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Huntington’s disease: 4 big questions

1. How does the mutant protein huntingtin cause Huntington’s disease?

Why it matters

Huntington’s disease is caused by a mutation in a single gene called huntingtin (HTT), which encodes the protein huntingtin. Understanding how the mutant protein causes disease could open up avenues for treating the condition and its symptoms.

What we know

Mutant huntingtin forms clumps inside the cell that seem to interfere with communication along the axons of neurons. Such aggregates can also throw a wrench into the transcription of other genes and hinder cells’ waste-removal systems.

Next steps

Various projects led by researchers, companies and non-profit organizations are using computational methods to better understand the shape of mutant huntingtin, how it aggregates, and how it interacts with other proteins in the cell.

2. What is the role of normal huntingtin?

Why it matters

To help develop treatments for Huntington’s disease, including those that use RNA interference, antisensense oligonucleotides (ASOs) or gene editing, it’s important to determine whether normal huntingtin, as well as the mutant version, can be reduced or eliminated safely.

What we know

Blocking Htt expression in mouse embryos is lethal. In adult mice, some studies show that removing normal huntingtin has only limited effects, whereas others indicate it shortens lifespan and causes nerve and behavioural problems. The effect of reducing huntingtin in people is unknown.

Next steps

Researchers are eliminating normal huntingtin in mammals with lifespans longer than those of mice to determine any long-term effects. Efforts are also underway to inactivate just the mutated copy of HTT, leaving the normal version intact, using the gene-editing tool CRISPR–Cas9.

3. How can we better characterize the progression of Huntington’s disease?

Why it matters

To more effectively assess treatments in trials, doctors need improved ways of measuring whether they slow disease progression. The current best tool is the clinician-rated Unified Huntington’s Disease Rating Scale, which is reliable but prone to the power of the placebo effect.

What we know

A 2017 study showed that changes in levels of neurofilament light polypeptide (NF-L) in blood correlate with the onset of Huntington’s disease, making it a possible biomarker. Other biomarkers that correlate with the condition can be measured by functional brain imaging.

Next steps

Three large long-term observational studies have been designed to assess the ability of potential biomarkers to measure disease progression. The team investigating NF-L has launched a 600-participant study, and is already monitoring NF-L levels in at least 80 people.

4. Will ASOs be the first effective treatment for Huntington’s disease?

Why it matters

ASOs are the first potential treatment to have successfully lowered levels of mutant huntingtin in trials conducted in people. But it’s uncertain whether these molecules can slow or halt progression of Huntington’s disease.

What we know

In a phase I/IIa trial, an ASO called IONIS-HTTRx reduced the levels of mutant huntingtin in participants’ cerebrospinal fluid. But the trial was too short to determine the treatment’s long-term effects. The drug is delivered once a month via an injection into the spine.

Next steps

Further trials of IONIS-HTTRx with larger numbers of participants are needed to determine whether the drug is effective at treating Huntington’s disease. Researchers are also monitoring the 46 participants of the initial trial for any long-term effects.

Nature 557, S48 (2018)


This article is part of Nature Outlook: Huntington’s disease, an editorially independent supplement produced with the financial support of third parties. About this content.


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