Amyotrophic Lateral Sclerosis (ALS)/ Motor Neuron Disease

Motor neurons are specialized nerve cells in the brain and spinal cord that normally control motor functions, such as walking, swallowing and breathing. However, in patients with motor neuron diseases (MND) such as amyotrophic lateral sclerosis (ALS), degeneration of motor neurons results in denervation of their target muscles, resulting in progressive loss of motor functions due to muscle paralysis and, ultimately, death. Despite intensive research world-wide, there remains no effective treatment or cure for this devastating disease, which currently, affects approximately 5000 patients in the UK. The development of an effective therapy therefore remains an imperative.

Although much progress had been made over recent years in our understanding of the molecular and genetic events that trigger the specific degeneration of motor neurons in ALS, it is clear that many of these processes are extremely complex and our understanding of them incomplete. In our lab, a major focus our ALS research is therefore to investigate potential underlying mechanisms (eg. aberrant protein chaperone function, axonal transport defects and mitochondrial deficits), as well as to develop and test novel therapeutic approaches that may have the potential to slow down or prevent motor neuron loss and thereby improve disease outcome. Additionally, we are also interested in finding novel diagnostic markers of ALS, known as biomarkers, which have the potential to speed up clinical diagnosis of ALS patients and can be used as a measure of the effectiveness of experimental therapies.

To accomplish these goals, we employ a multidisciplinary approach that includes the use of cellular and animal models of ALS, as well as examination of biological samples from ALS patients. In combination with a broad spectrum of analytical techniques (eg. confocal microscopy, live cell imaging, behavioural testing, in vivo muscle physiology recording, and ELISA), this approach has enabled us to make significant discoveries that have revealed mechanisms that contribute to motor neuron degeneration. This approach has also identified several strategies that could be effective for the treatment and management of ALS. Some of the recent and on-going projects undertaken in the lab are described below:

a) Therapeutic approaches:

Optical-control of muscle function by transplantation of stem cell-derived motor neurons in mice:

Led by Dr Barney Bryson

Barney Bryson

This project involves a novel approach to restore muscle function following motor neuron loss, using a combination of stem cell based replacement of motor neurons and the revolutionary technique of optogenetics {}. Briefly, we have shown that embryonic stem cell-derived motor neurons (ESC-MNs) can be transplanted into injured peripheral nerves that have lost their endogenous motor neuron axons and that these ESC-MNs can then reinnervate the target muscles (See Bryson et al, 2012, Science). Moreover, we genetically manipulated these ESC-MNs to express the light-sensitive ion channel, channelrhodopsin-2 (ChR2), so that when we optically stimulate these ESC-MNs with blue light, they can induce finely-controlled contraction of reinnervated muscles. This approach has the potential to overcome the normally permanent atrophy and paralysis of skeletal muscles that can occur as a result of diseases such as ALS as well as by traumatic neurological injury (eg. spinal cord injury). Our long-term aim is to use this approach to maintain function of the diaphragm muscle in models of ALS, since loss of function of this respiratory muscle is the main cause of death in ALS patients. To accomplish this, we are currently investigating whether it is possible to restore muscle function in the long term in mouse models of ALS, using an implantable optical stimulator device.

J. Barney Bryson, Carolina Barcellos Machado, Martin Crossley, Danielle Stevenson, Virginie Bros-Facer, Juan Burrone, Linda Greensmith, Ivo Lieberam. Optical Control of Muscle Function by Transplantation of Stem Cell–Derived Motor Neurons in Mice. Science 344, 94-97 (2014).

b) Biomarkers:

Plasma neurofilament heavy chain levels correlate to markers of late stage disease progression and treatment response in SOD1(G93A) mice that model ALS:

Led by Dr Ching-Hua Lu, as part of a collaboration with Dr Andrea Malaspina, QMUL

Ching-Ha Lu

In this project we have been examining whether plasma levels of neurofilament heavy chain (NfH) may be a useful biomarker of disease progression in ALS. NfH is a major structural protein that is normally contained with neurons. We have recently shown that NfH accumulates within the blood plasma following breakdown of motor neurons in a commonly used mouse model of ALS. Importantly, this study demonstrated that levels of NfH in plasma from these mice correlated with functional and histopathological markers of disease progression. Moreover, when these mice were treated with a drug that we have previously shown can slow down motor neuron degeneration (see Preclincical trials section below), NfH accumulation in the plasma was reduced. These results demonstrate that NfH levels in plasma could be used effectively as a biomarker to track the efficacy of experimental compounds in preventing motor neuron degeneration, at least in mouse models of ALS (see Lu et al, 2012). We are now investigating whether plasma NfH levels can be used as a biomarker of disease progression in large cohort of heterogeneous ALS patients, as part of a collaboration with Dr Andrea Malaspina (QMUL) and Dr Axel Petzold (UCL).

c) Pre-clinical trials in animal models:

Led by Dr Bernadett Kalmar

Bernadett Kalmar

We have a long-standing expertise in undertaking preclinical trials of potential therapeutic agents in mouse modes of ALS, both in investigator led trials as well as industry led trials for a number of pharmaceutical companies, including GSK. For example, we have shown that pharmacological up-regulation of an endogenous cellular defence mechanism, the heat shock response, can protect motor neurons from cell death and extend life span in the SOD1 mouse model of ALS. Following treatment of ALS mice with arimoclomol we observed a significant delay in disease progression, improvement in motor performance resulting in an increase in lifespan (Kieran et al, 2004; Nature Medicine 10, 402-405; Kalmar et al, 2008; J Neurochem. 107:339-50). This drug is now in Phase II clinical trials in ALS patients in the USA. In addition, we have shown that arimoclomol is also neuroprotective in a mouse model of Spinal Bulbar Muscular Atrophy, a genetic disease caused by a CAG repeat in the androgen receptor which leads to the selective motor neuron death (Malik et al, 2013; Brain 136:926-43). More recently, as part of a recent collaboration with GSK, we have been testing the potential of a novel anti-Nogo-A antibody to modify disease progression in the SOD1 mouse model of ALS (Hum Mol Genetics, In press).

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