Professor Linda Greensmith founded the Graeme Watts Laboratory at UCL Queen Square Institute of Neurology in London in 1999, supported by funds left to Brain Research UK by the family of Graeme Watts, who died of motor neurone disease (MND). Graeme’s family left a bequest in his name to fund research to improve the basic understanding of MND and to develop therapeutic strategies.
No-one at the Institute was strongly focused on MND at that time and Linda was recruited to set up a lab to take forward research into this devastating disease.
Twenty years on, she has had remarkable success. The Graeme Watts Laboratory is at the forefront of research into MND, and drug compounds that started life there are now undergoing clinical trial. We continue to fund work there using funds from the endowment established in Graeme’s name.
MND describes a group of diseases affecting the nerves (motor neurones) in the brain and spinal cord that control the muscles. These are fatal, rapidly progressing conditions that rob patients of their ability to walk, talk and eventually to swallow and breathe.
There is no cure for these diseases. They kill a third of patients within a year and more than half within two years of diagnosis.
In 1999, with funding from the Graeme Watts Endowment, Linda Greensmith took on the challenge of setting up a new laboratory for research into MND.
Since then, the Lab has grown enormously, with a team of around 20 people now working on MND and related diseases.
The Lab has played a huge role in developing research capacity in MND, with 15 post-doctoral fellows and 36 PhD students having trained there. Team members benefit from the close physical proximity to the National Hospital for Neurology and Neurosurgery, and enjoy good collaborative links with the clinicians there, unusual for a basic science lab but enormously important in ensuring that the work has translational relevance.
In some of the early research to take place in the lab, Linda demonstrated that one of the key features of MND is a clumping of proteins in motor neurones. This clumping also happens in other neurodegenerative diseases, but in different cells.
The team has subsequently been targeting this process as a possible therapeutic strategy to establish, firstly, whether they can find a way to prevent the clumping and, secondly, whether this halts disease progression.
They developed a drug that they showed could work on cells in a dish (in vitro) and also in animals (in vivo). The drug (Arimoclomol) has now undergone early phase trials in the US; results reported in 2016 showed that the drug is safe and well-tolerated in patients and appeared to show a slowing of functional decline. Accordingly, the drug is now progressing to a larger trial to establish its effectiveness in a larger group of people with MND.
As a basic scientist, Linda is interested in the processes underlying disease, and the boundaries between different diseases are quite fluid. The protein misfolding that takes place in motor neurones in patients with MND is also important for patients with other neurodegenerative diseases such as dementia and Parkinson’s disease. It just happens in different cells. So whilst the Graeme Watts Lab is set up to look at MND, the team’s work has relevance to many other diseases of the neuromuscular system, underscoring the huge importance of the cross-disciplinary working that is part of the Lab’s ethos.
Because of the group’s interest in the protein misfolding process, they have looked at a muscle disease called inclusion body myositis (IBM) in which clumps of proteins clog up muscle cells. They tested the same drug in this disease and, again, it showed promise at every stage of lab testing. Early stage trials with IBM patients in the UK have now taken place, again with positive results, and the drug is now moving forward to phase 3 trial.
Out of the tragic death of Graeme Watts, and the incredible generosity and foresight of his family, has grown two decades of game-changing research into motor neurone disease. The Graeme Watts endowment enabled the creation of the Graeme Watts Fellowship at UCL Institute of Neurology, with Linda Greensmith recruited into this post in 1999.
As set out above, this funding has had a tremendous impact on research capacity in MND - creating a new hub at UCL, with a major focus on training. Our funding has seeded many millions of pounds worth of grants from other sources.
In the last five years alone, the Lab has published 45 papers including two of particular note.
A paper published in 2014 reported the findings of a novel approach they had developed to restore function of paralysed respiratory muscles in MND patients. This approach used optogenetics, a technique that involves genetic modification of motor neurones so that they can be stimulated by light and then controlled via an optical pacemaker.
In 2016, the team reported on the early phase trials of Arimoclomol in patients with inclusion body myositis (IBM). This led to a phase 2b trial to test the efficacy of the drug in patients with IBM, and is now moving forward to a larger phase 3 trial.
These studies illustrate the highly translational research that is undertaken in the Graeme Watts Labs, where they take findings at the bench in cellular and animal models, right through to experimental medicine trials, working with their close clinical colleagues in the National Hospital for Neurology and Neurosurgery and their industrial partners Orphazyme APS.
There’s not many groups that get things through from working in cells to working in mice and then getting them into the clinic. That translation, hitting each part of the translational pipeline, is really nice and is very rare.
- Professor Linda Greensmith
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