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Fragile X Syndrome: Translating knowledge into real therapies.
Basel, 11 August 2009
This ‘PHC in Practice’ article exemplifies how translational medicine is at the core of enabling PHC and how it can be applied at a very early phase of drug development. This example from the Central Nervous System Disease Biology Area (CNS DBA) shows how we can use clinical research results to feedback into pre-clinical investigations and re-design our drug development approach. This is exactly what translational medicine is all about - by understanding mechanisms of drug action we are starting to ‘translate’ this knowledge into medicines and real therapies and, ultimately, treatments that fit the patients.
CNS uses a mechanism-driven approach to Research and Development (R&D)
In terms of strategy, the CNS DBA has modified its drug discovery and development strategy from a broad approach, targeting large symptom-defined disease classes towards a more mechanism driven approach. From discovery through early development to point-of-care, systematic, tailored strategies are being implemented for each programme. Translational medicine underpins this process (see on the right for more information) and is expected to deliver improved R&D success rates. A real example of this approach is a specific programme (mGluR5 antagonist) for the treatment of Fragile X Syndrome (FXS).
What is translational medicine?
Translational medicine is the ‘translation’ of basic research findings and knowledge into the development of concepts for therapies and how to test these in humans. This requires a close connection between the research laboratory and the practice of medicine with the patient (i.e., ‘from bench to bedside’).
Re-thinking the indication
In the late 1990s, anxiety researchers began focusing on a specific class of receptor molecules (mGluR5 protein) as a possible target for new drugs. This was a logical strategy since, in the brain, these receptors are primarily located in areas involved in emotions and motivation and are over-active in anxiety. Therefore, antagonists of mGluR5 were investigated as potential treatments for anxiety disorders. (see box below for more information on receptors and inhibitors.)
The development approach in anxiety was halted due to neuropsychiatric side effects observed in healthy volunteers during Phase I clinical trials. This would normally mean the end of a drug. However, this setback did not stop our Roche teams. Several colleagues in Roche, including Will Spooren, Rich Porter and Georg Jaeschke, wanted to understand the mechanism of the observed side effects of mGluR5 antagonists.
Why choose Fragile X Syndrome?
Fragile X Syndrome (FXS) is the most common form of inherited mental retardation, affecting approximately 1 in 2,500 men and 1 in 6,000 women (see on the right for more information on the cause of FXS). Mental retardation is characterised by intellectual impairment (low IQ) and limitations in communication, self-care, and social and interpersonal skills.
FXS is also associated with severe psychiatric symptoms such as attention-deficit/hyperactivity disorder (ADHD), anxiety, aggression, mood liability?, seizures, autism and self-injury. There is currently no treatment available for FXS patients, but animal models have shown that symptoms can be reduced by targeting mGluR5.
The molecular basis of FXS
Fragile X Syndrome is caused by the absence of a protein - the Fragile X Mental Retardation Protein (FMRP). FMRP regulates the production of other proteins in the brain. Without FMRP, another protein, mGluR5 - which acts as an accelerator of protein synthesis - is uncontrolled. This leads to over-activity in the brain (i.e., Fragile X Syndrome).
Therefore, ‘turning down’ mGluR5 activity in FXS patients is a logical therapeutic strategy - we are currently investigating to see whether this principle works in practice.
Moving forwards: Clinical development and diagnostics
In the late 1970s, the drug fenobam was unsuccessfully developed by McNeil Laboratories for treating anxiety but was never further investigated in this indication.
More recently, Roche researchers discovered that fenobam interacts with mGluR5, ‘turning down’ the effects of this protein. Led by Will Spooren and Georg Jaeschke, Roche researchers have now synthesised compounds with a similar mode of action as fenobam but with increased stability and therefore likely to have a longer duration of action. This may result in less frequent dosing for patients. There could now be tangible treatment options for people with FXS. See below box for information on how translational medicine and PHC have been integral in identifying the right patients for treatment with mGluR5 antagonists.
Furthermore, there is an opportunity to develop a diagnostic test to detect the gene mutation which prevents the synthesis of the FMRP protein and leads to the development of FXS. Differentiating between a full mutation and a partial mutation (or ‘premutation’) may be important for dosing of mGluR5 antagonists. In addition, screening for FXS in newborns could allow early treatment that might prevent the development of some symptoms, such as severe mental handicap. The need for these key technology platforms underscores Roche Diagnostics’ pivotal role in helping to making PHC a reality for patients.
With the two pillars of Pharma and Diagnostics working together across the entire value chain, Roche is uniquely positioned to deliver Personalised Healthcare.
Other opportunities with mGluR5 inhibitors
Another indication for mGluR5 antagonists is being explored on the basis of their mechanism of action - a further example of how knowledge at the molecular level translates into identification of appropriate patient populations and underpins PHC. Patients suffering from depression and experiencing at least two unsuccessful treatment courses with conventional medications are very unlikely to respond to other conventional antidepressant drugs. A short, inpatient study is planned as an initial investigation of whether treatment with mGluR5 antagonists might benefit people with treatment-resistant depression.
PHC: Developing and fitting the right treatments for the right patients
The revitalisation of mGluR5 antagonists as potentially important therapies in new indications highlights how discovery research can provide new insights into the biology and molecular pathways of different diseases, and how translational medicine can help investigation of these pathways in order to provide better outcomes for patients. With the development of diagnostic tests to drive treatment decisions, we aim to deliver clinical utility to patients and physicians - this is exactly what PHC is all about.
Roche continues to lead in developing innovative approaches to combating disease, and Personalised Healthcare is a key enabler allowing us to deliver clinically differentiated medicines and new standards of care for diverse patient populations. |
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