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Research Update: July/August 2017

By Dr Graeme Bertuch OAM

Ask the Experts

This years’ research update for MND took place at the Florey Institute on 9th May 2017. The presenters were Dr Brad Turner who heads the MND laboratory at the Florey Institute of Neuroscience and Mental Health at the University of Melbourne, Dr Peter Crouch, researcher, and Ms Silvia Done, Clinical Manager of Neuroscience Trials Australia [NTA] which is a business within the Florey.

[Right] PHOTO OF SPEAKERS: Dr Brad Turner, Rod Harris, Sylvia Done and Dr Peter Crouch

Dr BRAD TURNER spoke on causes of MND, clinical trials for MND, on endaravone, an antioxidant which originated in Japan but has been accepted for use in USA and on MND research at the Florey Institute.

MND can be genetically linked which occurs in 10% of cases therefore affecting family members over Conf Speakersgenerations, or sporadic, affecting the remaining 90% of sufferers. Sporadic MND arises spontaneously and has multiple genes involved, possibly triggered off by environmental, physical or other epigenetic causes such as retroviruses which lurk in our genome. In fact 8% of our genetic makeup is due to retroviruses [AIDS is a retrovirus but not part of our ancient genome] and were probably introduced about 25 million years ago to our primitive ancestors’ genetic makeup.

Dr Brad Turner spoke about retroviruses and about a trial of an antiretroviral medication, Triumeq, to see if treatment modifies the disease.

Also mentioned were physical trauma introduced by sport. There has shown an increased risk of MND among professional football players in Italy over a 10 year period. It is not known whether this was due to extreme physical activity, repeated head trauma, performance enhancing drug abuse or exposure to environmental toxins such as fertilisers and pesticides from the playing fields. Blue-green algae was also discussed as a possible cause of MND. This stems from the fact that on the Pacific island Guam, there was a hundred fold increase in a type of MND related to the eating of fruit bats which concentrated blue-green algae after eating cycads. A protein [BMAA] then became involved in the genetic train and caused the disease.

What relevance is this to MND in general? Researchers look for clusters of disease and regions where blue-green algae is likely to be found for instance around lakes and watercourses, possible regions for concentration of cases.

Recent progress in MND genetics has been exponential. This is especially seen in the genetic causes of inherited MND. Prior to 2007 80% of genetics were unknown, with only the SOD1 gene discovered. Move on to 2017 and only 30% of the genetic causes for inherited MND are unknown.

Below we will reproduce a timeline of Genetic Discoveries, courtesy of Dr Brad Turner. This shows the recent increase of gene discovery largely because of New Generation DNA Technology. Two newly discovered genes were introduced at the meeting. They were ANXA11 and UBQLN4. Although only found in less than 2% of MND cases, their discovery adds more to the mosaic of causes of MND.

Graph – Timeline of Genetic Discoveries in MND:

Genetic timeline

The genes involved can be divided into 3 groups which affect 3 different anatomical regions on the motor neuron. Those involved with the nucleus of the motor neuron alter the genetic quality control. 

Others cause problems in the scaffolding of the motor neuron which is found along the length of the nerve. The motor nerve is the longest in the body at up to one metre in length, and problems in the traffic, or passage of information along this part of the nerve can lead to nerve death. The last group is involved with the part of the nerve which communicates with the muscle and cause waste disposal build up thereby interfering with the passage of electrical signals to the muscle, causing hyper-excitation and eventually death of the nerve.

Dr Turner then spoke about clinical trials in MND, more particularly about two that are undergoing stage 1 assessment in Australia and an antioxidant that has just been accepted for use in the USA. Triumeq, a medication active against retroviruses is under investigation in Sydney and Melbourne. The theory is that ancient retroviruses could be involved in the genesis of MND and the trial aims to see if this medication can supress and alter the disease.

The next trial taking place is based on copper and has started stage 2 testing, once again in Sydney and Melbourne. We will discuss this in the next section which is based around the presentation by Dr Peter Crouch.

The main news of the day was the registration by the FDA of the first new drug for ALS treatment in 22 years. This drug is endaravone, an antioxidant that has been used in Japan for stroke recovery but found to have an ameliorating effect in some cases of ALS/MND. Previous articles have been ambiguous about the efficacy of endaravone, but then when applied to a narrow subgroup of cases of ALS/MND it was found to have some benefit by slowing physical decline. It works on the mitochondria, the powerhouses of the cell found in the nucleus of the motor neuron.

This drug has a few major drawbacks. Currently it has to be administered intravenously on a 2 week on, 2 week off routine for up to 6 months and possibly indefinitely. This is best administered in a hospital setting usually as an outpatient. The next main drawback is the cost. At $1000 per course and $150,000 per year it is an expensive exercise. It has not yet been shown to be efficacious outside of Japan. Currently this drug is not registered for use in Australia.

[Author’s Opinion: Sufferers of MND and their families might be anxious to be able to access this medication, but given the narrow spectrum of MND patients who could use this, the inconvenient administration and given the cost, can it be justified? I think that quality of life should be a major determinant of MND management and I don’t necessarily equate increased life span with quality of life.]

Finally, Dr Turner mentioned future directions for MND research at the Florey Institute. A world first drug screening platform has the objective of “rapid discovery and screening of therapeutics using MND patient-derived cells to identify priority agents in Australia to advance potential clinical trials and off-label treatment”. This screening platform will rapidly screen 1000’s of existing drugs and compounds increasing the efficiency of drug screening for MND by 150 times. Recent funding from the Victorian Government, Cure for MND Foundation and Balcon Group Pty.Ltd. has made the objective into an exciting future for MND research at the Florey.

Dr PETER CROUCH took over the podium to talk on his topic of “The copper drug Cu-ATSM as a treatment option for MND”. This topic has been covered extensively in past issues of the Newsletter [March-April 2016] and in interviews with Dr Crouch [Nov-Dec 2016].

CU-ATSM has been found to be an effective drug in the treatment of mutant SOD1 mice, significantly increasing their lifespan. How does this translate to MND in humans? This compound has been used in PET investigations for some time as a contrast agent. It becomes concentrated in areas of the brain that are under oxidative stress. In some ALS/MND cases one of the defects is a genetic mistake in the SOD1 gene that causes mis-folding of the SOD1 protein. There seems to be an associated copper deficiency in these tissues and Cu-ATSM has been found to deliver copper to cells producing this misfolded protein. This, along with introducing a human copper carrier into the SOD1 mice significantly increases their lifespan. Dr Crouch and colleagues at the Florey Institute found MND-affected tissues obtained from people who died because of sporadic MND had important similarities to mice that responded to Cu-ATSM. This suggests that CU-ATSM may have activity in both sporadic and familial MND and it is now undergoing a stage 1 trial to see if this is so.

SYLVIA DONE through NTA has been involved in the design, execution and management of clinical trials in therapeutic areas for 16 years. She spoke about the processes involved in progressing a potential drug from thought through to a therapeutic option.

The salient points were that from over 10,000 compounds synthesized in the laboratory, ONE compound reaches the market as a new drug. The second point is that it takes an average of 12-15 years to develop a drug at a cost of around $800 million [discovery to approval].

The stages of clinical development are:

1. Pre-clinical testing [2-3 years] consisting of laboratory and animal studies.

2. Phase 1 trials [1-2 years] giving medication to healthy volunteers to assess safety and dosage.

3. Phase 2 trials [2-4 years] giving medication to patient volunteers to assess effectiveness and to look for side effects.

4. Phase 3 [4-6 years] giving medication to a larger number of patients to verify effectiveness and to look at adverse effects from long term use.

Once these phases have been worked through, then the drug company can apply for FDA approval [in America and Australia often follows via TGA], which could take another 1-2 years.

Because Australia has a high biotech performance rating, it is a favoured country for neuroscience trials. It is not a straightforward or cheap process to develop a drug from the initial stages to an end marketable medication.

There are hundreds of researchers working every day hoping to find drugs that can treat MND.

Genetics2

Dr Brad Turner and his crew at the Florey Institute in Melbourne are developing a rapid screening process to look at 1000’s of potential drugs.Dr Brad Turner and his crew at the Florey Institute in Melbourne are developing a rapid screening process to look at 1000’s of potential drugs.

The future is exciting and we are taking massive steps using new technology to find treatments for MND and one day perhaps a ….. CURE!