Understanding the genetic basis of pain
10 December 2014
Research at UCL has had a significant impact on both clinical and public understanding of human pain disorders, and on the commercial development of selective analgesics with fewer side-effects. As well as meeting a pressing patient need for more effective treatments, these promise major rewards for the pharmaceutical industry.
At any time, more than three million people are in pain in the UK. The side-effects or lack of efficacy of available drugs means that many of these receive inadequate analgesic treatment.
Research at UCL funded by the Medical Research Council and the Wellcome Trust has enhanced clinical understanding of several human pain disorders by linking these conclusively to specific molecular mechanisms and human mutations. This has improved the accuracy with which these disorders can be diagnosed and, thereby, the efficacy with which they can be treated. As well as improving clinical practice and patient experience, the research has also had important effects on the huge neuropathic pain market, supporting the development of more specific analgesics to help meet the challenge of reducing the side-effects associated with pain treatments.
These useful translational consequences derive from fundamental research into mouse genetics. Interestingly, all recent analgesic drug targets have been identified in academic laboratories, underlining the critical role of government and charity funding of basic research for improvements in human health care. - Professor John Wood
These benefits have their origins in research conducted by a UCL group led by Professor John Wood to explore the genetic basis of pain pathways, and particularly to understand the involvement of two molecules known as Nav1.7 and Nav1.8.
In 2004, the Wood Lab was the first to show that Nav1.7 played a key role in peripheral pain pathways in mice, a discovery that paved the way for their subsequent demonstration of its contribution to human pain, too. In 2006 Professor Geoff Woods at Cambridge University demonstrated that hereditary loss of Nav1.7 function leads to congenital loss of human pain, whilst the Wood lab showed that in animal models or some rare human heritable pain disorders increased Nav1.7 activity leads, conversely, to increased pain.
By allowing clinicians to better understand the link between human pain and Nav1.7 and Nav1.8 mutations, the UCL research has facilitated better diagnosis of the large patient population suffering from pain. It has, for example, been used by the Department of Clinical Neurophysiology at the UK's National Hospital for Neurology and Neurosurgery. Here, clinicians have increasingly used sequencing for mutations in Nav1.7 and Nav1.8 in differential diagnoses of small fibre neuropathies, a new line of diagnostic procedure which may help to define useful therapeutic approaches.
In the Netherlands, genetic testing drawing on the UCL work has revealed Nav1.7 mutations in some 30% of patients with idiopathic painful neuropathy (a condition affecting up to 5% of the general population) and Nav1.8 mutations in a further 10% of those patients.
The UCL work has, moreover, proven of interest to public as well as clinical audiences, and has been featured on popular television programmes including The One Show and BBC Horizon's The Secret World of Pain, which reached an audience of nearly two million people.
Increasing public awareness of the many possible physiological origins of pain is extremely important, especially since patients with chronic pain whose physiological basis is unclear often face the additional trauma of having their pain dismissed as purely 'psychological'. However, The Secret World of Pain also highlighted to public audiences the beneficial role that pain can play in our lives, and the serious physical injuries that can result from its absence. In addition to its role in increasing public understanding of this important point, the documentary has since been used in some clinical practices to help explain the function of pain to patients.
Beyond their interest to clinical and public audiences, the UCL insights have also focussed the attention of the pain pharmaceutical community on the Nav1.7 and Nav1.8 channels as useful and specific analgesic drug targets. Indeed, all major pharmaceutical companies now have programmes based on these targets, with the research findings informing a particularly strong interest in Nav1.7.
Already the UCL work has allowed pharmaceutical companies to develop more than 1,000 patents on new analgesic compounds targeting Nav1.7 and Nav1.8 and other pain targets identified in the Wood lab , many of which are now in clinical trials. The Nav1.7 blockers Ralfinamide and Eladur (under development by Newron and Durect/King/Pfizer respectively), for example, are currently in Phase II clinical trials for neuropathic lower back pain and post-herpetic neuralgia. As well as meeting the pressing patient need for more effective treatments with fewer side effects, the development of these new analgesic compounds promises major rewards for key players within the pharmaceutical industry: If Ralfinamide and Eladur go to market they are expected to reach peak year sales of $120 million and $198 million respectively by 2019.