Life According To Sam

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the beneficial effect of antioxidants in broccoli

The extreme aging in Progeria is caused by an accumulation of a fatty protein that is called Progerin. The presence of Progerin blocks a number of functions in the cell nucleus. This poor protein, which normally would be disposed of in large part, can not be degraded because a genetic code is missing. The clean-up system in the cell is not functioning due to a mutation in the LMNA gene.

The accumulation of Progerin affects several cellular functions. It is also found in healthy cells, but to a much lesser extent. In children with Progeria ten to twenty times more Progerin has been found in the nucleus.
These patients can only make an incomplete form of the protein lamin A. Healthy lamin A has an important function in the wall of the nucleus, it protects the DNA in the cell and plays a role in gene expression. Progerin, a byproduct, only has a function in the construction phase of the protein; it should be disposed of once the nucleus has been formed. However, when it accumulates in the nucleus, progerin causes problems. Patients with progeria develop many problems, including atherosclerosis and osteoporosis, they run the risk of an early stroke or heart attack.

Researchers from the Technical University of Munich (TUM) found more than 28 proteins with a wide range of functions that were not effective in the nuclei of HGPS patients - all the result of the mutation in the lamin A gene. However, they have also shown that the level of progerin in diseased cells can be lowered, by reactivation of the 'cleaning' process. They found a beneficial effect of the antioxidant sulforaphane, found in broccoli (especially in young broccoli sprouts) and other cruciferous vegetables such as cabbage and Brussels sprouts. Sulforaphane (1-isothiocyanato-4-methylsulfinylbutane), showed to reduce the accumulation of Progerin. The progeria cells they treated with sulforaphane also showed decreased DNA damage and less deformation of the nucleus.

source: Sulforaphane enhances progerin clearance in Hutchinson–Gilford progeria fibroblastst, Diana Gabriel, et al., Aging Cell - Doi:10.1111/acel.12300

special... with good reason

In this documentary three members of the progeria family circle 'dreamteam' explain why they help to bring the progeria children and their families together.

new approach for progeria treatment with inhibitor for ICMT

Researchers at Sahlgrenska Academy, the University of Gothenburg, Sweden, have published new results of their work in Science. The group investigated the progeria mutation, that occurs in the protein prelamin A and causes it to accumulate in an inappropriate form in the membrane surrounding the nucleus.

The target enzyme of this study is called ICMT, it attaches a small chemical group to one end of prelamin A. In progeria, blocking this attachment could possibly reduce the development of premature ageing symptoms more effectively. The publication in Science is based on in vitro studies on cells, and has been tested in vivo on mice, treated with a common inhibitor of ICMT. The impact of inhibiting ICMT will need further testing on progeria mouse models with more specified candidate ICMT inhibitor drugs -developped by a collaborating group in Singapore- before it can be offered in a trial to patients.

ICMT has also become the focus of research in the quest for discovering new and more effective cancer therapies. The article Targeting Isoprenylcysteine Methylation Improves Disease Phenotypes in a Mouse Model of Accelerated Aging has been published on May 16. Further reading at Science and the University of Gothenburg.

Unique molecular mechanism protects neurons in progeria patients

Progeria is an extremely rare genetic disease, which induces premature and accelerated ageing in patients. The mutation causing the syndrome affects the LMNA gene that encodes proteins called “lamins” A and C.

Lamins are involved in maintaining the structure of the nuclear membrane. They determine nuclear shape and stiffness and allow communications within the cells. In the case of progeria, lamin A is defective. In its mutated form, it becomes toxic and damages the membranes of the nucleus, disrupts the message and causes accelerated ageing of cells. In 2003 the research team of Dr. Nicolas Levy in Marseille identified the origin of this disease.

The development of this syndrome is rapid: it is estimated that each year, affected children age by more than ten years, leading to their premature death between 13 and 16 years. This accelerated ageing affects most tissues: skin, blood vessels, heart, bones or muscles. Very quickly, patients suffer from muscular and skeletal disorders, stunted growth (their size does not exceed 110 cm for a weight of 15 kg). In contrast, their cognitive abilities are usually not affected. This has always been considered a surprising phenomenon, given the overall disease involvement to which these patients are subjected.

One of the studies of Xavier Nissan et al. in their progeria project showed a unique molecular mechanism that specifically protects neurons in patients with Hutchinson-Gilford progeria syndrome from the defective prelamin A processing.

Skin cells sampled from patients with progeria were induced into pluripotency then differentiated into mature nerve cells. Tuj1 markers highlight nerve cells in green; other markers highlight DNA in blue. Lamin A, if present, would appear in red; the protein is however completely absent in this cell view. 

Copyright: Xavier Nissan, I-Stem 

You can download the extended PDF file of this publication HERE.

The strategy at I-Stem

Recently two phase II clinical trials were initiated by treating HGPS patients with Farnesyltransferase inhibitors (FTIs) and/or the combination of Zoledronate and Pravastatin to prevent or delay the gravest infringements of the disease. Although these two studies have produced promising results, as well as in vitro and in vivo, there is currently no cure for HGPS patients.

In collaboration with Professor Nicolas Lévy, the I-Stem team has generated induced pluripotent stem cells from progeria patients’ cells. Thanks to this unlimited and standardized biological resource they are preparing a high throughput screening campaign of pharmacological compounds in order to identify new treatments of this disease.

Progeria Reunion and Scientific Workshop

In september 2012 scientific researchers from all over the world met in Italy to share the results of their search for a treatment for progeria children. This congress was organised by Giovanna Lantanzi and Stefano Squarzoni form the University of Bologna, and made possible through donations of the Italian organisation for children with progeria: A.I. Pro Sammy Basso.
At the same time and place, all European progeria families gathered for our annual progeria reunion.

While the children enjoyed a party with clowns and jugglers, parents were informed about different plans for new steps towards a trial. Due to the efforts of high qualified researchers, parents of progeria children are now in the position that they can choose between different options for a treatment. To help them make this difficult decision, doctors explained their approach and illustrated on what grounds they expect the proposed therapy to be benificial.

options for therapy

Reducing the toxicity of progerin is possible with an FTI (Lonafarnib, and/or Vasten). The Progeria Research Foundation plans to continue the use of FTI's, perhaps in combination with an immunosuppressant drug (used to prevent rejection after organ transplantation) in the next trial. In vivo testing on mice will hopefully show that Rapamycin can improve the effectiveness of the FTI’s.

Another approach is the antisense therapy, with a morpholino. Annachiara De Sandre presented findings in research done by Carlos Lopez-Otin and her research team in Marseille. Tests on mice showed promising results, since this medication can not only reduce the toxicity, but also lower the quantity of progerin.  

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. 

Christian

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

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

"Race Against Time"

can treatment with IGF1 help children with progeria?

Carlos López Otín and his team observed that their progeroid mice had low levels of the hormone called IGF1.
They used recombinant IGF protein produced in the laboratory to treat the mice and the results were positive in terms of extension of longevity and improvement of progeria symptoms.
The improvement was clear and significant, but lower than that observed with the combination of statins and bisphosphonates which they reported two years ago in Nature Medicine and which has been the basis of the current clinical trial, first conducted by Dr. Nicolas Lévy in Marseille and adopted by the American Progeria Research Foundation in Boston.
The good thing is that additional - yet unpublished work - indicates that positive effects of IGF (albeit not so impressive) could be additive to the pharmacological treatment. Another good thing is that IGF1 has been widely used in children with Laron syndrome with no adverse effects.

Although this finding is interesting, researchers are very cautious regarding immediate translation of laboratory findings in animal models to patients. The option to add IGF to children treated with statins-bisphosphonates will be discussed, for the moment these children will have an adequate follow up of the current treatment that is offered in Marseille.

new development in research

The group of researchers led by Carlos Lopez Otin at the University of Oviedo, has found that insulin growth factor - or IGF1 - extends life in an animal model of human premature aging. The work was published yesterday.

The treatment developed by these researchers can extend a 25 percent longevity of mice with progeria. According to the authors, this represents an important step toward understanding the mechanisms involved in the development of this disease. In addition, it raises a new therapeutic option for patients affected by syndromes of accelerated aging, those who develop during the first years of life characteristic symptoms of old age: osteoporosis, loss of subcutaneous fat and hair, and cardiovascular failure, among others.The life expectancy of people with the most common form of progeria syndrome, Hutchinson-Gilford-is less than 20 years.

The scientists used genetically modified mice created previously in his laboratory. And they found that levels of a hormone known as insulin-like growth factor or IGF1 were abnormally low in these conditions. They decided to restore hormone levels, and treatment with IGF1 led to a marked improvement in various alterations in these mice, including weight gain, recovery of subcutaneous fat and locomotive ability, reduced hair loss and increased significant life expectancy.

According Otín, this paper raises an option "to improve the clinical situation and extend the life of those suffering from premature aging." In work previously published in Nature and Nature Medicine, the same researchers from the University of Oviedo reported that the accelerated aging was associated with abnormal activation of protective mechanisms against cancer and designed a pharmacological strategy aimed at blocking the accumulation protein responsible for this disease. This work has led to an international clinical trial, currently underway in Marseille, to treat children suffering from this dreadful disease.
spanish source

progeria family circle

presentation EURORDIS - Rare Diseases Europe