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- 2003 Annual meeting - Conference and discussion |
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Genetic Research: Doctor Anne JOUTEL
Dr Anne JOUTEL, working in Professor Elisabeth TOURNIER-LASSERVE’s genetic research laboratory, describes the current state of genetic knowledge and research studies that are currently performed.
The Notch 3 gene located on the 19th chromosome was identified in 1996. It permitted to discover the protein that is modified as a consequence of the mutations in this gene. The strategy that was built then, aimed at understanding the reasons of the mutations’ consequences. It was observed that this protein was present exclusively in the vessels’ walls.
The question which has to be solved is the following one: why do the cells in vessels get spoiled when the Notch3 gene is modified, provoking a bad blood circulation in some brain areas?
If we understand what occurs at the levels of the protein, of the cell and of the vessels, a therapeutic preventive strategy could be conceived.
In order to understand these matters, two different approaches have been set up:
- researches on the cells having the muted protein, in comparison with cells having the normal protein.
- generation of animal models (mice) presenting the same lesions, in order to understand what doesn’t work correctly in the small vessels and to find treatments hypotheses.
Here are the major outcomes obtained in 2003:
- This protein works like a « lock », a receptor. If it doesn’t work correctly, a way has to be found in order to activate the key lock, nevertheless. The studies performed on laboratory animals having different forms of the mutation show that the “key” is intact, whereas the “lock” is failing.
- Laboratory mice with the muted gene present the same brain lesions, which are characteristic of CADASIL, as human beings, with deposits of protein in the small blood vessels’ walls. But the appearance of these abnormalities occurs too late in the mice’s life expectancy, which doesn’t leave enough time for testing some medicines. At the present time, biologists try to generate some mice that would develop these lesions earlier, 2 or 3 months after their birth (instead of at the age of 18 months now). These animals are very important for understanding what occurs, particularly:
o If the accumulation of proteins is responsible for the lesions. In that case, solutions for destroying these deposits would have to be found.
o Or if first and foremost, the protein receptor has to be protected. It has indeed been observed that these animals have brain lesions before the apparition of protein deposits in the wall of the small vessels that feed the brain. It seems that this “track” is the most important one and it is therefore essential to study how the vessels’ contraction works.
- Some works are also performed on the functioning of vessels, and their contraction process.
- The studies carried out on mice have permitted to show the progression of the lesions, and to observe that the first damage is the armature, the skeleton, of the cells located in the vessels’ walls.
Additional information:
- About 200 different mutations, provoking CADASIL, have been identified in the world, on the Notch 3 gene.
- Some mice have been brought to life without this gene: it has been observed that their vessels’ armatures are quite abnormal. This gene plays therefore a role in the functioning of this framework.
- The genetic laboratory of Doctor JOUTEL and Professor TOURNIER-LASSERVE gathers various expertises, among which a physiologist, some students, engineers... This team works with a network of neuropathologists in France and in foreign countries (Belgium…) and with other Research teams abroad (in particular a German team in Berlin and another one in California, that had developed the mice deprived of the Notch 3 gene). The results obtained by Dr DICHGANS, in Germany, mostly correspond to those collected in France.
Professor Hugues CHABRIAT
Professor CHABRIAT expounds the progress in the current research study on 200 patients having CADASIL.
The main objectives of this study, begun in 2003, are the following:
- Collect data on clinical aspects, by submitting all these patients to the same medical examinations, with the same follow-up during three years, in order to get a better evaluation of symptoms.
- Collect data on MRI images of persons having CADASIL, at different steps of their disease, and identify the evolution of their brain images in the course of their illness.
- Gather around this project various researchers and practitioners who are in charge of researches and who take care of ill persons.
- Determine parameters for testing the efficiency of future treatments. Actually, if, for instance, the number of TIAs would be a criterion, hundreds of ill persons would have to be followed, over a very long period, in order to prove that a medicine gives some benefits. In the same way, it would also be very hard to measure the benefits of a treatment, if we would evaluate its impact on memory capacities and concentration abilities… But MRI results could more easily permit this evaluation. The follow-up study of 200 patients is therefore very important, in order to establish methods and criteria.
In order to enrol these 200 participants in this research program, contacts had been made with all TIAs specialists in France and a mailing was sent to 680 French neurologists. The Research Team needs nevertheless that families get involved and help in order to find volunteers.
The financial envelope of this program permits to pay for the required medical examinations in order to follow 200 patients during three years. The number of participants required has not yet been reached. French persons knowing that they have the muted gene are therefore invited to join the program.
The examinations performed in the frame of this study are organized in Mrs Marie-Germaine BOUSSER’s neurology department of Lariboisiere Hospital in Paris, in partnership with the Clinical Research Unit of this hospital, the mission of which being to check that each participant undergoes exactly the same analyses, in the same conditions, in respect of the protocols defined for the project.
The study includes a psychological evaluation (cognitive tests, memory and concentration exercises), directed by the psychologist in the neurology department of the Lariboisiere Hospital, Mrs Annie KURTZ and her two collaborators, all of them being present during our general assembly.
After the first appointment with initial examinations during one day, (MRI, neurology evaluation, measurement of memory, attention and concentration abilities, blood punctures, doppler), and after half-yearly and three-year term appointments, the results are transmitted to the personal general practitioner of each participant. If the blood punctures show other risk factors, like cholesterol, corrective treatments are prescribed.
Six-monthly consultations will permit to check the initial information collected during the first appointment, and to detect the occurring of new events and the evolution of each person’s data.
Professor CHABRIAT is convinced that searching for a treatment in CADASIL will have a larger interest and could be useful for other vascular diseases. This product would probably be helpful for a great number of ill persons, outside CADASIL patients. On that subject, he announces that some contacts are presently developed with some pharmaceutical laboratories, in order to evaluate the interest of some new treatments that could be active against some symptoms of CADASIL.
For taking part in this Research program, ill persons must have had previously a CADASIL diagnosis by a genetic test or a positive skin biopsy.
Reminders on the approach when someone who has no symptom requires a genetic test in Professor BOUSSER’s department:
- The person whose father or mother has CADASIL and who has therefore a 50% risk of having the muted Notch3 gene must initially meet with a neurologist, un genetics and a psychologist.
- After a two- or three months waiting period, the next step – the blood puncture- is proposed to the candidate.
- When the genetic analysis of the blood sample is performed : another thought period is left before the results are communicated to the individual, who can then choose not to collect the results.
L’étude de suivi réalisée en France a lieu de la même manière en Allemagne (Dr DICHGANS, à Münich).
Medical discussion
(No translation available) ♦
Written by Chantal Neau
Creation date : 12/03/2009 @ 18:24
Last update : 07/09/2009 @ 21:39
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