What can we learn from Huntington's Disease therapy?

It's great to see our UCL colleagues in the news this week with a potential breakthrough in neurodegenerative disease - for the first time a therapy has been shown to lower levels of the damaging huntingtin protein in Huntington's disease

https://www.ucl.ac.uk/news/news-articles/1217/111217-huntingtons-disease-protein

Of course, the headlines mention potential to see this therapy used in other neurodegenerative disease. But could a similar 'gene silencing' therapy have any use in Parkinson's? The timely review below summarises the current situation with antisense oligonucleotide (ASO) therapy. These drugs target RNA, the product of DNA. Usually RNA goes on to produce proteins but by binding to specific forms of RNA, protein production can be prevented or altered. Development of these molecules has led to highly specific and minimally toxic agents that seem to be ideally suited to address the protein build-up found in neurodegenerative disease. ASOs have shown very positive results in the childhood condition Spinal Muscular Atrophy, where Nusinersen reduced risk of death or invasive ventilation by 47%.

One of the main challenges in neurological disease is that these molecules can't cross between the blood and the brain, meaning they currently have to be delivered directly into the spinal column. Another challenge for Parkinson's is that most cases of the disease are not caused by a specific gene defect - in rare cases with alpha-synculein mutations, ASOs aiming to silence the gene by switching off protein production may be useful but this is unlikely to be useful for most patients.

However, the potential of these molecules to interact with proteins in multiple ways - either halting protein production, changing the type of protein produced or restoring healthy protein production has huge potential. We eagerly await the follow up results from the Huntington's study and will continue to follow this story closely.

Nat Rev Neurol. 2017 Dec 1. doi: 10.1038/nrneurol.2017.148. [Epub ahead of print]

Antisense oligonucleotides: the next frontier for treatment of neurological disorders.

Rinaldi C Wood MJA

Antisense oligonucleotides (ASOs) were first discovered to influence RNA processing and modulate protein expression over two decades ago; however, progress translating these agents into the clinic has been hampered by inadequate target engagement, insufficient biological activity, and off-target toxic effects. Over the years, novel chemical modifications of ASOs have been employed to address these issues. These modifications, in combination with elucidation of the mechanism of action of ASOs and improved clinical trial design, have provided momentum for the translation of ASO-based strategies into therapies. Many neurological conditions lack an effective treatment; however, as research progressively disentangles the pathogenic mechanisms of these diseases, they provide an ideal platform to test ASO-based strategies. This steady progress reached a pinnacle in the past few years with approvals of ASOs for the treatment of spinal muscular atrophy and Duchenne muscular dystrophy, which represent landmarks in a field in which disease-modifying therapies were virtually non-existent. With the rapid development of improved next-generation ASOs toward clinical application, this technology now holds the potential to have a dramatic effect on the treatment of many neurological conditions in the near future.