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Targeting the heat shock response in ALS

Project details

Researcher
Professor Linda Greensmith
Institute
UCL Queen Square Institute of Neurology
Research area
Motor neurone disease
Funding type
Programme grant
Awarded in
September 2019
Completion
Ongoing

Overview

Professor Linda Greensmith heads the Graeme Watts Laboratory at UCL Queen Square Institute of Neurology in London.

She founded the Lab 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 wanted these funds to support 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 Greensmith was recruited to set up a lab to take forward research into this devastating disease.

The Graeme Watts Laboratory is now at the forefront of research into MND, and drug compounds that started life there are now undergoing international clinical trial in patients with MND. We continue to fund work there using funds from the endowment established in Graeme’s name. In 2019 we awarded this grant to support a five-year programme of work focused on a cytoprotective cellular mechanism called the heat shock response.  

About amyotrophic lateral sclerosis

Motor neurone disease (MND) describes a group of diseases affecting a particular group of neurons in the brain and spinal cord that send nerves out to skeletal muscles to control their function.

Amyotrophic lateral sclerosis (ALS) is the most common form of MND. It is a fatal, rapidly progressing neurodegenerative disease in which motor neurons progressively die, resulting in muscle paralysis. It robs patients of their ability to walk, talk and eventually to swallow and breathe. There is no cure and patients with ALS typically survive for only two to five years from diagnosis.

Read more: About motor neurone disease

Targeting the heat shock response in ALS

One of the key features of MND is clumping of proteins within motor neurones. This clumping, known as protein aggregation, is a characteristic feature of most other neurodegenerative diseases, but affects different types of neurons in different diseases.

In some of the early research undertaken in the Graeme Watts Labs, Professor Greensmith's team demonstrated that strategies that target protein aggregation in ALS may be a possible therapeutic strategy.

They developed a drug that they showed could work in both cellular models of ALS, where neurons are grown in a dish (in vitro), and also in mouse models of ALS (in vivo). Their results showed that treatment with a new compound called Arimoclomol prevented protein aggregation in neurons and, as a result, improved the disease in ALS mice. Arimoclomol has now undergone early phase trials in the US; results reported in 2018 showed that the drug is safe and well-tolerated in patients and appeared to show a slowing of functional decline in ALS patients. Accordingly, the drug is now being tested in an international trial to establish its effectiveness in a larger group of people with ALS.

Arimoclomol has been shown to act by boosting a mechanism present in all cells called the heat shock response, which protects cells under stress. However, Arimoclomol was not originally designed or optimised to target this particular mechanism, nor to act on motor neurons within the central nervous system. The Greensmith team now wants to identify compounds that target the heat shock response more optimally, both alone and in combination with other promising ALS therapies. They subsequently aim to undertake a pre-clinical trial of the most promising compounds in mice that model ALS.

Impact

Motor neurone disease is a devastating, incurable condition that gradually robs people of their most basic functions. Professor Greensmith and team have already made great strides in the quest to find effective treatments for MND, with the drug Arimoclomol, which started life in their lab, now undergoing a large clinical trial.

In this new programme of work the Greensmith team is putting MND under multi-pronged attack by focusing on ways to protect motor neurones by boosting the cell-protective heat shock response.

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