Antisense drugs reverse ataxia, ALS symptoms in mice

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The antisense drugs directly targeted the mutation responsible for ataxia, but works indirectly to alleviate ALS symptoms.

University of Utah scientists found that antisense drugs reversed symptoms in mouse models of ataxia and amyotrophic lateral sclerosis.

Ataxia, a rare neurodegenerative disease characterized by a lack of muscular control, is usually caused by damage to the cerebellum, which is responsible for muscle coordination. While ataxia patients survive much longer than ALS patients after diagnosis, ataxia resembles ALS in its most severe cases. As ALS progresses, patients lose the ability to move their muscles, which weaken and waste away, ultimately leading to paralysis and death.

In their study, published in Nature, the team engineered mice to carry the ataxin-2 gene, which causes ataxia in humans, according to a statement. They then injected the animals with antisense oligonucleotides—small pieces of manufactured, modified DNA—which targeted instructions from the mutated gene and marked them for destruction.

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Two months later, the mice did “significantly better” on a balance and coordination test, the team said in the statement. And the cells in the mice’s cerebellums started firing at normal rates.

“This is a proof of concept that these new compounds could become the basis for new therapies for neurodegenerative disease, which so far have been largely impenetrable,” said senior author Stefan Pulst, chair of neurology at University of Utah Health, in the statement.

In a separate study, the antisense therapy improved movement and prolonged survival in mice with ALS. While the treatment directly targeted the root cause of ataxia, it seems to work indirectly for ALS, where the ataxin-2 gene is not mutated.

Pulst’s team is now investigating how the therapy eases ALS symptoms and whether ataxin-2 could be a target for other neurodegenerative diseases.

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This isn’t the first time antisense oligonucleotides have been deployed against genetic disorders. Last year, the FDA approved Biogen and Ionis’ Spinraza for spinal muscular atrophy and Sarepta’s Exondys 51 for Duchenne muscular dystrophy. And Ionis is trialing its volanesorsen in multiple diseases. In December, the antisense drug proved effective in a phase 3 trial for hypertriglyceridemia.

But it hasn’t been all smooth sailing for Ionis. Just last month, volanesorsen hit its primary endpoint in a phase 3 trial for familial chylomicronemia syndrome, but safety concerns sent the company’s shares down 8%.