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Potential ALS treatment in clinical trial

An exciting new study has identified a potential new treatment for ALS. Now in a phase three clinical trial, researchers hope the drug will be able to slow down disease progression in patients.

What is ALS?

Amyotrophic lateral sclerosis (ALS), also known as motor neurone disease, is a fatal neurological disorder. ALS is characterised by a progressive degeneration of the patient’s motor neurones (MNs). This results in the gradual loss of muscle control, eventually leading to an inability to speak, eat and breathe. 

Mutations in an RNA-binding protein called fused in sarcoma (FUS) are associated with aggressive early-onset forms of ALS. FUS usually has functions in DNA repair and RNA metabolism. However, how mutant FUS causes the death of MNs has been unclear. The team behind a new study, published in Nature Medicine, investigated this further using FUS mutant mice.

Motor neurone degeneration

To explore the disease mechanisms of FUS-dependent ALS, the team generated a series of FUS knock-in mouse lines that expressed the equivalent of two ALS-associated mutated FUS proteins.

First, the researchers analysed the MNs of these mice to determine whether the mutated FUS proteins caused any neurone degeneration. The team found that by two years of age, the mutated mice had 22% fewer MNs than wild-type mice. In addition, mutated mice suffered reductions in neurones in skeletal muscle. The team also showed that when a mouse had multiple copies of a mutant FUS allele, they experienced accelerated MN degeneration.

Delaying ALS onset

Having determined that mutated FUS results in progressive MN degeneration, the team wanted to test whether lowering FUS levels in vulnerable neurones could work as a potential ALS treatment. To do this, they treated the mutant mice with a novel drug called ION363, also known as jacifusen. Jacifusen is a FUS antisense oligonucleotide, meaning it inhibits FUS mRNA translation, essentially silencing the gene.

The scientists injected new-born mutant and wild-type mice with a single dose of jacifusen. The results showed that the treated mutant mice showed an overall decrease in FUS protein to around 20-50% of the levels observed in control mice. Amazingly, the results also showed that jacifusen treatment greatly delayed the symptoms of ALS. At six months of age, treated mutant mice showed no MN loss. However, the mice did show signs of muscle denervation by this time.

Treatment in a human patient

In 2019, an individual patient suffering from ALS was granted jacifusen treatment thanks to the US Food and Drug Agency’s compassionate use programme. The researchers witnessed a significant slowdown in her functional decline with no side effects, which suggested the drug was working. Sadly, the patient’s ALS was already advanced by the time treatment began, and she passed away around a year later. 

The patient’s family kindly donated her brain tissue to the study. Analysis of the tissue revealed that jacifusen significantly reduced the levels of mutant FUS in the patient’s brain cells to almost undetectable levels. In addition, there was a reduction in abnormal protein aggregates in the brain, which is a pathological hallmark of ALS. Although these results were only gained from one patient, they suggest that FUS silencing by jacifusen is a promising therapeutic strategy.

Future work

The findings of this study have greatly increased our knowledge of how FUS mutations contribute to disease progression. Amazingly, the researchers have also identified a potential method to reduce the effects of mutated FUS. In fact, the jacifusen drug is currently in ongoing phase three clinical trials.

“This trial will determine if jacifusen is safe, and if it can effectively slow disease progression in symptomatic FUS-ALS patients. If approved, jacifusen would be the first treatment for this highly aggressive form of early-onset ALS,” senior author Neil Shneider said. “This study is an example of truly personalised medicine in the 21st century.”

Picture credit: Canva