Hello and welcome to our first Cure for MND research Blog! Here I will provide you with new and interesting updates on MND discoveries and research progress from here in Australia and all over the world. A little about me to start with…

My name is Bec Sheean and I am the newly appointed Research Co-ordinator at the Cure for MND Foundation. My background is in MND research, over the last 10 years I have completed my PhD and have been working as an MND researcher. In my new role at the foundation I am focused on keeping you all up-to-date with what is happening in MND research and what discoveries will mean for MND patients, as well as updating you on the progress and outcomes of MND clinical trials.

With the recent announcement of our Cure for MND Foundation Translation Research Grants, I thought I would focus on what is “Translational Research” and why is it important? 


Focus on translational research

In the last few years, medical research in Australia has switched its focus from basic research and discovery to “translational research”, with terms such as “bench-to-bedside” becoming vital components of any research grant proposal. But what does translational research mean and why, even with this shift in focus, are we still currently unsuccessful when it comes to treating MND?

Translational research is a pipeline involving basic research discoveries, pre-clinical development and trials and clinical research. Basic research is vital for gaining a better understanding of what factors contribute to the cause and progression of MND. Determining the roles that individual genes and proteins play in the disease identifies targets for potential MND therapies. For more than two decades the SOD1 mouse (Gurney et al., 1994), the most commonly used model of MND, has provided an important and incredibly informative tool for MND researchers. Using this and other MND models, scientists can target specific genes and/or proteins that are thought to be involved in MND and can elevate, mutate or delete them. Outcomes from these studies provide evidence that will support continued investigation or shifted research focus to other potentially important disease-associated processes and pathways. Once a disease-modifying target has been identified, the tricky process of research translation begins.

The drug development pipeline

Lost in translation: why most laboratory discoveries don’t work in the clinic.

The key aspect of translational research is that the therapy must be readily amenable to humans, meaning it is safe to deliver and effectively reaches its target. So why is the translational part of translational research so difficult?

lostUsing genetic modification techniques combined with breeding strategies, scientists can quickly and effectively modify genes and/or proteins in a cell or animal model, but this is not so easy in a human! Thus scientists must come up with a way to modify their target using a drug or therapy. The drug has to be safe and easy for patients to take (e.g. orally or intravenously) and if delivered this way it must be able to cross the “Blood-Brain Barrier (BBB)”. The BBB is an important barrier that separates the central nervous system (your brain, spinal cord and cerebral spinal fluid (CSF)) from your blood in the periphery. While the BBB is vital for protection against any large molecules, pathogens or neurotoxins that may be circulating, it also provides a real hurdle for getting drugs into central nervous system to target motor neurons or the neighbouring cells.

Now of course a cell grown in a dish or a mouse is a long way from a human! Thus even if a drug is effective in an animal model it may not be effective in a patient. Key differences between the design of a pre-clinical and clinical trial are likely to be contributing to these outcomes. In pre-clinical trials, scientists aim to remove as many variables as possible to reduce the risk that differences in trial outcomes are occurring due to gene/environment variables. For example, in a pre-clinical study, allocation of mice to drug or placebo groups is sex matched (male vs male, female vs female) and litter matched (half the litter will get drug and half placebo) to allow comparisons between genetically matched animals. In laboratory conditions, diet and environmental factors can also be controlled for. While in clinical trials researchers attempt to match patients according to a range of variables including age, sex, age and site of symptom onset, genetics etc., other variables such as environment cannot be controlled for. In addition, MND populations are incredibly heterogeneous and even patients with the same gene mutation can vary drastically in their disease course. With this in mind, it may be less of a surprise that the efficacy of therapies tested in a tightly controlled environment with a genetically similar cohort is not reflected in the general population of MND patients.

Overcoming these hurdles

Frustrated with failed outcomes of Phase III trials, MND researchers have proposed to focus their efforts on improving pre-clinical studies, pharmacological issues and clinical trial design (For more information see DeLoach et al., (2015)). With the development of new technologies, huge advancements in the field of disease modelling are occurring and now a range of animal and cellular models (including motor neurons grown from a patient’s own skin cells!) of MND are available. The use of a patient’s own cells for testing therapies means that the therapy can be personalised for each individual patient and also allows scientists to have a model of sporadic MND, the un-inherited form of MND, that often does not involve any genetic mutation.

MND researchers are also investigating new drug delivery techniques. Here, chemists and biochemists are invaluable in their ability to adapt the structure of drugs to make them more BBB-penetrable. Scientists are even taking clues from viruses, which are particularly good at sneaking through the barrier, and are investigating ways to package their therapies into similar type structures.

Lastly improvements in clinical trial design, including well powered studies, transparent reporting and clear biological and functional readouts are being implemented. Also the generation of large databases including the PRO-ACT (Pooled Resource Open-Access ALS Clinical Trials) platform and Australian MND Registries including AMNDR and SALSA allows for the collation of huge amounts of patient data. This increases the power of studies and can determine if subtypes of patients are likely to be more or less responsive to particular therapies.

With the MND research field rapidly advancing, the development of better models of MND and improved methods of drug delivery will lead to more reliable pre-clinical data, more effective therapies and lower doses of drugs which reduces both the cost of the treatment and the chances of side-effects. These advancements in basic scientific research and pre-clinical trial will improve MND research translation and increase the likelihood of successful MND clinical trials.