therapy with antisense oligonucleotide

In this video, medical students from Leiden University Medical Center show how therapy with an antisense oligonucleotide can influence the structure of an incomplete protein by masking a missing link. Like progeria, Duchenne muscular dystrophy (DMD) is a lethal disease which is caused by non a functional protein. For Duchenne and Progeria patients, this approach offers new perspectives.

It illustrates the process:
Proteins are encoded by a gene, which consists of arrays of exons (E) and introns (I). To make proteins, the introns have to be spliced out by the spliceosome. The exons are then joined together and the amino acids (AA) are synthesized.
When there is a mutation (STOP) in the gene, the protein cannot be synthesized properly and is therefore not functional. This protein makes the muscle weak, more prone to damage and eventually degenerates. An approach called 'exon skipping' could correct a faulty gene using a molecule called antisense oligonucleotides (AON). What does it do? The AON is designed to target, bind and mask/hide the mutated exon. The hidden exon will be treated as an intron by the spliceosome, and spliced out together with the other introns.
The protein produced after exon skipping will be shorter, but is expected to function better than the original, mutated protein. 



German documentary in which Christian tells about the way he copes with his condition. Once a year, he meets his friends at the progeria family circle reunion.

Progeria: Ein Leben in Zeitraffer


gene therapy for children with progeria

Scientific research into progeria has made huge progress over the last few years. In 2003 the ‘progeria gene’ was discovered by Nicolas Lévy’s team, and in collaboration with Carlos López-Otín at the University of Oviedo, in 2008, 12 progeria children were offered a clinical protocol in which two molecules were combined to slow down the process of premature aging. 
These researchers have continued their efforts to counter the consequences of the genetic defect that causes progeria.

Until now, no mouse model could accurately imitate the effects of the disease in humans. After several years of research, teams led by Nicolas Lévy and Annachiara De Sandre-Giovannoli at Inserm/Université de la Méditerranée in Marseille and by Carlos López-Otín in Oviedo have succeeded in making such a model. The lifespan of mice treated through gene therapy is significantly extended and several other parameters related to them are improved. 
The research, published October 26, 2011 in Science Translational Medicine, was made possible by the AFM thanks to donations from the Téléthon.

Carlos López-Otín
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.

European clinical trials began in 2008 on twelve children suffering from progeria. This 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, the 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. 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 progeria children, i.e. the source of anomalies characteristic of the disease.

towards 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 is based on introducing a synthetic antisense oligonucleotide into mice’ explains Nicolas Lévy. ‘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, in continued collaboration with Carlos López-Otín, now intends to translate this preclinical research into a new therapeutic trial for progeria children, possibly combined with other pharmacological molecules. Other research is being conducted in parallel to find alternative administration channels for antisense oligonucleotides.

source: inserm

other related publications by Tom Mistelli and Paola Scaffidi:
reversal of the cellular phenotype in the premature aging disease HGPS
Lamin A-dependent nuclear defects in human aging


En busca de la eterna juventud

This Spanish video (august 2011) provides an overview of medical research on ageing. 


Hayley's Story

There was no sign of the nightmare to come when Hayley was born in 1997. She had fine blonde hair, blue eyes and her parents were besotted with her. At 10 months she walked for the first time. The only concern was she was so petite and didn’t appear to be growing: at 13 months, Hayley still wore clothes for a three-month-old. Her parents took her to a specialist. Six months later a biopsy revealed her skin had an alarming lack of elasticity. In September 1999 the diagnose progeria was confirmed.

Her parents faced a difficult time, but decided that they would make her life special and pack it with wonderful memories…

Read the story of Hayley Okines Life with Progeria in old before my time.


theatre benefit show

In the past decade a bond has grown between dance school MGDance and the Progeria Family Circle. On European reunions Marianne de Pagter has been present. She always knows to put a fabulous show together with the progeria children and their siblings. For all parents it is a moving experience to see their children in a starring role on stage.

To make a new reunion possible, Marianne de Pagter now organises a spectacular theatre show with dancers and musicians from her dance school.

date: 10 sept 2011
location: theatre Junushoff, Wageningen, the Netherlands

Pre-ordered entrance cards cost €10,- and can be purchased at ronmgdance@live.nl.
All profits will go the the Progeria Family Circle.

image ©: Benno Neeleman


Mon étoile filante - the Story of Mégane and Sabrina

Sabrina Durel has two children when she gives birth to Mégane. Last of the tribe, this child is blessed and the center of attention. But soon she shows difficulties in developing normally. This mother is determined to know what's wrong, after several tests the diagnosis falls: Mégane suffers from progeria, a genetic disorder responsible for accelerated aging that leads to early death. Sabrina will fight for her daughter by challenging hospitals and physicians across the Atlantic to get to the world center for the study of this disease that no one would recognize. She seeks hope for a cure and supports Mégane in an environment that excludes different beings. But the life of Mégane and Sabrina is not just a fight. It is certainly not easy, but full of joy and happiness, pushed to the extreme face of approaching death and the overwhelming desire to live.

available in French


telomeres and progerin

A new study was published today as early online edition of the JCI, Journal of Clinical Investigation. It concludes that in normal aging, short or dysfunctional telomeres stimulate cells to produce progerin, which is associated with age-related cell damage.
Researchers from the National Human Genome Research Institute, NIH, Bethesda, Maryland, and the Department of Cell Biology and Molecular Genetics, University of Maryland in the USA have discovered a previously unknown link between Progeria and aging. Their findings provide insights about the relationship between the toxic, Progeria-causing protein known as progerin and telomeres, which protect the ends of DNA within cells until they wear away over time and the cells die.

For the first time, we know that telomere shortening and dysfunction influences the production of progerin," says doctor Leslie B. Gordon, medical director of the Progeria Research Foundation. "Thus these two processes, both of which influence cellular aging, are actually linked."
Prior research has shown that progerin is not only produced in children with Progeria, but that it is produced in smaller amounts in all of us, and progerin levels increase with aging. Independently, previous research on telomere shortening and dysfunction has been associated with normal aging. Since 2003, with the discovery of the Progeria gene mutation and the progerin protein that causes the disease, one of the key areas of research has focused on understanding whether and how Progeria and aging are linked.


R.I.P Leon Botha - 4th June 1985 – 5th June 2011

Leon Botha, a South African artist, died on Sunday from complications related to progeria, a day after his 26th birthday. Botha was one of the longest-living persons documented with the Hutchinson-Gilford Progeria Syndrome.

In 2009, Leon worked with Gordon Clark on a photo series called Who Am I? Transgression, depicting him in theatrical projections of how society might see him. This exhibition still travels around the world. Leon also held a number of art exhibitions, and as a DJ he became widely known through his association with the band Die Antwoord.

read more
Leon Botha

Leon was an inspiration to many people, shared his wisdom and touched many hearts. He will live on through his art and music.


Nestors hope

Nestor and Guillermo are the first patients whose unknown aging disease is diagnosed with a new technique, based on a complete sequencing of the genome. With them begins a new era, which will bring remarkable changes in the approach of certain diseases, including some hitherto unnoticed for science. Carlos López-Otín tells their story (Spanish)


Rare Disease Day

February 28th 2011 will mark the fourth International Rare Disease Day coordinated by EURORDIS and organised with rare disease national alliances in 25 countries. On that day patient organisations from more than 40 countries worldwide will be organising awareness-raising activities and converging around the slogan “Rare but Equal”. A multitude of events will draw attention to rare diseases and the millions of people who are affected by them.

See: Rare Disease Day 2011