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Australasian MND Symposium – live blog (Day 2)

Genetics, Research

22 March 2018

Australasian MND Symposium 2018 - day 2

Live updates from the Australasian MND Symposium, March 23, 2018.

Written by a non-scientist for a layperson audience. This means we're skipping the complicated science and going straight for the highlights.

Typing fast and editing slow, so excuse spelling mistakes. DRUG DEVELOPMENT AND CLINICAL TRIAL DESIGN SESSION


Dr Lucie Bruijn – Opportunities and Advances in Drug Development for ALS

Rate of progress in recent years is very exciting.

Explore therapeutics approaches as any one could make a big impact on ALS – small molecules, antisense therapy, and biologics (stem cells, antibodies, gene theray)

Failure in clinical trials not unique to ALS but shared with neurodegenerateive diseases.

Are we looking at correct target? Are we administering in the correct time frame?

Other bootlenecks: disease modelling, biomarkers, clinical trial design

Biggest challenge is that ALS is not one disease. Like the cencers it is a heterogeneous population. Do we think it can br solved by one treatment? I think we all agree that this is not the case.

ALS Association now has many idustry partnersships (GSK, Ionis)

The ALS Association has been supporting antisense therapy since 2004. From investment of $1.5 million, this mobilised an additional $100 milion in reserach funds from industry. Led to FDA approval for SMA in 2016. In second clinical trial for SOD1, first clinical trials for Huntingtons and Alzheimers. C9orf72 trial starting any day.

ALS Assoc funding leads to much more significant (x200) industry funding.

ALS Assoc was forutnate to receive a significant boost to fnding ina small time frame (Ice Bucket!).

Best to seed fund small areas

Most promising targets are:

  • SOD1 mutations – 2%) of ALS
  • C9orf72 – 10% of ALS
  • TDP43 – almost all cases of ALS

Time frames for targetting disease is really important.

Genetics discoveries point to the pathways for disease.

ALS Assoc has been comitted to investing in large data – clinical and environmental information. Really need to understand more about the whole of a person living with MND and not aspects in isolation.

Why fund similar initiatives? Many came from different angles and bring unique opportunities.

Mouse models help us understand complexity of the disease.Dog model is also being widely used to test genetherapy and antisense – to help solves the problem in dogs too. Won't be successful if won't be relevant to human MND.

Biomarker discovery – improves diagnosis, helps stratify clinical trials.

Clinical trials networks – being well organised with enrollment in many places makes it a more tractable area for pharam industry.



Prof Jeremy Shefner – Clinical Trials Design for ALS trials

Clinical trials should be a world wide effort.

Progress in ALS therapeutic development has been slow. Multiple failed trials between riluzole and edaravone.

Main barriers:

  • incomplete understanidn of ALS triggers and cascade (insufficient animal models)
  • experimental drsigns that are inefficient and insensitive

Design issues we can change. We can better define target populations to get a more homogeneous group. We can find better biomarkers. Predicting disead progressions better can help. Predicting better endpoints related to disease progression.

Prof Shefner describes some failed clinical studies (telempanel, cefriaxone, dexpramipexole) and why they failed. “This is the depressing part of the presentation.”

Why aren't our phase 2 studies predicting these poor phase 3 results? Prof Shefner thinks they are predicting this.

Many small modestly aimed studies don't have a significant follow-up planned.


Edaravone – altered inclusion criteria to patients early in disease course, this led to showing a modest but statistically significant effect.

Predicting disease progression can also help improve clinical trials.

To improve: develop better endpoints for functional analysis in phase 2. Some other potentially useful endpoints are:

  • electrical impedance myography (painless, non-invasive test of tissue resistance in muscle);
  • hand held dynameter (measure force in muscles)

These offer the chance of being able to significantly reduce sample sizes.

Patients measuring themselves every day give accurate results because of volume of measurements.


Edaravone – to the extent that you look at the trends, all patients showed a trended benefit. The second study chose a homogeneous population (early in disease, fast progressing) but there's no indication this can't be translated to wider patient population.

Combination therapy – The effect of edaravone is only known in conjunction with riluzole. If edaravone was a pill, all new studies will be in combination of riluzole + edaravone. We have to add an investigatory agent on top of a known therapy.

Staging system – shows how long patients spend in a particular stage and predicts how long until they enter the next stage. This can also show when a treatment may be useful (eg riluzole). As an outcome measure in clinical trials – need to move toward a more precise outcome measure. Just four outcomes (the stages) risks losing outcome sensitivity. Timing to a particular stage could be an outcome measure.

Cognitive measures – we increasingly recognise that cognitive change in an important and intrinsic apart of the disease in a sub-set of patients. ‘ECAS' (Edinborough scale) includes behavioural and cognitive component. Longituninal studies show cognitive change increases as disease progresses (up to 50% show some small affects by end of disease).




Prof Kevin Talbot – Modelling early phase pathogensis in MND

Some fundamental principals about ALS are not agreed among experts.

ALS is heterogenous – there are multiple triggers.

It may have a focal onset but were is the biological point of convergence?

We are in a phase of defining the disease. Trying to break down the disease, moving into the era of precision/personalised medicine.

MND is a loss of tolerance for cell mutations.

Barriers to effective treatment include late diagnosis, high level of biological complexity, poorly predictive pre-clinical models.

When does ALS begin? Susceptibility based on genetic profile lasts decades. Unknown period of time where system in a state of dysfunction but patient is compensating. Begin to see patients when compensation is breaking down and symptoms beginning, this is when clinical trial process begins.

We know TDP-43 over-expression is highly toxic. It is a stress response reaction during times of cellular stress.

Other key molecular discovery is ALS/FTD connection. Mutations in c9orf72 explains 40% of ALS/FTD.

What is the function of c9orf72? May regulate extracellular and intacellular vesicle trafficking.



Prof Peter Todd – How repeats get translated in c9orf72 ALS

Three proposed mechanisms for c9orf72

It's unexpected that this type of protein translation should occur at all.

This type of RAN translation happens in other repeat expansion diseases.

If you develop a drug that blocks this, you have a drug that can block multiple neurodegenerative diseases.

When cells undergo stresses (viral, oxidative, nutrient limitation etc…), leads to a global decrease in translation initiation. This triggers stress granule formation.

NB This presentation was highly technical, the above is simply the basic information as I understood it. 



Thanuja Dharmadasa – Cortical dysfunction identifies regions of onset in ALS

The human hand is a common site of onset of ALS – it's a vulnerable area for neurodegeneration because it's so highly evolved.

MND is a disease of two motor systems (upper and lower), with enormous heterogeneity.

She measured cortical hperexcitability using MRI across all four limbs. Reduced cortical hyperexcitability in affected limbs.

Results support the ‘dying forward' hypothesis of MND.

Bulbar onset has increased cortical hyperexcitability.

Cortical hyperexcitability is a focal phenomenon associated with a descreet area of onset. Opportunity to apply regional therapies to stop spread.

Prominent cortical dysfunction in hand motor region across all MND subgroups. Is this a critical trigger in MND pathogenesis?



Mehdi van den Bos

Focal onset typical, evolving to global dysfunction.

Long pre-clinical period.

Several competing ideas as to progression of desease.

Cortical hyperexcitability is a key point in the cascade of neuronal death.

Probing using Transcranial Magnetic Stimulation found that SCIF and SICI shift towards and excitary state early in the disease. Could help early diagnosis of cortical dysfunction or be useful as a biomarker.




Emma Scotter – Loss of blood-spinal cord barrier integrity displays regional patterning in ALS

TDP-43 proteinopathy gives a setting to examine non-cell autonomous factors.

TDP43 gives us  a target common to almost everyone with MND. Deposits in brain, spinal cord. All NZ banked MND brains have TDP43 in motor cortex.

TDP43 aggregates correlates with motor neuron death.

Pattern of TDP deposition maps to ,motor neuron loss. Map TDp43 across spinal cord, maps against hot spots of motor neuron loss.

Used imaging to see aggregation of TDP43 in spinal cord.

Breakdown of blood-spinal cord barrier (BSCB) might worsen outcomes for pwMND.

The BSCB is ‘leakier' than the blood-brain barrier (BBB), especially cervical and lumbar cord. Proposed to be a mechanism that may influence course of ALS.

Spinal cord in ALS shows BSCB disturbance. Neurotoxic blood components found in cord.

We don't yet know what is causing this leakage in the spinal cord. Probably some deficit in micro-circulation.

Speculate that BSCB leakage develops and resolves first in the cervical and lumbar cord, persisting in the thoracic cord at the end of life.

MND research in NZ: hoping to collaborate with Australia. Doing primary human brain cell work.

Thank you to the people who donated brain and spinal cord to our research.



c9 generally talk about pw more than 30 repeats – generally thousands. some people have 28 or 30. should we count those people as having a risk of ALS or FTD? Right now we're cautious about whether what we're seeing at 30 and 70 repeats is the same as at 500 repeats. 500 repeats might make a much more toxic protein.

Prof Cleveland follows up – do we see multiple polydipeptides in some cells in patients? We've assumed expansion is a perfect repeat but do we know that? We don't know what the endogenous transcript is in RAN transcription.

Have repeat when born, may get bigger over life, what drives penetrance when get to be 50 or 60 or 70? Stress could be a driver.




Rachael Russell – Clinical reasoning for the implementation of eye gaze technology for pwMND

Occupational Therapist, introduces Christine (video) who tells about her experience with eye-gaze technology.

Eye-gaze camera plugs into computer or tablet, picks up reflection of pupils. Works when eye control most efficient and reliable movement.

Many options to access technology – direct access (with hands) or indirect (eg head mouse, switch scanning, eye gaze).

Eye gaze technology is now sleek, accessible, portable. Can be used in many environments and allows for flexibility where mounted – wheelchair, bed, recliner chair. Integrates nicely with mainstream technology eg Windows tablet. (iPads don't have USB port.)

Eye gaze is a viable option for those unable to use regular computer/mouse/tablet or is having difficulty – or will soon lose the movement required to access.

Individual needs: Does eye gaze really require less effort than other access methods? Does client have a support person/team around who can help out with troubleshooting/charging/storing/positioning?

Cost $7000-$16,000, so funding options need to be considered before offered as a solution.

Case study: Narelle. Her goals were communication, social media, email, internet access, eBay, e-books, TV control. Different alternate access options were trialed over 3 sessions. First revealed that eye-gaze least fatiguing. Second looked at brands of software and some training to ID the best. Third session did more training and made decisions about mounting.

The set-up takes time – admitting to ward for a week allowed time for training, set up of mounts and apps, training carers. After she goes home follow-up continues. Low-tech back up required, ongoing trouble-shooting, ensuring support people doing updates.

Direct touch will always be most efficient option – until it's not (fatiguing/laborious – hand function change). Need to think ahead and be prepared when hand function in changing.

Eye-gaze is tiring – concentration, using your eyes.

When successful, reduces carer burden, provides pwMND with purpose – impacts levels of anxiety – and independence, provide environmental control, sense of enjoyment and meaning, retain employment or do volunteering, maintain sense of self and creative outlet.

One of many access methods. Requires thorough assessment. Clients need to be motivated and ready to practice. Can have an amazing impact on quality of life.



Charlene Cullen – Hold onto your voice: options for voice banking

Stephen Hawking had his voice from 1986. He didn't update it because he identified with it.

Our voice is our acoustical fingerprint. Voice banking = recording a list of phrases with your own voice (via voice bank service) – then a synthetic voice is created.

Require voice banking service – some include ModelTalker, my-own-voice, CereVoiceMe, VOCALiD. Cost range from $100 to $4500. Phrases required range 1500-3500. Many hours to do recordings (case study mentioned later took 16 hours and wished he hadn't “rushed it so much”). With fatigue it can take weeks/months. Can decide if want voice or not at the end.

Some voice bank to leave a ‘legacy voice' for family to listen to after gone.

Once you have a voice banked file, you can use on many apps. Predictable is popular for Mac users. Communicator 5 and Grid 3 popular for Windows – but many other options exist for both.

Need to be very disciplined at – takes time, need to do at same time and in good environment.

At end you are given options – voice 1, voice 2, you need to choose which sounds best to you. Can be a difficult choice.

Message banking – generates a lot of sound files that need to be well organised. Can be linked to speech generation devices, but can't create novel messages. A good hand-held recorder is recommended. Can be good to record in real-time, naturally over time.

Considerations: time investment, current speech, expectations of created voice, is it a priority?

If it looks like you will be using a device, do voice banking as soon as you can.

You can donate your voice:



Control Bionics, Rob Wong – The Neuronode

Thank you to Stephen Hawking who was a very early tester of the technology.

Neuronode is a EMG wireless wearable communications device suitable for MND conditions. Uses electrical signal moving across muscles, Can go on any viable muscle site.

Extremely low levels of movement generate a positive signal. Can go arm, forehead, quad, jaw – where can you find a muscle that you can still send a signal to?

Once you have the skills to use, not difficult to transfer to a different muscle site as required due to prgression of disease.

Completely re-evaluated product to become reliable, simple, flexible for individual, clinicians and caregivers. Have to be mindful of changing carers. Needed to work on a variety of platforms, situations and conditions.

Allows switch-like access to computer, choose commands based on left-right and up-down scan.

Threshold settings control for tremor and spasm.

Case study: 45 yr old male with MND whose signal declines during the day due to fatigue. Introduced feature that scales threshold throughout day.



Price of Neuronode? Price is not yet where they want it to be: $16,800. $325 to do a week trial.

Does it work with non-Bluetooth devices? No.

Time taken and price has gone down dramatically over time and will continue to reduce.

Uptake of voice banking? Not large figures yet.




Dr Joseph Nicolazzo – The blood-brain barrier: An obstacle for CNS drug delivery impacted by MND

Overview of factors affecting transport of therapeutics across the blood-brain barrier (BBB).

About 640km of micro-vessels in the brain. Endothelial cells surround these, creating the BBB, or ‘neuro-vascular unit'.

In a healthy BBB, movement between these cells is impossible. Proteins are very well organised and have tight junctions.

If inject radioactive compounds, measure brain to plasma ratio, see how much cross BBB. The more luquifillic the molecule the more cross BBB.

Many anti-cancer and antiretroviral drugs are substrates for efflux transporters – a biochemical barrier that prevents therapeutics from getting into brain fluid.

It's not impossible for molecules to get into the brain. Some transporters take glucose and other small endogenous molecules across. Scientists can try to get drugs to mimic these molecules to cross the BBB – if changing structure of the drug doesn't change its efficacy.

Peptides, antibodies can also be trafficked across the BBB (like insulin). Many scientists trying to exploit this to get large molecules across.

In Alzheimers, rate of transport across BBB is reduced (it was previously thought to increase). There is an association with thickening of cerebrovascular membrane in AD.

Could MND also have an impact on BBB transport of drugs? Blood has been found in spinal cord of pwMND. Suggestive of paracellular permeability and dysfunctional tight junctions. If large molecules detected in brain of pwMND could mean improved uptake of large molecule drugs.

Need to be mindful of co-existing conditions, non-MND drugs could start to go into brain. Concern from pharamacological perspective.

Or perhaps BBB in MND is more of a barrier for therapeutics for some types of drugs (P-gp). Inhibiting P-gp could lead to better uptake of riluzole.

We need to understand better what is going on at BBB with MND – permeability, transporters.



Prof Don Cleveland – Gene silencing therapy for ALS and beyond

Development of “designer DNA” drugs about to be in trial for ALS.

Will be more widely used in other neurodegenerative conditions also.

4-5 million people now alive today will die from ALS.

First causative gene discovered in 1993 – SOD1. When mouse model created, led to worldwide agreement that mutations provoke disease through a toxic property, not loss of activity.

We think SOD1 is in every cell. By silencing it in motor neurons, get disease later. Deleted in astrocytes, mice lived twice as long. Deleted in microglia, lived three times as long. Deleted from oligodendrocytes, delayed onset. Conclusion that disease is non-cell autonomous, SOD1 within motor neurons and oliodendrocytes drive onset.

Led to gene silencing therapy: antisense oligonucleotides (ASOs).

Strategy started in 1990s, failed many times. Chemists modified DNAs – current version of oligonucleotides bind to RNAs.

Strategy for ASO delivery = inject directly into cerebral spinal fluid, so crosses BBB.

Inject at onset, you double survival after onset.

Huntington's disease – know the mutation, unknown toxicity. Reduce mutant hungtintin synthesis in cells = long-term, partial disease reversal in mice, stopping further loss of brain mass in another mouse model. Sustained gene suppression throughout the nervous system after ASO injection at base of spinal cord. Single dose injection led to 3-month efficacy of target mRNA suppression.

Ionis partnered with Roche for first trial in July 2015. Found safe and successfully lowered mutant huntingtin in Dec 2017.

Spinal muscular atrophy (SMA) affects one in 90,000 children. ASO injection trial stopped at halfway point because all efficacy endpoints were met – 2016.

Largest cause ofinherited MND discovered Sept 2011. Most frequent cause of inherited ALS and FTD. 3 proporsals for what might go wrong. Most agree that if look in patients, reduced level of RNA encoded by this gene. RNA or protein toxicity?

Create mice that express c9 expansion. Develop age and dose dependant, sense and antisense strand encoded polydipeptides and RNA foci. Mice develop FTD-like behavioural abnormalities but not MND.

What happens if lower c9 levels? Not much in nervous system. Loss of function of c9 associated with gain of toxicity. Have to lower the bad RNA but not the good RNA.

Injecting single dose of ASO lowers RNA level in c9. Did it before disease onset, one dose, suppressed acquisition of cognitive phenotype with a single dose.

Expecting to get to human trial in second quarter 2018 – just 6.5 years after the gene was discovered!

A clinical trial of ASO therapy in Alzheimers to lower tau launched in 2017.

10-year predictions:

  • ALS and FTD – lowering c9 (2Q, 2018)
  • sporadic ALS – lowering ataxin 2
  • spinal cerebellar ataxias – lowering mutant ataxins
  • chronic brain injury – lowering tau
  • Parkinson'ns – lowering alpha-synuclein
  • AD – lowering tau
  • glioblastoma – lower cell growth genes

ALS Association invested right from the beginning when no-one else would. Was not initiated with corporate money.


Missed the following due to attending palliative care session at 4:30pm:

(Jing Zhao – Inhibition of Eph A4 improves functional performance in the SOD1 mouse)

(Rosie Clark – Targetting the neuropeptide Y sustem as a therapeutic strategy in ALS)

(Julie Atkin – Novel therapeutic strategies for MND)


Fazel Shabanpoor – CNS delivery of oligonucleotide for treatment of neurodegenerative diseases

How can we deliver ASOs? Development of peptides as a delivery vector.

ASOs are a single string of nucleic acids, interfere with gene expression by altering RNA function.

Approved for SMA, Duchene Muscular Dystrophy, Huntington's, ALS (SOD1, C9). Also in clinical trial for cancer. Really useful technology.

All treatments so far require large doses, repeating dosing, invasive injections. Require repeat doses because big, bulky. Need to cross BBB, neuronal cell membrane.

Other vectors for delivery:

  • nanoparticles
  • liposome
  • antibodies
  • peptides

Peptide-assisted delivery of ASOs: easy to synthesise and modify, more selective targeting, low cost of manufacturing. Downsides: short half-life.

When people diagnosed, already have RNA toxicity.

Spinraza (for SMA) injected intrathecal injection (in babies – highly invasive).

ASO are large, cannot cross BBB. Inject mice with peptide-PMO. Effective.



C9 – targets sense strand RNA (not antisense) because can't measure antisense. If you can turn down RNA, you turn down translation product. You won't get dead nerons back but have a chance of getting damaged neurons back.

Peptide ASO – what would the final product look like? A daily dose? If can improve half-life to 1-2 hours that determines dosing. Won't have to do it every day.

Don – it's possible to silence any gene we have tested to 95%. Peripheral therapy could be of additional advantage.




Prof Samar Aoun – The palliative approach to caring for MND

12 steps of palliative care.

Palliative care is an approach that improves quality of life of patients and their families, through relief of suffering of all types.

Survey of bereaved families: 64% of pw cancer received palliative care. Non-malignant illnesses was 4-10% – still under-represented in palliative care. That hasn't changed for 10 years.

Patients usually accepted into palliative care usually in last 3 months of life. Discharged if improved or stable.

In practice, Palliative care has been equated with service provision, rather that its original intent which begins at time of diagnosis.

True palliative approach promotes early interventions aimed at having conversations with patients and family members about their goals of care, comfort measures, and needs and wishes.

Essential = ‘upstream orientation' ie early in illness trajectory, even as soon as time of diagnosis. Emphasis on anticipatory planning and open conversations. Adaptation of palliative care in primary care.

Especially important to start from diagnosis in MND because of smooth downward trajectory.

Diagnosis. National survey of all neurologists in Aus, carers. One of the most sensitive steps. 36% of patents dissatisfied with way diagnosis delivered. Conservative estimate. High skills = empathy, imparting knowledge.

Some real talk here about neurologists! “It's up to them to learn some skills.” Powerful quotes from patients/carers.

WHO says palliative approach should be adopted by primary care professionals. 22 health profs come into contact with one pwMND. Imagine if all took a palliative care approach!

Need for education/training in palliative approach to caring for pwMND.

PwMND: “My fear of life is greater than death.”

West Australia runs one-day training programme – very popular.

MND Associations: “Until there is a cure, there is care.” Rural clients not satisfied because not funded to take support to rural areas.

Family carers: experience like PTSD, prolonged grief. Carer Support Needs Assessment Tool (CSNAT) opens opportunity for systematic conversations about needs of carers. Need to do early enough with carer – prepares them well to accept help.

Highest priorities for carers: knowing what to expect, knowing who to contact if concerned, equipment to help care, dealing with feelings and worries.

CSNAT intervention significantly reduced family carer strain and distress. Positive impact on perceived adequacy of support and achievement of preferred place of death. These benefits reinforce the need for early intervention of palliative care.

About 10% of people at high risk for complex grief issues (need professional support). 30% at moderate risk. 60% are okay with support from family and friends.

Large amount of bereavement support comes from funeral providers.

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