Scott Sullivan MND Research Fellow – Update Nov 2017 – MND and Me Foundation

Scott Sullivan MND Research Fellow – Update Nov 2017

Recipient:  Dr Shyuan Ngo

1. Aim of the Fellowship:
Develop a translational research program that bridges the clinical and basic sciences, to decipher the mechanisms by which altered metabolic balance contributes to disease pathology.

2. Outcomes:
Research outcomes during the last two and a half years:

Clinical –

Our team’s clinical research aims to study the relationship between energy balance, dietary intake, gut function, physical activity and disease progression. It is a holistic research program that incorporates multiple facets of human biology to better understand how MND affects each individual as a whole. In Brisbane, this research is conducted in collaboration with Dr Frederik Steyn, Prof Pamela McCombe, and A/Prof Robert Henderson.

This arm of the research has led to the conferral of a Masters degree to Dr Zara Ioannides. Through this project, we have established a long-term collaboration with Prof Leonard van den Berg, who oversees the MND clinic at the Utrecht Medical Centre (Netherlands). Recruitment of patients into the Netherlands arm of the study is ongoing. This project has also attracted the attention of Prof Ammar Al-Chalabi at the King’s MND Care and Research Centre, who has now replicated our metabolic assessment platform in his clinic.

Our study cohort has reached 68 MND patients and 81 control individuals. Our cross-sectional studies compare whole body energy use between MND patients and non-MND controls. Our longitudinal studies to determine whether changes in energy use occur as disease progresses are still ongoing.
We have completed analysis of cross-sectional data of energy use from 58 MND and 58 control individuals. Our data show that hypermetabolism (when energy use is higher than what is expected) is associated with greater functional decline in MND patients, that it is linked to a type of MND that is clinically characterised by the loss of motor neurons in the spinal cord, and that hypermetabolic MND patients are at risk of earlier death.

This work has been submitted to Neurology for publication.
Dietary data that has been collected as part of the metabolism study are ongoing. We are currently analysing a number of diet diaries in collaboration with Dr Veronique Chachay at the School of Human Movements and Nutrition Sciences. Once the in-depth breakdown of macro- and micronutrient intake in our MND patients and control participants is completed, we will compare data to the metabolic phenotypes of MND patients and controls and data of the gut microbiome from each patient.

We have been collecting fecal samples from the patients who are enrolled in our study of energy use. We have collected over 50 MND and 50 control samples in a cross-sectional study design. We have also collected follow-up samples from MND patients as they progress through the disease. Samples are processed at the Australian Centre for Ecogenomics. In collaboration with Prof Naomi Wray, we are developing pipelines for data analysis to compare fecal microbiome diversity relative to the energy use of respective donors.

Tracking of physical activity in the field is ongoing. We currently have physical activity data for 33 MND patients and 12 control individuals. This part of the research program has led to new research questions surrounding the excessive fatigue that is experienced by MND patients and we are developing new research questions to trial drugs that may be able to alleviate fatigue to improve quality of life.

Blood samples from MND patients and control participants in the study of energy use have been analysed for circulating hormones and metabolic markers. This data is currently being run through statistical analysis and correlated to measures of energy use and body composition.

In February 2017, we initiated the collection of skeletal muscle biopsies from MND patients and control individuals to determine whether changes in whole body energy use were due to alterations in the capacity for skeletal muscle to use and generate energy. To date, we have collected a total of 44 skeletal muscle biopsies 30 from MND patients and 14 from healthy controls.

In October 2017, we initiated the collection of skin biopsies for the generation of induced pluripotent stem cell derived neurons (skin cells which are turned into stem cells and then subsequently turned into neurons) as well as directly reprogrammed neurons (skin cells turned directly into neurons). To date, we have collected skin samples from seven MND patients and three healthy controls.

All muscle and skin cells will be or are currently being used to:

  • Determine whether the way in which the cells use and generate energy is related to the changes in the way the body uses energy. This work is currently funded by a MNDRIA Charcot Grant.
  • Study unique signatures in individual cells that can provide critical information to help us understand why these cells are susceptible to death in MND. We have secured funding through a MNDRIA MonSTaR MND Grant to support this work in 2018.
  • Support high-throughput screening of lead compounds (including those that improve energy use) to determine if they can improve survival of these cells in the dish. Screening of lead compounds is currently supported by FightMND (through a collaborative project) and we aim to apply for funding (as an additional collaborative project) to initiate screening of our next lead compound.
  • Establish a platform to drive precision medicine for MND. This platform is supported through research infrastructure at the Australian Institute for Bioengineering and Nanotechnolgoy.

All muscle and skin samples that are collected in Brisbane can be shared with other MND investigators (nationally and internationally) to enhance collaboration and to speed up drug development.

Basic –

Our team’s basic research aims to identify the mechanisms that cause metabolic dysfunction in MND, with the view to identify targets for therapeutic development. This research is conducted in collaboration with Dr Frederik Steyn, Dr Jean-Philippe Loeffler, Dr Bradley Turner, and Prof Ernst Wolvetang.

To date, our projects have used the SOD1G93A mouse model of MND, and a unique mouse that I have generated by crossing SOD1G93A mice to mice that have no growth hormone receptor signalling (GHR). Our data in SOD1G93A mice show that there are significant changes in how fat is used as an energy source during the course of disease. This work has formed the majority of the PhD thesis for Ms Rui Li and data are being prepared for publication.

Using our unique SOD1/GHR mouse, we have shown that manipulation of signalling pathways that modulate energy balance can lead to the delaying of the onset of muscle weakness by 11 weeks, and extend survival by 11 days. We continue to breed the SOD/GHR mouse to complete assessment of skeletal muscle and spinal cords to see if reduced growth hormone signalling in these mice can save neurons in the spinal cord and rescue connections between these neurons and skeletal muscle.
As part of our clinical research, we have found that MND patients experience significant fatigue. We have initiated treatment of SOD1G93A mice with a compound that has been found to alleviate fatigue in mice and humans. In the first study, SOD1G93A mice were either placed on a control (chow) diet, or a diet supplemented with our compound at an age that corresponded to a time when disease symptoms first present (10 weeks).

Our data show that SOD1G93A mice supplemented with this compound have an initial improvement in hind limb grip strength relative to non-supplemented mice, with a peak response occurring three weeks after diet initiation. Following this three week time period, SOD1G93A mice on the compound start to lose grip strength, yet their grip strength still remains higher than that of non-supplemented SOD1G93A mice. Future experiments will focus on placing 10 week old wild-type and SOD1G93A mice on chow or treatment diet for three weeks. Mice will be assessed for motor neuron numbers in the spinal cord, and the integrity of connections between motor neurons and skeletal muscle to determine whether our compound is neuroprotective.

Through collaboration, I have secured funding as co-CI from FightMND. This project will test the effects of modulating the metabolism of a unique group of fats on disease outcome in multiple mouse models of MND. We have promising lead compounds in hand and the timeline for completion is 2020.

3. Research Input and Output since 2015
I have secured ~$4.1M in research funding as lead or co-investigator via grants received from the NHMRC, MNDRIA, Wesley Medical Research, FightMND, and University of Queensland. I am also an investigator on two NHMRC-MEI grants valued at ~$450K.

Since 2015, I have published 15 peer-reviewed articles and one book chapter. I have presented our work at numerous national and international conferences.

4. Future directions
To date, I have strategically developed transdisciplinary collaborative links and projects that are aimed at advancing research discovery. In July 2017, I moved my laboratory from the School of Biomedical Sciences to the Australian Institute for Bioengineering and Nanotechnology (AIBN). As part of this move, I will fully integrate my clinical research with research expertise and infrastructure at UQ StemCARE at AIBN to foster the next phase of our research – the use of human-derived cells for precision medicine.

With the Ross Maclean Fellow scheduled to commence at QBI in 2018, I aim to collaborate with Dr Walker to further drive MND research in Brisbane towards treatments for motor neurone disease.