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Old 14-06-2010, 07:45 AM
Dingo Dingo is offline
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[SIZE="4"]Part 2[/SIZE]

Question 3) Your team in Quebec is developing the world’s first Scoliosis blood test. What can parents expect from this test?

Dr. Moreau) First of all, I would like to clarify the nature of our scoliosis blood tests since we have developed two distinct and complementary tests.

Functional scoliosis test: The first test is a functional assay performed with blood cells obtained from 10 ml of blood (equivalent to 2 tea-spoons). As you know, we have previously discovered that many cell types obtained from patients suffering from idiopathic scoliosis (IS) display a differential response in the transmission of melatonin signals. This is possible because melatonin receptors are present in most if not all cell types including blood cells. In other words, the test measures how the cells respond to melatonin. Three distinct responses among IS patients were obtained allowing their classification into three functional subgroups. It should be noted that two distinct methods were performed to determine the functional classification of IS patients, the first using the measurement of cAMP, an intracellular messenger (Moreau et al Spine 2004 & Azeddine et al CORR 2007) and more recently using a more accurate technology called cellular dielectric spectroscopy (Akoume et al Spine 2010), giving both the same functional classification. This functional test has the added advantage of being performed on asymptomatic kids (boys and girls) as well to predict their risks of developing scoliosis. Moreover this functional blood test is also superior because it can be performed without prior knowledge of specifically mutated genes causing IS since we are measuring a function. To better understand the usefulness of this functional assay, I often use the example of how cystic fibrosis (CF) is diagnosed. CF is a monogenic disease, which means that it is caused by mutations in a single gene (CFTR) that plays a role in the transport of chloride ions. Today, there are about 1500 mutations known to affect the function of this gene. CF however, is initially diagnosed using a functional test measuring the level of chloride ions in sweat after provoking perspiration at the surface of the skin. Then, if you are positive for CF and depending on which part of the globe you are from, specific mutations will be tested, since it is not clinically and economically relevant to test for all possible mutations. For instance in Quebec, we would test for the 6 most prevalent mutations for our pediatric population.

What can a parent expect from this functional test? This functional test is performed only once and it reflects the genetic predisposition or susceptibility of developing scoliosis. It can be performed at any age (although we prefer not to test babies).

According to the functional subgroup in which the patient is classified, we can determine the following:
  1. A risk-score to establish the susceptibility of developing scoliosis among asymptomatic kids and to predict the risk of disease progression for those at an early stage of the disease. Parents need to keep in mind that this functional test, like any genetic test, cannot assess with 100% certainty if their child will or will not develop scoliosis because the etiology of IS involves a crosstalk with the environment. In other words, kids with a great genetic predisposition (high risk) may develop a severe scoliosis if they are often exposed to specific environmental factors. Inversely, the same kids with a limited environmental exposure could develop a mild scoliosis or none at all.
  2. The risk of developing specific co-morbidities (osteoporosis, anxiety, depression, etc.) which are known to be associated with IS. This aspect is unique to our test and we are in the process of validating whether or not some functional subgroups are more often associated with the risk of developing an early onset of osteoporosis. In that case, knowing a child’s functional subgroup could delay or prevent the development of osteoporosis by increasing his/her bone mass using exercise, diet and medication (which are proven and already available). In the same way, testing scoliotic adults could improve their health outcome and prevent complications simply by knowing which functional subgroup they belong to.
  3. In the long term, this functional classification will be essential for the development of tailored pharmacological treatments (personalised medicine). This will reduce possible side-effects and better define the best treatment for a given patient to stop curve progression and eventually to prevent scoliosis when combined with an early screening using this functional test. We are conducting tests to identify potentially useful therapeutic agents, but parents and patients must be aware that these drugs won’t be tested in clinical trials that soon since we are just now beginning this phase of our research.

Biochemical scoliosis test: The second scoliosis predictive test is a biochemical one where two proteins called Osteopontin (OPN) and soluble CD44 (sCD44) are measured in the blood. Our clinical data in Montreal, Milan and Hong Kong clearly demonstrated that plasma OPN elevation is associated with IS onset and disease severity since all surgical cases (Cobb angle ≥ 45°) exhibit the highest values when compared to mild scoliosis and healthy control subjects. Conversely, sCD44 is a protective molecule that can prevent OPN from triggering scoliosis or spinal deformity progression by binding free OPN. This explains why IS surgical cases exhibit the lowest sCD44 values when compared to mild scoliosis cases and healthy controls subjects. OPN is not only a biochemical marker, it is the key player causing IS onset and it is responsible for spinal deformity progression. It is true that OPN and sCD44 are not disease-specific but when the observations of the effects of both are combined it does appear they become highly specific for IS. These data will be published in the upcoming months.

What can a parent expect from this biochemical test? First, this biochemical test must be combined with our functional test to predict the risk of developing scoliosis and spinal deformity progression. Secondly, the biochemical test will be used to monitor at regular intervals the following:
  1. Risk of disease progression over a given period of time since plasma OPN and sCD44 levels are determined by individual genetics as well as by specific environmental factors. This represents the main advantage of this test since it monitors the impact of the environment on IS progression.
  2. Effectiveness of bracing, physical therapy or pharmacotherapy because OPN is the molecule triggering scoliosis onset and inducing spinal deformity progression. Therefore, any treatment decreasing OPN levels is expected to have a beneficial impact.
  3. Measurement of plasma OPN and sCD44 levels will allow contribute to determining the contribution of environmental factors known to trigger high OPN levels. Interestingly, OPN is a multifunctional cytokine that responds to many stimuli such as mycobacterial infections, drugs, diet, exercise, and biomechanical changes. It would be too long to go into detail for each of these factors but there are several papers demonstrating that OPN expression and synthesis can be increased or decreased in response to external factors. This aspect cannot be considered by genetic tests.
  4. Elimination those factors or reducing the exposure to such factors may greatly reduce the risk of spinal deformity progression. For instance, this approach has been proven effective for the treatment of other diseases like asthma. There is no treatment for asthma but drugs are available to treat acute crisis as well as to reduce the number of attacks. However, reducing exposure to allergens (pet, dust, carpet, chemicals, and wooden stoves) has been shown to be very effective in controlling asthma. It is anticipated that regularly monitoring OPN and sCD44 blood levels will help parents and patients to work with us in the identification of those environmental factors.

Question 4) Do you know when your test will become available?

Dr. Moreau) This is a good question since I have previously predicted that the tests would be available in 2008-2009 and we are now in 2010! The main reason for this delay is it took us more time than expected to complete the clinical trial in Montreal, and launch clinical trials in Italy (Milan) and Hong Kong (China) to demonstrate the universality of our scoliosis blood tests in different pediatric populations. It is worth mentioning that the biochemical tests performed in Milan and Hong Kong were performed by others and yet still confirmed the validity of our own clinical data in Montreal. I can assure you that we are putting forth our best efforts to put our tests on the market as soon as possible.

Question 5) Can your tests be used for juveniles as well as adolescents? What about infantile Scoliosis?

Dr. Moreau) The aforementioned tests were validated in juveniles and adolescents. In regards to infantile scoliosis, we do not know at this point since we did not yet test this form of scoliosis, as infantile scoliosis is such a rare disease in North America. In principle, the tests should work but we need to assess such possibilities in Europe where the cases are more frequent.
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