Editing Huntington's disease (section)

==Research directions==

Research into the mechanism of HD is focused on identifying the functioning of Htt, how mHtt differs or interferes with it, and the brain pathology that the disease produces.<ref name="NIHHope2020">{{cite web |title=Huntington's Disease: Hope Through Research |url=https://www.ninds.nih.gov/disorders/patient-caregiver-education/hope-through-research/huntingtons-disease-hope-through |website=www.ninds.nih.gov |access-date=16 November 2020 |archive-date=25 October 2020 |archive-url=https://web.archive.org/web/20201025060231/https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Huntingtons-Disease-Hope-Through |url-status=live }}</ref> Research is conducted using ''[[in vitro]]'' methods, [[genetically modified animal]]s, (also called [[transgene|transgenic animal models]]), and human volunteers. Animal models are critical for understanding the fundamental mechanisms causing the disease, and for supporting the early stages of [[drug development]].<ref name=ross-tabrizi />  The identification of the causative gene has enabled the development of many [[genetically modified organism]]s including [[nematode]]s (roundworms), ''[[Drosophila melanogaster|Drosophila]]'' [[Drosophila melanogaster|fruit flies]], and [[genetically modified mammal]]s including mice, rats, sheep, pigs and monkeys that express mutant huntingtin and develop progressive [[neurodegeneration]] and HD-like symptoms.<ref name=ross-tabrizi>{{cite journal | vauthors = Ross CA, Tabrizi SJ | title = Huntington's disease: from molecular pathogenesis to clinical treatment | journal = The Lancet. Neurology | volume = 10 | issue = 1 | pages = 83–98 | date = January 2011 | pmid = 21163446 | doi = 10.1016/S1474-4422(10)70245-3 | s2cid = 17488174}}</ref>

Research is being conducted using many approaches to either prevent Huntington's disease or slow its progression.<ref name="NIHHope2020"/> Disease-modifying strategies can be broadly grouped into three categories: reducing the level of the mutant huntingtin protein (including [[gene splicing]] and [[gene silencing]]); approaches aimed at improving neuronal survival by reducing the harm caused by the protein to specific cellular pathways and mechanisms (including [[protein homeostasis]] and [[histone deacetylase inhibitor|histone deacetylase inhibition]]); and strategies to replace lost neurons. In addition, novel therapies to improve brain functioning are under development; these seek to produce symptomatic rather than [[Disease-modifying treatment|disease-modifying therapies]], and include [[phosphodiesterase inhibitors]].<ref name="ReferenceA">{{cite journal | vauthors = Wild EJ, Tabrizi SJ | title = Targets for future clinical trials in Huntington's disease: what's in the pipeline? | journal = Movement Disorders | volume = 29 | issue = 11 | pages = 1434–45 | date = September 2014 | pmid = 25155142 | pmc = 4265300 | doi = 10.1002/mds.26007}}</ref><ref name="20170503TOI">{{cite news| vauthors = Solomon S |title=Taube to fund $3m Huntington's disease research in US|url=http://www.timesofisrael.com/taube-to-fund-3m-huntingtons-disease-research-in-us/|access-date=5 May 2017|work=[[The Times of Israel]]|date=3 May 2017|url-status=live|archive-url=https://web.archive.org/web/20170503135635/http://www.timesofisrael.com/taube-to-fund-3m-huntingtons-disease-research-in-us/|archive-date=3 May 2017}}</ref>

The [[CHDI Foundation]] funds a great many research initiatives providing many publications.<ref name="CHDIA">{{cite web |title=Scientific Publications {{!}} CHDI Foundation |url=https://chdifoundation.org/scientific-publications/ |website=chdifoundation.org |access-date=12 December 2021 |archive-date=12 December 2021 |archive-url=https://web.archive.org/web/20211212175055/https://chdifoundation.org/scientific-publications/ |url-status=live }}</ref> The CHDI foundation is the largest funder of Huntington's disease research globally and aims to find and develop drugs that will slow the progression of HD.<ref name=chdi-nature-moneytree/><ref name="CHDI">{{cite web |title=CHDI Foundation |url=https://chdifoundation.org/ |website=chdifoundation.org |access-date=13 November 2020 |archive-date=14 November 2020 |archive-url=https://web.archive.org/web/20201114214504/https://chdifoundation.org/ |url-status=live }}</ref> CHDI was formerly known as the High Q Foundation. In 2006, it spent $50 million on Huntington's disease research.<ref name=chdi-nature-moneytree /> CHDI collaborates with many academic and commercial laboratories globally and engages in oversight and management of research projects as well as funding.<ref name=chdi-nature-philanthropy>{{cite journal | vauthors = Check E | title = Biomedical philanthropy: love or money | journal = Nature | volume = 447 | issue = 7142 | pages = 252–3 | date = May 2007 | pmid = 17507955 | doi = 10.1038/447252a | bibcode = 2007Natur.447..252C| s2cid = 4318384 | doi-access = free }}</ref>

===Reducing huntingtin production===

[[Gene silencing]] aims to reduce the production of the mutant protein, since HD is caused by a [[Genetic disorder#Single-gene|single dominant gene]] encoding a toxic protein. Gene silencing experiments in mouse models have shown that when the expression of mHtt is reduced, symptoms improve.<ref name=munoz-bates-jci>{{cite journal | vauthors = Munoz-Sanjuan I, Bates GP | title = The importance of integrating basic and clinical research toward the development of new therapies for Huntington disease | journal = The Journal of Clinical Investigation | volume = 121 | issue = 2 | pages = 476–83 | date = February 2011 | pmid = 21285520 | pmc = 3026740 | doi = 10.1172/JCI45364}}</ref> The safety of [[RNA interference]], and [[allele-specific oligonucleotide]] (ASO) methods of gene silencing has been demonstrated in mice and the larger primate macaque brain.<ref>{{cite journal | vauthors = McBride JL, Pitzer MR, Boudreau RL, Dufour B, Hobbs T, Ojeda SR, Davidson BL | title = Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington's disease | journal = Molecular Therapy | volume = 19 | issue = 12 | pages = 2152–62 | date = December 2011 | pmid = 22031240 | pmc = 3242667 | doi = 10.1038/mt.2011.219}}</ref><ref>{{cite journal | vauthors = Kordasiewicz HB, Stanek LM, Wancewicz EV, Mazur C, McAlonis MM, Pytel KA, Artates JW, Weiss A, Cheng SH, Shihabuddin LS, Hung G, Bennett CF, Cleveland DW | title = Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis | journal = Neuron | volume = 74 | issue = 6 | pages = 1031–44 | date = June 2012 | pmid = 22726834 | pmc = 3383626 | doi = 10.1016/j.neuron.2012.05.009 }}</ref> Allele-specific silencing attempts to silence mutant htt while leaving wild-type Htt untouched. One way of accomplishing this is to identify polymorphisms present on only one allele and produce gene silencing drugs that target polymorphisms in only the mutant allele.<ref name=sah-aronin>{{cite journal | vauthors = Barnes DW, Whitley RJ | title = Antiviral therapy and pulmonary disease | journal = Chest | volume = 91 | issue = 2 | pages = 246–51 | date = February 1987 | doi=10.1378/chest.91.2.246| pmid = 3026739 }}</ref> The first gene silencing trial involving humans with HD began in 2015, testing the safety of IONIS-HTTRx, produced by [[Ionis Pharmaceuticals]] and led by [[UCL Institute of Neurology]].<ref name=bbc-news-gene-silencing-trial-starts>{{cite news|title=Landmark Huntington's trial starts|url=https://www.bbc.com/news/health-34552041|access-date=19 October 2015|url-status=live|archive-url=https://web.archive.org/web/20151021214158/http://www.bbc.com/news/health-34552041|archive-date=21 October 2015}}</ref><ref>{{cite web|title=Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS-HTTRx in Patients With Early Manifest Huntington's Disease - Full Text View |url=https://clinicaltrials.gov/ct2/show/NCT02519036|publisher=ClinicalTrials.gov |access-date=18 April 2016|url-status=live|archive-url=https://web.archive.org/web/20150929080905/https://clinicaltrials.gov/ct2/show/NCT02519036|archive-date=29 September 2015}}</ref> Mutant huntingtin was detected and quantified for the first time in [[cerebrospinal fluid]] from Huntington's disease mutation-carriers in 2015 using a novel "single-molecule counting" [[immunoassay]],<ref name="mhtt-detection-jci-2015">{{cite journal | vauthors = Wild EJ, Boggio R, Langbehn D, Robertson N, Haider S, Miller JR, Zetterberg H, Leavitt BR, Kuhn R, Tabrizi SJ, Macdonald D, Weiss A | title = Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington's disease patients | journal = The Journal of Clinical Investigation | volume = 125 | issue = 5 | pages = 1979–86 | date = May 2015 | pmid = 25844897 | pmc = 4463213 | doi = 10.1172/jci80743}}</ref> providing a direct way to assess whether huntingtin-lowering treatments are achieving the desired effect.<ref>{{cite journal | vauthors = Chase A | title = Huntington disease: cerebrospinal fluid and MRI biomarkers for prodromal HD | journal = Nature Reviews Neurology | volume = 11 | issue = 5 | page = 245 | date = May 2015 | pmid = 25896083 | doi = 10.1038/nrneurol.2015.63 | s2cid = 38300571}}</ref><ref>{{cite journal | vauthors = Keiser MS, Kordasiewicz HB, McBride JL | title = Gene suppression strategies for dominantly inherited neurodegenerative diseases: lessons from Huntington's disease and spinocerebellar ataxia | journal = Human Molecular Genetics | volume = 25 | issue = R1 | pages = R53–64 | date = April 2016 | pmid = 26503961 | pmc = 4802374 | doi = 10.1093/hmg/ddv442}}</ref> A phase 3 trial of this compound, renamed tominersen and sponsored by [[Hoffmann-La Roche|Roche Pharmaceuticals]], began in 2019 but was halted in 2021 after the safety monitoring board concluded that the risk-benefit balance was unfavourable.<ref>{{Cite journal| vauthors = Kwon D |date=2021-04-06|title=Genetic therapies offer new hope against incurable brain diseases|journal=Nature|language=en|volume=592|issue=7853|pages=180–183|doi=10.1038/d41586-021-00870-x|pmid=33824521|bibcode=2021Natur.592..180K|s2cid=233173862 |doi-access=}}</ref> A huntingtin-lowering gene therapy trial run by Uniqure began in 2019, and several trials of orally administered huntingtin-lowering splicing modulator compounds have been announced.<ref>{{Cite web | vauthors = Harding R | date = 26 April 2021 | veditors = Fox L |title=Huntington's disease clinical trial round up|url=https://en.hdbuzz.net/303|access-date=2021-05-05|website=HDBuzz|language=en|archive-date=5 May 2021|archive-url=https://web.archive.org/web/20210505134715/https://en.hdbuzz.net/303|url-status=live}}</ref> [[Gene splicing]] techniques are being looked at to try to repair a genome with the erroneous gene that causes HD, using tools such as [[CRISPR#Cas9|CRISPR/Cas9]].<ref name="20170503TOI" /> [[PTC Therapeutics]] is evaluating small molecules that induce [[poison exon]] inclusion in ''HTT'' transcript as a therapeutic strategy to lower ''HTT'' expression.<ref>{{Cite journal |last1=Bhattacharyya |first1=Anuradha |last2=Trotta |first2=Christopher R. |last3=Narasimhan |first3=Jana |last4=Wiedinger |first4=Kari J. |last5=Li |first5=Wencheng |last6=Effenberger |first6=Kerstin A. |last7=Woll |first7=Matthew G. |last8=Jani |first8=Minakshi B. |last9=Risher |first9=Nicole |last10=Yeh |first10=Shirley |last11=Cheng |first11=Yaofeng |last12=Sydorenko |first12=Nadiya |last13=Moon |first13=Young-Choon |last14=Karp |first14=Gary M. |last15=Weetall |first15=Marla |date=2021-12-15 |title=Small molecule splicing modifiers with systemic HTT-lowering activity |journal=Nature Communications |language=en |volume=12 |issue=1 |pages=7299 |doi=10.1038/s41467-021-27157-z |issn=2041-1723 |pmc=8674292 |pmid=34911927|bibcode=2021NatCo..12.7299B }}</ref><ref>{{Cite web |title=A Study to Evaluate the Safety and Efficacy of PTC518 in Participants With Huntington's Disease (HD) |url=https://clinicaltrials.gov/study/NCT05358717}}</ref>

===Increasing huntingtin clearance===
Another strategy to reduce the level of mutant huntingtin is to increase the rate at which cells are able to clear it.<ref name=":0">{{cite journal | vauthors = Djajadikerta A, Keshri S, Pavel M, Prestil R, Ryan L, Rubinsztein DC | title = Autophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases | journal = Journal of Molecular Biology | volume = 432 | issue = 8 | pages = 2799–2821 | date = April 2020 | pmid = 31887286 | doi = 10.1016/j.jmb.2019.12.035 | series = Autophagy in Neurodegenerative Diseases | s2cid = 209518157 | url = https://www.repository.cam.ac.uk/handle/1810/299796 | access-date = 20 June 2023 | archive-date = 23 May 2022 | archive-url = https://web.archive.org/web/20220523210125/https://www.repository.cam.ac.uk/handle/1810/299796 | url-status = live }}</ref> As mHtt (and many other [[Protein aggregation|protein aggregates]]) are degraded by [[autophagy]], increasing the rate of autophagy has the potential to reduce levels of mHtt and thereby ameliorate disease.<ref>{{cite journal | vauthors = Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ, Rubinsztein DC | title = Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease | journal = Nature Genetics | volume = 36 | issue = 6 | pages = 585–595 | date = June 2004 | pmid = 15146184 | doi = 10.1038/ng1362 | s2cid = 7749825 | doi-access = free }}</ref> Pharmacological and genetic inducers of autophagy have been tested in a variety of Huntington's disease models; many have been shown to reduce mHtt levels and decrease toxicity.<ref name=":0" />

===Improving cell survival===
Among the approaches aimed at improving cell survival in the presence of mutant huntingtin are correction of [[transcriptional regulation]] using [[histone deacetylase inhibitor]]s, modulating [[Protein aggregation|aggregation]] of huntingtin, improving [[metabolism]] and [[Mitochondria|mitochondrial function]] and restoring function of [[synapses]].<ref name=munoz-bates-jci/>

===Neuronal replacement===
[[Stem-cell therapy]] is used to replace damaged neurons by transplantation of [[stem cell]]s into affected regions of the brain. Experiments in animal models (rats and mice only) have yielded positive results.<ref name="Holley Kamdjou Reidling Fury pp. 329–342">{{cite journal | vauthors = Holley SM, Kamdjou T, Reidling JC, Fury B, Coleal-Bergum D, Bauer G, Thompson LM, Levine MS, Cepeda C | title = Therapeutic effects of stem cells in rodent models of Huntington's disease: Review and electrophysiological findings | journal = CNS Neuroscience & Therapeutics | volume = 24 | issue = 4 | pages = 329–342 | date = April 2018 | pmid = 29512295 | pmc = 6489814 | doi = 10.1111/cns.12839 | publisher = Wiley }}</ref>

Whatever their future therapeutic potential, stem cells are already a valuable tool for studying Huntington's disease in the laboratory.<ref>{{cite journal | vauthors = Cundiff PE, Anderson SA | title = Impact of induced pluripotent stem cells on the study of central nervous system disease | journal = Current Opinion in Genetics & Development | volume = 21 | issue = 3 | pages = 354–61 | date = June 2011 | pmid = 21277194 | pmc = 3932563 | doi = 10.1016/j.gde.2011.01.008}}</ref>

===Ferroptosis===
[[Ferroptosis]] is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. [[ALOX5]]-mediated ferroptosis acts as a cell death pathway upon oxidative stress in Huntington's disease.<ref name = "Stockwell_2017">{{cite journal | vauthors = Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE, Noel K, Jiang X, Linkermann A, Murphy ME, Overholtzer M, Oyagi A, Pagnussat GC, Park J, Ran Q, Rosenfeld CS, Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni S, Woerpel KA, Zhang DD | title = Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease | journal = Cell | volume = 171 | issue = 2 | pages = 273–285 | date = October 2017 | pmid = 28985560 | pmc = 5685180 | doi = 10.1016/j.cell.2017.09.021 }}</ref> Inhibitors of ferroptosis are protective in models of degenerative brain disorders, including
Parkinson's, Huntington's, and Alzheimer's Diseases.<ref name = "Stockwell_2017" />

===Clinical trials===
In 2020, there were 197 [[clinical trial]]s related to varied therapies and biomarkers for Huntington's disease listed as either underway, recruiting or newly completed.<ref name="Trials">{{cite web |title=Search of: Huntington Disease - List Results - ClinicalTrials.gov |url=https://clinicaltrials.gov/ct2/results?cond=Huntington+Disease&term=&cntry=&state=&city=&dist= |website=clinicaltrials.gov |language=en |access-date=16 November 2020 |archive-date=11 November 2021 |archive-url=https://web.archive.org/web/20211111192242/https://clinicaltrials.gov/ct2/results?cond=Huntington+Disease&term=&cntry=&state=&city=&dist= |url-status=live }}</ref> Compounds [[clinical trial|trialled]] that have failed to prevent or slow the progression of Huntington's disease include [[remacemide]], [[coenzyme Q10]], [[riluzole]], [[creatine]], [[minocycline]], [[ethyl-EPA]], [[phenylbutyrate]] and [[dimebon]].<ref>{{cite web|title=Completed Clinical Trials|url=http://www.huntington-study-group.org/ClinicalResearch/CompletedClinicalTrials/tabid/65/Default.aspx|publisher=Huntington Study Group|access-date=4 February 2012|archive-url=https://web.archive.org/web/20120628020904/http://www.huntington-study-group.org/ClinicalResearch/CompletedClinicalTrials/tabid/65/Default.aspx|archive-date=28 June 2012}}</ref>