\n
1. How does the mutant protein huntingtin cause Huntington\u2019s disease?<\/b><\/p>\n
<\/p>\n
Why it matters<\/i><\/p>\n
Huntington\u2019s disease is caused by a mutation in a single gene called huntingtin (HTT<\/i>), which encodes the protein huntingtin. Understanding how the mutant protein causes disease could open up avenues for treating the condition and its symptoms.<\/p>\n
<\/p>\n
What we know<\/i><\/p>\n
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\u2019 waste-removal systems.<\/p>\n
<\/p>\n
Next steps<\/i><\/p>\n
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.<\/p>\n
<\/p>\n
<\/p>\n
2. What is the role of normal huntingtin?<\/b><\/p>\n
<\/p>\n
Why it matters<\/i><\/p>\n
To help develop treatments for Huntington\u2019s disease, including those that use RNA interference, antisensense oligonucleotides (ASOs) or gene editing, it\u2019s important to determine whether normal huntingtin, as well as the mutant version, can be reduced or eliminated safely.<\/p>\n
<\/p>\n
What we know<\/i><\/p>\n
Blocking\u00a0Htt<\/i>\u00a0expression 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.<\/p>\n
<\/p>\n
Next steps<\/i><\/p>\n
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\u00a0HTT<\/i>, leaving the normal version intact, using the gene-editing tool CRISPR\u2013Cas9.<\/p>\n
<\/p>\n
<\/p>\n
3. How can we better characterize the progression of Huntington\u2019s disease?<\/b><\/p>\n
<\/p>\n
Why it matters<\/i><\/p>\n
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\u2019s Disease Rating Scale, which is reliable but prone to the power of the placebo effect.<\/p>\n
<\/p>\n
What we know<\/i><\/p>\n
A 2017 study showed that changes in levels of neurofilament light polypeptide (NF-L) in blood correlate with the onset of Huntington\u2019s disease, making it a possible biomarker. Other biomarkers that correlate with the condition can be measured by functional brain imaging.<\/p>\n
<\/p>\n
Next steps<\/i><\/p>\n
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.<\/p>\n
<\/p>\n
<\/p>\n
4. Will ASOs be the first effective treatment for Huntington\u2019s disease?<\/b><\/p>\n
<\/p>\n
Why it matters<\/i><\/p>\n
ASOs are the first potential treatment to have successfully lowered levels of mutant huntingtin in trials conducted in people. But it\u2019s uncertain whether these molecules can slow or halt progression of Huntington\u2019s disease.<\/p>\n
<\/p>\n
What we know<\/i><\/p>\n
In a phase I\/IIa trial, an ASO called IONIS-HTTRx<\/sub>\u00a0reduced the levels of mutant huntingtin in participants\u2019 cerebrospinal fluid. But the trial was too short to determine the treatment\u2019s long-term effects. The drug is delivered once a month via an injection into the spine.<\/p>\n <\/p>\n
Next steps<\/i><\/p>\n
Further trials of IONIS-HTTRx<\/sub>\u00a0with larger numbers of participants are needed to determine whether the drug is effective at treating Huntington\u2019s disease. Researchers are also monitoring the 46 participants of the initial trial for any long-term effects.<\/p>\n <\/p>\n
<\/p>\n<\/div>\n
Nature<\/span>\u00a0557<\/strong>, S48 (2018)<\/p>\ndoi: 10.1038\/d41586-018-05180-3<\/div>\n<\/div>\n
<\/p>\n
<\/p>\n","protected":false},"excerpt":{"rendered":"
(\uc6d0\ubb38) Although potential treatments are now entering the pipeline, the molecular cause and progression of Huntington\u2019s disease continue to elude researchers.(more…)<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[33,29,30],"tags":[7,3,4],"class_list":["post-590","post","type-post","status-publish","format-standard","hentry","category-do-biology","category-lets-do-science","category-recent-science-news","tag-do-biology","tag-lets-do-science","tag-recent-science-news"],"aioseo_notices":[],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"","jetpack-related-posts":[{"id":3625,"url":"https:\/\/biochemistry.khu.ac.kr\/lab\/?p=3625","url_meta":{"origin":590,"position":0},"title":"Principles of and strategies for germline gene therapy","author":"biochemistry","date":"June 4, 2019","format":false,"excerpt":"\u00a0 \u00a0 Abstract Monogenic disorders occur at a high frequency in human populations and are commonly inherited through the germline. 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