Editing Huntington's disease (section)

===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>