § */§ Contributions égales des auteurs.

(1) Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK

(2) Laboratory for Regenerative Medicine, Department of Surgery, West Forvie Building, Robinson Way, University of Cambridge, Cambridge, CB2 0SZ, UK

(3) Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge. CB0 2XY, UK

(4) Innate Immunity Unit, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale U668 , Paris, France

(5) Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-UC-SODERCAN Avda. Cardenal Herrera Oria s/n 39011 Santander, Spain (

6) Sangamo BioSciences Inc., Richmond, CA 94804, USA

(7) Dept. Biologia e Biotecnologie 'Charles Darwin', Universita'

Contact: Marion Doucet
INSERM (Institut national de la santé et de la recherche médicale)


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