Six steps to ALS may provide novel therapeutic targets

Neurodegenerative disorders

By Mardi Chapman

25 Jul 2019

Mathematical modelling on an Australian population has confirmed earlier European evidence that the development of amyotrophic lateral sclerosis (ALS) involves a six-step process.

Using mortality data from the Australian Institute of Health and Welfare (AIHW), the local study identified 6,524 deaths from ALS between 2007 and 2016. The ALS deaths were used as a proxy for disease incidence.

The modelling was able to demonstrate a linear relationship between log incidence and log age of onset of disease in both sexes.

The study said the slope estimate in the total cohort was five – indicating that six steps were required in the pathogenesis of ALS.

Lead author Professor Steve Vucic, from the University of Sydney, told the limbic it was important to reproduce the European findings in a separate population.

“The theory behind the six-step process is that there are environmental factors involved so presumably the environmental factors would have been different in Europe and Australia.”

“But by reaffirming there are six steps, it tells you about the intrinsics of the pathophysiology of these disease – mainly that the disease has roughly a similar process both in Australia and also in Europe.”

“So there are some intrinsic factors to the patients – molecular, genetic, epigenetic, perhaps even neonatal factors – together with environmental factors and they seem to be common environmental factors or acting in a common way.”

Professor Vucic said ALS and neurodegenerative diseases were extremely complicated.

“There are intricacies which are beyond our understanding at this stage. What is important about this paper, is that it shows that you need six sequential steps to get the disease.”

Identifying some of the myriad of contributing actors involved could help with the development of new treatments, he said.

“You would think that unlocking one or two steps, depending on where the steps are, might slow the trajectory of the disease. And one factor, for example certain genetic mutations, could trigger two or three steps.”

Professor Vucic said recognising the multistep process should also change the current mindset about how to treat the disease.

“You treat cancers by giving many treatments. At this stage in ALS, we have only been giving one treatment, that acts against a particular pathway and that hasn’t been successful.”

“So maybe going forward, we need to be doing combination therapies – combining three or four drugs that act on different pathways. Maybe that is the key to success.”

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