MICA: Evaluation of AZD1080 (GSK-3 inhibitor) in a preclinical mouse model of motor neuron disease (MND)

Motor neurone disease (MND, also known as amyotrophic lateral sclerosis) is a progressive, debilitating neurodegenerative disease where the motor neurones which control muscle movement gradually degenerate and die. This causes the muscles to waste away and leads to death because patients chest muscles cannot generate enough force in breathing to remove carbon dioxide from the blood. Unfortunately the disease progression is usually very rapid and life expectancy is about 3-5 years. There is a drug available which extends the lifespan of patients by 2-3 months but new therapies are urgently needed.

An enzyme called glycogen synthase kinase-3 (GSK-3) is expressed at a higher level and is more active in MND patients brain cells. We have also shown that a pathway which stops GSK-3 from working is active in motor neurones that survive in MND patients. Studies in animal models of the disease suggest that if you block GSK-3 from working with drugs, you can slow down the disease process. However the drugs used so far are not ideal and the data isn't clear enough yet to give enough confidence to test these drugs in patients. AstraZeneca (AZ), a pharmaceutical company, want to work with us to test one of their GSK-3 blocking compounds, a drug called AZD1080, in our animal models of MND. Their drug is specific for GSK-3 and doesn't have the side-effects associated with some other GSK-3 blockers such as lithium. Importantly, it has also been tested in healthy human volunteers and shown to be safe. Our methods for studying the effects of drugs in our mouse model of MND are very robust and will give better quality information than is already available. We have designed a series of experiments which will give us definitive information on the concentrations of AZD1080 we need in blood to see effects in our model. This will help in future clinical trials as it gives us a target to aim for when we treat patients.

Another strand to this work is to look at AZD1080 in combination with some drugs which we have already shown to work in our mouse model of MND. These drugs activate a pathway that increases defences against free radicals (oxidative stress). They do this by activating a protein called Nrf2. Oxidative stress is also active in MND and contributes to motor neuron injury. Using AZD1080 with our Nrf2 activators may lead to better protection against oxidative stress, and an improved effect in our mouse model. We will also understand more of the biology of how GSK-3 regulates Nrf2 in animals.

Ultimately if we can find a drug or drug combination that works well in our animal model we aim to start a new project take this forward to testing inpatients.

Motor neurone disease (MND) is a devastating neurodegenerative disorder with rapid progression to death from neuromuscular respiratory failure in the majority of afflicted individuals. There is an urgent need for improved approaches to achieve neuroprotection in ALS. Aberrant over-expression and activation of glycogen synthase kinase 3 (GSK-3) is implicated in neurodegeneration in MND and several studies in animal models suggest inhibition of this pathway may be beneficial, however the compounds used are unselective and associated with side effects (lithium) or the studies were sub-optimal and so do not give a true reflection of the therapeutic potential of GSK-3 inhibitors in MND.
The AstraZeneca compound, AZD1080 is a CNS-penetrating, potent and selective reversible inhibitor of GSK-3 which has been tested in 224 healthy volunteers in Phase I studies and shows PK profile commensurate with exposures observed in preclinical models of inhibition of Tau phosphorylation in the hippocampus. We have developed a preclinical mouse model and screening approach for candidate MND therapeutics which can provide rigorous, high quality data on a variety of readouts of motor neuron degeneration. We will use AZD1080 and our preclinical model to provide definitive information on the therapeutic potential of GSK-3 inhibition in MND with a view to further clinical development of AZD1080 in the human disease.
In addition, recent in vitro data has shown that GSK-3 can promote degradation of Nrf2, a key regulator of cellular oxidative stress responses. We have identified compounds which activate this transcription factor, providing protection for motor neurones from oxidative stress. We will probe, in vivo, the importance of GSK-3 in regulating this pathway in our MND model using one of our Nrf2 activating molecules with AZD1080 to determine whether a combination of these compounds leads to a greater improvement in motor function than we have already achieved.

The ultimate intended beneficiaries of this research are patients suffering from MND. A key feature of MND is the speed of progression in most affected patients. This poses huge problems of adjustment for affected individuals; an escalating burden on carers and families; and a challenge to those purchasers and providers of healthcare who are involved in meeting the variable, rapidly changing and complex care needs. MND has until now been a neglected condition both in terms of research and clinical care funding, and is designated an orphan disease. To date only one drug, riluzole, has been approved for clinical use in MND. It has a very modest effect in slowing disease progression, prolonging average survival by only approximately 3 months. New therapies are urgently needed and these will not only improve the quality of life of patients, carers and family but also reduce this significant burden for healthcare providers.
The high cost of drug development when set against the relatively low predicted return from subsequent sales to a small group of patients, dissuades large pharmaceutical companies from drug development programmes in MND. However Pharma have highly valuable drug assets, developed originally for other indications, which may be applicable in such orphan diseases. Academic institutions with disease specific expertise and access to patient resources, can play an important role in harnessing these assets for further development. This project will harness one such asset from AstraZeneca (AZ) for development in MND This benefits not only MND patients but AZ also, as it provides an opportunity to derive value from compounds which would otherwise not be taken forward but which have benefited from significant investment, increasing the competitiveness of UK industrial research.