Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Progeria: Promising results from new gene therapy on animals

28.10.2011
Researchers are continuing their efforts in an attempt to counter the consequences of the genetic defect that causes Progeria.

Until now, no model had been able to accurately imitate the effects of the disease in humans. For several years, research has been conducted in close collaboration from teams led by Nicolas Lévy and Annachiara De Sandre-Giovannoli at Inserm/Université de la Méditerranée and from a team led by Carlos López-Otín (University of Oviedo) and has succeeded in making such a model possible. The lifespan of mice treated through gene therapy is significantly extended and several other parameters related to them are improved.

The research, published on 26 October 2011 in Science Translational Medicine, received backing from the AFM thanks to donations from a Telethon.

Progeria is a rare genetic disease. Children suffering from it seem to experience accelerated aging (chronic hair loss, joint pains, thin and hairless skin, cardiovascular problems). In 2003, Nicolas Lévy and his team identified the cause of the disease when they discovered the involvement of the LMNA (nuclear protein-coding) gene, lamin A/C. The mutation causes the production of a truncated protein, progerin, which accumulates in the nuclei of cells and its toxic effects cause their deformation and various other malfunctions. It has since been proven that progerin progressively accumulates in normal cells, thus establishing a link between the disease and physiological aging.

In 2008, European clinical trials began on twelve children suffering from Progeria. The treatment is based on a combination of two existing molecules: statins (prescribed in the treatment and prevention of atherosclerosis and cardiovascular risks) and aminobisphosphonates (prescribed in to treat osteoporosis and to prevent complications in some forms of cancer). The use of both these molecules aims to chemically alter progerin to reduce its toxicity. However, although this treatment aimed to slow down the development of the disease, it did not reduce the quantities of progerin. To study this aspect, researchers needed to obtain a relevant animal model.

An "authentic" Progeria model…

To generate a model of this kind, Spanish and French researchers decided to introduce a gene mutation (G609G), equivalent to that identified in humans (G608G), in mice to reproduce the exact pathological mechanism found in the children, with a view to then blocking it. The mice models were created under the supervision of Bernard Malissen using the IBISA platform located at the Marseille-Luminy Centre of Immunology . This approach made it possible to obtain young mice that produced progerin, characteristic of the disease in humans. After three weeks alive, the mutated mice displayed growth defects, weight loss caused by bone deformation and cardiovascular and metabolic anomalies mirroring the human phenotype and considerably reducing their lifespan (an average of 103 days compared with two years for wild mice). The progerin thus produced accumulates in mouse cells via genetic mechanisms (abnormal splicing) identical to those observed in humans, i.e. the source of anomalies characteristic of the disease.

… for a targeted gene therapy

Using this unique Progeria animal model, the researchers focussed their efforts on implementing a mutation-targeted treatment, with a view to reducing, and, if possible, preventing the production of progerin. To this end, they used "vivo-morpholino" antisense oligonucleotide technology. "This technology, explains Nicolas Lévy, is based on introducing a synthetic antisense aglionecleotide into mice. As is the case with progeria, this sequence is applied to block (or facilitate) the production of a functional protein using a gene. In this case, the production of progerin, as well as lamin A from the gene, were reduced."

There was a highly significant increase in life expectancy of mice treated using this new technology, from an average of 155 days to a maximum of 190 days.

Nicolas Levy's team, with continued collaboration with Carlos López-Otín, now intend to translate this preclinical research into a new therapeutic trial for children, possibly combined with other pharmacological molecules. Other research is being conducted in parallel to find alternative administration channels for antisense oligonucleotides.

For more details:

Splicing-Directed Therapy in a New Mouse Model of Human Accelerated Aging
Fernando G. Osorio,1 Claire L. Navarro,2 Juan Cadiñanos,1 Isabel C. López-Mejía,3 Pedro M. Quirós,1 Catherine Bartoli,2 José Rivera,4 Jamal Tazi,3 Gabriela Guzmán,5 Ignacio Varela,1 Danielle Depetris,2 Félix de Carlos,6 Juan Cobo,6 Vicente Andrés,4 Annachiara De Sandre-Giovannoli,2,7 José M. P. Freije,1 Nicolas Lévy,2,7 Carlos López-Otín1†

1Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain. 2Université de la Méditerranée, Inserm UMR_S 910, Faculté de Médecine de Marseille, 13385 Marseille cedex 05, France. 3Institut de Génétique Moléculaire, UMR 5535 CNRS, 34293 Montpellier cedex 5, France. 4Departamento de Epidemiología, Aterotrombosis e Imagen, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain. 5Servicio de Cardiología, Hospital Universitario La Paz, 28046 Madrid, Spain. 6Departamento de Cirugía y Especialidades Médico-Quirúrgicas and Instituto Asturiano de Odontología, Universidad de Oviedo, 33006 Oviedo, Spain.7AP-HM, Département de Génétique Médicale, Hôpital d'Enfants de la Timone, 13385 Marseille cedex 05, France.

Science Translational Medicine, October 2011

Research contacts:
Nicolas Levy or Annachiara De Sandre-Giovannoli
annachiara.desandre-giovannoli@univmed.fr

Priscille Rivière | EurekAlert!
Further information:
http://www.inserm.fr

More articles from Life Sciences:

nachricht Magic number colloidal clusters
13.12.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg

nachricht Record levels of mercury released by thawing permafrost in Canadian Arctic
13.12.2018 | University of Alberta

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: An energy-efficient way to stay warm: Sew high-tech heating patches to your clothes

Personal patches could reduce energy waste in buildings, Rutgers-led study says

What if, instead of turning up the thermostat, you could warm up with high-tech, flexible patches sewn into your clothes - while significantly reducing your...

Im Focus: Lethal combination: Drug cocktail turns off the juice to cancer cells

A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.

The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...

Im Focus: New Foldable Drone Flies through Narrow Holes in Rescue Missions

A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.

Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...

Im Focus: Topological material switched off and on for the first time

Key advance for future topological transistors

Over the last decade, there has been much excitement about the discovery, recognised by the Nobel Prize in Physics only two years ago, that there are two types...

Im Focus: Researchers develop method to transfer entire 2D circuits to any smooth surface

What if a sensor sensing a thing could be part of the thing itself? Rice University engineers believe they have a two-dimensional solution to do just that.

Rice engineers led by materials scientists Pulickel Ajayan and Jun Lou have developed a method to make atom-flat sensors that seamlessly integrate with devices...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

New Plastics Economy Investor Forum - Meeting Point for Innovations

10.12.2018 | Event News

EGU 2019 meeting: Media registration now open

06.12.2018 | Event News

 
Latest News

Magic number colloidal clusters

13.12.2018 | Life Sciences

UNLV study unlocks clues to how planets form

13.12.2018 | Physics and Astronomy

Live from the ocean research vessel Atlantis

13.12.2018 | Earth Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>