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Publication in <em>NATURE</em> Magazine of an article describing the design of a Therapeutic Meganuclease to treat a severe skin inborn disease by the CNIO, the CRG and Cellectis

Press Release Number: 
PR-169-CELLECTIS-08-1
Date: 
Wednesday, November 5, 2008

Madrid, Spain and Biocitech, France, 5 November 2008 - The CNIO (Spanish National Cancer Research Centre), CRG (the Center for Genomic Regulation) and Cellectis SA, the rational genome engineering company specializing in the production of meganuclease recombination systems and in meganuclease engineering, today announced the publication of a new paper in the high-profile journal Nature.

“For some genetic diseases, cells with the damaged DNA can be extracted from the patient, and be repaired before reimplanting them into the patient using current stem cells technology", describes Guillermo Montoya, head of the Macromolecular Crystallography Group (MCG) of the Spanish National Cancer Research Centre (CNIO in Madrid). “The effectiveness of such a molecular scalpel has earned the publication of this paper in the latest issue of Nature Magazine”.

“Basically, the goal is to bring the cells with a damaged DNA into a “repair shop”, cutting the altered DNA sequence exactly where desired, remove the damaged segment, replace it and then reintroduce a normal cell in the body, but without the defect that causes the disease. What has been achieved by the MCG, in close collaboration with the Center for Biological Systems regulations and Genomics (CRG in Barcelona) and with Cellectis SA (at Biocitech, France), is to design the right tool for this process with the highest specificity: what in the genome engineering jargon is known as a “molecular scalpel”, he added.

Dr. Pâques, CSO of Cellectis, said, “This publication in Nature Magazine illustrates the growing value recognition of Cellectis’ technology by the scientific community. It also shows the quality of our collaborative policy with world-class research institutions across Europe and the United States.”

This publication entitled “Molecular basis of xeroderma pigmentosum group C DNA recognition by engineered meganucleases” describes the extensive characterization of two novel engineered meganucleases, from their structural characteristics to in vivo DNA cleavage and DNA recombination. It is the first time a meganuclease with an extensively redesigned DNA binding interface has been characterized at this level; this paper provides new insight into the rules that govern protein/DNA interactions. As such, it is an important milestone towards the rational design of novel proteins.

The findings include the structural characterization of the meganucleases bound to their cognate target and determination of their activity and specificity in living cells. Structural data were also analyzed in silico to investigate the energetic changes in protein/DNA interactions. This extensive study is the result of a close collaboration between three teams with different areas of expertise. The two meganucleases, which were engineered at Cellectis (Romainville, France), were studied for their biochemical properties and crystallized at the laboratories of Prof. Guillermo Montoya and Francisco Blanco, at the CNIO (Madrid, Spain). Computational analysis was performed in the laboratory of Prof. Luis Serrano at the CRG (Barcelona, Spain). In vivo characterization was conducted jointly by Cellectis and the CNIO.

Prof. Guillermo Montoya commented, "Our work shows that it is possible to design "molecular scalpels" based on the scaffold of homing endonucleases. This work has established a proof of principle, with many potential applications in gene targeting. The combined use of crystal structures at atomic resolution and experimental evidence in cell culture is a good approach for unraveling the mechanisms underlying the specificity of these enzymes. We are very excited about these findings and hope that they will open up opportunities for the application of this technology in the treatment of monogenic diseases.”

The results shown in this paper demonstrate that meganucleases, which have a very complex protein/DNA interaction pattern, can be redesigned without losing their essential properties in terms of activity and specificity. This notion is further illustrated by the generation of a variety of engineered meganucleases on Cellectis’ platform.

About Cellectis
Cellectis SA (www.cellectis.com) is a world leader in genome engineering and genome surgery. The company focuses on developing and producing custom meganucleases for in vivo DNA surgery and provides new tools for rational reverse genetics and targeted recombination. Cellectis’ products induce unique, site-directed, double-strand DNA breaks in a living cell and can be used in a wide range of biotechnological and therapeutic applications. To date, Cellectis has entered into more than 50 agreements on its genome engineering technologies with major players in the pharma, biotech and agrobiotech industries. Cellectis is listed on the NYSE-Euronext Alternext market (ticker code: ALCLS). For more information on Cellectis, visit our website: www.cellectis.com

Disclaimer
This communication expressly or implicitly describes certain predictive statements concerning Cellectis SA and its business activities. Such statements involve certain known and unknown risks, uncertainties and other factors, which could cause the actual results, financial condition, performance or achievements of Cellectis SA to be materially different from any future results, performance or achievements expressed or implied by such predictive statements. Cellectis SA is providing this communication as of this date and declines all responsibility to update any predictive statements contained herein as a result of new information, future events or otherwise. For a discussion of the risks and uncertainties which could cause actual results, financial conditions, performance or achievements of Cellectis SA to differ from those contained in the predictive statements please refer to the Risk Factors ("Facteurs de Risque") section of the prospectus approved by the French Autorité des Marchés Financiers (“AMF”) on January 22nd, 2007 under visa number 07-023, available on the websites of the AMF (http://www.amf-france.org) and Cellectis (http://www.cellectis.com).

The original news release can be found at: http://www.cellectis.com/news/clspr-gb-081105.pdf (PDF).

Note: Published in Nature, 456, 107-111 (6 November 2008) | doi:10.1038/nature07343; Pilar Redondo, Jesús Prieto, Inés G. Muñoz, Andreu Alibés, Francois Stricher, Luis Serrano, Jean-Pierre Cabaniols, Fayza Daboussi, Sylvain Arnould, Christophe Perez, Philippe Duchateau, Frédéric Pâques, Francisco J. Blanco & Guillermo Montoya; "Molecular basis of xeroderma pigmentosum group C DNA recognition by engineered meganucleases".

Data collection took place at the European Synchrotron Radiation Facility, beamline ID23; and at the Swiss Light Source, beamline PX.

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