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 Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery
20.01.2017 | GSI Helmholtzzentrum für Schwerionenforschung GmbH

nachricht Seeking structure with metagenome sequences
20.01.2017 | DOE/Joint Genome Institute

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Traffic jam in empty space

New success for Konstanz physicists in studying the quantum vacuum

An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Sustainable Water use in Agriculture in Eastern Europe and Central Asia

19.01.2017 | Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

 
Latest News

Helmholtz International Fellow Award for Sarah Amalia Teichmann

20.01.2017 | Awards Funding

An innovative high-performance material: biofibers made from green lacewing silk

20.01.2017 | Materials Sciences

Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery

20.01.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>