Scoliosis Australia Forums  

Go Back   Scoliosis Australia Forums > Research > The genetics of scoliosis

Reply
 
Thread Tools Search this Thread
  #1  
Old 14-06-2010, 08:43 AM
Dingo Dingo is offline
Registered User
 
Join Date: May 2010
Posts: 7
Default Interview with Dr. Alain Moreau, creator of the Scoliosis blood test

Dr. Alain Moreau is the director of the The Viscogliosi Molecular Genetics Laboratory of Musculoskeletal Disorders and the developer of the Scoliosis blood test. He was kind enough to share some of his valuable time with me to explain his revolutionary blood test and the latest thinking on Scoliosis. This interview was conducted over e-mail.

I moved question 19 near to the top because it contains information that parents can use to potentially help a child living with Scoliosis. The rest of the interview is in order.

[SIZE="4"]Part 1[/SIZE]

Question 1) What attracted to you to the field of Scoliosis research?

Dr. Moreau) I have had a long standing interest in bone diseases. I was trained in bone molecular biology at the Shriner’s Hospital for Children in Montreal, which allowed me to be recruited at Sainte-Justine University Hospital Research Center 10 years ago, to lead a new laboratory dedicated to studying the causes of idiopathic scoliosis.

Question 2) How long have you studied Scoliosis?

Dr. Moreau) I have been actively involved in this field since 2000.

Question 19) Can you offer parents of children with Scoliosis any general recommendations on diet or lifestyle? Is there anything they should do or avoid?

Dr. Moreau) Right now, it is difficult to make any recommendation without knowing the functional and biochemical status of an asymptomatic child or a scoliotic patient. Having said that, there are a few things that could be considered:

There is no proven diet to avoid scoliosis. It is true that selenium is a known inhibitor of OPN, but this nutrient can be highly toxic at high doses, especially in children. Moreover, we have experimental evidence that shows that selenium will not work in the majority of IS patients due to their genetic make-up and the fact that we already have enough selenium in our diet in North America.

Reducing exposure to mycobacteria could be a good way to reduce the risk and I would start by cleaning all shower heads in the house on a monthly basis or even changing them annually since they represent an important source of mycobacteria (Opportunistic pathogens enriched in showerhead biofilms. Feazel LM, et al., Proc Natl Acad Sci U S A. 2009 Sep 22; 106(38): 16393-9. Epub 2009 Sep 14). A second thing to consider is that personally, I would remove the fish tank (aquarium) from the room of my own daughter because mycobacteria are always present in such environments. Again, I would like to stress the point that you won’t catch scoliosis by taking a shower or having a gold-fish in your home! The general idea here is to reduce the exposure to specific environmental factors to decrease risks. In order to do that, we will need to work together with parents and monitor OPN and sCD44 blood levels regularly to identify all potential environmental factors. Some patients will be more sensitive while other will be more resistant to the same environmental factors, so this is a new area of research. Only time will tell if such measures will have positive impacts, but we need to start somewhere.
Reply With Quote
  #2  
Old 14-06-2010, 08:45 AM
Dingo Dingo is offline
Registered User
 
Join Date: May 2010
Posts: 7
Default Part 2

[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.
Reply With Quote
  #3  
Old 14-06-2010, 08:46 AM
Dingo Dingo is offline
Registered User
 
Join Date: May 2010
Posts: 7
Default Part 3

[SIZE="4"]Part 3[/SIZE]

Question 6) Can you foresee a day when it will become practical for medical professionals to use your test to screen large populations of children for Scoliosis?

Dr. Moreau) We already have the capacity using our robotic platform to screen hundreds of samples/patients per day in Montreal. Secondly, our tests have been specifically designed to screen large populations of children. Our partner in Milan (Italy), Dr. Marco Brayda-Bruno has received a first grant from the Italian government for a pilot project to screen 1200 school children for scoliosis using our tests.

Question 7) How will manufacturers of braces and medical devices use your test to build better products?

Dr. Moreau) Monitoring plasma OPN and sCD44 levels should be considered as a clinical tool to evaluate bracing efficacy and even treatment compliance. Since both molecules, OPN in particular, are known to be modulated by biomechanical forces, which make our biochemical tests the ideal tool for clinicians and physical therapists to evaluate whether or not bracing and/or physical therapy are really efficient. Secondly, it is anticipated that evaluation of plasma OPN and sCD44 levels in combination with our functional assay will identify scoliotic children for whom a specific brace could represent a better therapeutic option vis-ŕ-vis others. In the same vein, a better selection of patients might improve their health outcome not only by choosing the best brace but by intervening at an earlier stage or by the identification of children having a higher risk of spinal deformity progression for which a minimally invasive surgery with fusionless devices could be a possible option. In addition, better selection of patients might reduce the need to prescribe a brace in a child having a low or non-existing risk of progression, thus reducing the psychological impacts of wearing a brace as well as financial costs to patients.

Question 8) In 2008 you stated, “We are now, for the first time, in the exceptional position of being able to foresee the eradication of the disease in the very near future with the development of the first drugs within ten years' time.” That’s very exciting! How do you think Scoliosis treatment will evolve over the next 20 years?

Dr. Moreau) It is anticipated that a new continuum of care will emerge with the arrival of early scoliosis diagnostic/prognostic tests. Prevention will be possible using biochemical assays for periodic monitoring of OPN and sCD44 levels and will increase our awareness of environmental factors exacerbating the risk of developing scoliosis. The discovery of OPN and how it acts to trigger scoliosis onset will surely lead to identifying useful therapeutic agents that can prevent scoliosis or stop its progression over the next 20 years. However, more immediate impacts will probably come from our functional classification of IS patients for the prevention of serious co-morbidities like osteoporosis or depression in some scoliotic patients. One third of IS patients become osteopenic and often develop osteoporosis during their thirties. We believe that our functional test is the only tool that can be used to identify at an early stage those patients at risk of developing osteoporosis and could potentially be used to prevent it or stop its progression using proven nutraceutical and pharmacological therapies available on the market.

Question 9) In 2004 you published a landmark study (source) that found that children with progressive AIS shared a central nervous system disorder called Melatonin Signalling Dysfunction. In healthy children the presence of Melatonin lowers the level of a molecule called cAMP. In children with MSD this system is broken. Is there evidence that indicates where the physical “break” in the nervous system is located? Is it in the brain, spinal cord or somewhere else?

Dr. Moreau) We reported in 2004 that melatonin signalling defect (MSD) is caused by an aberrant chemical modification (called phosphorylation) affecting the activity of small proteins called G inhibitory proteins (Gi) through the transfer of phosphate group on serine residues. The alpha subunits of these small Gi proteins are all impaired in IS. The Gi proteins which are normally coupled to melatonin receptors belong to a large family of membranous receptors encompassing about 150 different members normally coupled to Gi proteins while others are coupled to Gs or Gq proteins. This means that all GPCR receptors coupled to Gi proteins are affected in IS and not only those specific to melatonin. Indeed, all tissues exhibiting Gi-coupled receptors are affected by such impairment but we don’t yet know if IS results from a specific tissue, like the nervous system or is the summation of all affected tissues. To answer that question, revisiting animal models will be necessary to specifically inactivate Gi signalling in a tissue specific manner.

Question 10) Do you know at what age MSD manifests itself? Is it something that children are born with or is it triggered during childhood or even adulthood? Is MSD something the body has the ability to repair?

Dr. Moreau) It is most likely that children are born with the Gi-signalling defect but its clinical manifestation (disease onset) is induced later, around puberty, because estrogens play a key role in exacerbating such a pre-existing condition. In other words, during infancy, the pool of Gi proteins is so abundant that it is impossible to inactivate all Gi proteins by phosphorylation because the proteins are renewed so quickly. However, it has been reported that estrogens induce a significant decrease in the production of Gi proteins, allowing their full inactivation in IS patients during puberty. This phenomenon can easily be demonstrated in vitro and explains the following: (1) the greater incidence of IS during puberty and (2) why girls are more affected in number and severity than boys. The delay observed in the first menstrual cycle of IS girls may play a rather protective role and should be seen as a compensatory mechanism to protect the body against scoliosis. Unfortunately, the body doesn’t have the ability to correct this signalling defect.

Question 11) Identical twins are not 100% concordant for Scoliosis (source) (source) (source). Has any research been conducted that tells us if identical twins are 100% concordant for Melatonin Signalling Dysfunction?

Dr. Moreau) We are in the process of attempting to verify that. More importantly, in families exhibiting several IS cases, we have demonstrated that all affected family members belong to the same functional subgroup indicating that they share the same set of genes predisposing them to scoliosis, independently of their curve pattern or severity. Therefore, it is possible that discordant identical twins will display the same potential (genetic predisposition) but the development of scoliosis in one twin will be triggered by his/her exposure to specific environmental factors. For instance, identical twins do not necessary like the same things: one may prefer sports while the other is more sedentary, and similarly for their diets, with one preferring to eat pasta while the other one fish! Thus, they are experiencing different environments even if they stay under the same roof!

Question 12) Scientists have produced evidence that heredity plays a role in Scoliosis. However it’s not clear as to what degree genetics are involved. In some diseases like Cystic Fibrosis or Sickle Cell Anemia heredity is the direct cause of the disease. In other diseases like Multiple Sclerosis or Type 1 Diabetes genes play a role but an environmental component is also required. Are there clues that suggest whether MSD is triggered solely by heredity or alternately heredity in combination with an environmental component?

Dr. Moreau) We have solid evidence that IS is caused by both genetics and the environment. This is why genetic tests won’t work because they cannot simultaneously consider the environment.

Question 13) According to your patent a protein called Osteopontin is closely associated with curve progression in children with AIS. OPN can be a marker for inflammation (source). Does this suggest that curve progression is induced by a type of chronic inflammation?

Dr. Moreau) Osteopontin (OPN) is a multifunctional cytokine involved in normal and pathophysiological conditions. We have discovered a new facet of this molecule and I don’t think we should associate curve progression with chronic inflammation.
Reply With Quote
  #4  
Old 14-06-2010, 08:56 AM
Dingo Dingo is offline
Registered User
 
Join Date: May 2010
Posts: 7
Default Part 4

[SIZE="4"]Part 4[/SIZE]

Question 14) When mice don’t produce Osteopontin Scoliosis doesn’t occur. The following quote is from your patent, “OPN-knockout mice do not develop a scoliosis (NS) even if they are in the same genomic background (C57BI6/J)”. What does this tell us about OPN and Scoliosis?

Dr. Moreau) This experiment indicates that OPN is required to trigger scoliosis onset. It is worth mentioning that bipedal surgeries (amputation of forelimbs) performed on C57Bl6 mice, which are naturally deficient in melatonin synthesis, induce scoliosis through an acute condition (the surgery) resulting in an elevation of OPN levels (since wound healing is a naturally inflammatory process), which cannot be decreased in absence of melatonin because melatonin is a powerful OPN inhibitor. The same phenomenon occurs after a pinealectomy (removal of the pineal gland, which is the main source of melatonin) in chickens. The fact that treatments of pinelactomized animals with pharmacological doses of melatonin prevent scoliosis has nothing to do with a lack of melatonin but is rather associated with the property of melatonin to repress the production of OPN. Having said that, I do not recommend the use of melatonin because (1) melatonin may trigger many side effects including the promotion of dormant tumours and (2) genetic predisposition toward scoliosis may affect how the cells respond to melatonin and so far the results published by my colleague Dr. Machida are not at all convincing about the usefulness of melatonin.

Question 15) Can Osteopontin stay elevated even after skeletal maturity?

Dr. Moreau) Osteopontin levels decline in healthy females at around 15 years of age and typically remain low during adulthood. Interestingly, in most of IS patients, OPN levels decline during puberty, which may explain why spinal deformities progressing toward surgery occur only in less than 1% of IS patients. It is also worth mentioning that elevation of OPN has been detected in adult pathologies like cancers (mesothelioma, bone metastases associated with breast or prostate cancers), cardiac conditions, Parkinson’s diseases, etc but the presence of other factors like sCD44 protect these patients against the development of scoliosis.

Question 16) High levels of Osteopontin are associated with a variety of autoimmune diseases and cancers (source). Does this suggest that children or adults with Scoliosis may have an increased susceptibility to other disease processes?

Dr. Moreau) It may be premature to make such a claim. However the opposite may be true since scoliosis is a clinical feature (phenotype) often associated with many syndromes and pathological conditions.

Question 17) Most adolescents with Scoliosis have small curves that don’t progress significantly. Osteopontin is known to increase in the presence of bacterial infections (source). Could some of these small curves be the artifacts of childhood disease?

Dr. Moreau) As mentioned previously, many factors can stimulate the production of OPN, including some bacterial infections, especially those with mycobacteria. For most healthy individuals exhibiting no genetic predisposition for scoliosis, OPN is a protective cytokine that helps fight, among others, mycobacterial infections. It that case, elevation of OPN won’t trigger scoliosis because other factors like sCD44 are there to counteract the negative effect of OPN on scoliosis. In children having a genetic predisposition for scoliosis, exposure to mycobacteria and other environmental factors could induce scoliosis onset. Having said that, I want to clarify to parents and patients that scoliosis is not an infectious disease!

Question 18) In 2003 Dr. Vert Mooney, a spine surgeon from California released a study that found that Torso Rotation Strength training was beneficial for children with Scoliosis (source). Since that time two small studies produced similar results (source) (source). Here is a short news video of a young girl doing TRS (news video). Does your research shed any light on why this kind of strength training might be helpful?

Dr. Moreau) I cannot comment about the validity of these studies because it is difficult to actually demonstrate the degree of effectiveness of any method or device to prevent scoliosis or spinal deformity progression, because the natural history of most IS patients indicates that they are non-progressors. In other words, this method like any other should be challenged by performing clinical trials only with individuals presenting a high risk of progression. Such a selection will be possible using our scoliosis blood tests.
Reply With Quote
Reply

Thread Tools Search this Thread
Search this Thread:

Advanced Search

Posting Rules
You may not post new threads
You may not post replies
You may not post attachments
You may not edit your posts

BB code is On
Smilies are On
[IMG] code is Off
HTML code is Off

Forum Jump


All times are GMT +10. The time now is 10:44 AM.

This forum is a project of

  

This forum is supported by

Spine Society of Australia

Powered by vBulletin
Copyright ©2000 - 2017, Jelsoft Enterprises Ltd.