In Germany at least 8000 and probably up to ca. 14,000 people currently suffer from clinically manifest Huntington's disease (HD). In addition, an estimated 24,000 Germans carry the HD mutation in the huntingtin (HTT) gene and will develop HD during their lifetime. Although HD is a rare neurodegenerative disease, it is currently in the focus of general medical interest: clinical trials have begun that provide a rational basis for hope to slow down the so far relentless progression of the disease, ultimately resulting in patients becoming entirely dependent on nursing care. If treatment is started early enough it may be possible to mitigate the clinical manifestation of HD. These innovative therapeutic approaches aim at inhibiting the de novo production of mutant HTT gene products. A first clinical drug trial to demonstrate the efficacy (phase III) of intrathecal antisense oligonucleotides (ASO, active substance RG6042) was started in 2019. Additional clinical studies on alternative treatment approaches with allele-selective ASOs as well as gene therapeutic approaches using RNA molecules and zinc finger repressor complexes are imminent. This article gives an overview of the current gene-selective therapeutic approaches in HD under discussion.

Abteilung Neurologie Universitätsklinikum Ulm Oberer Eselsberg 45 1 89081 Ulm Deutschland

Huntington Zentrum NRW Neurologische Klinik der Ruhr Universität Bochum St Josef Hospital Bochum Deutschland

Klinik für Neurologie und Zentrum für klinische Neurowissenschaften 1 Medizinische Fakultät Karlsuniversität Prag Tschechien

Klinik für Psychiatrie und Psychotherapie Charité Universitätsmedizin Berlin Berlin Deutschland

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Nervenarzt. 2019 Aug;90(8):781-786 PubMed

Neuroepidemiology. 2016;46(2):144-53 PubMed

Nat Rev Mol Cell Biol. 2010 Mar;11(3):165-70 PubMed

Exp Neurol. 2012 Nov;238(1):1-11 PubMed

Arch Dis Child Educ Pract Ed. 2016 Aug;101(4):213-5 PubMed

Brain. 2020 Feb 1;143(2):407-429 PubMed

Lancet Neurol. 2011 Jan;10(1):83-98 PubMed

J Virol. 1994 Sep;68(9):5656-66 PubMed

Clin Genet. 2016 Mar;89(3):367-70 PubMed

Science. 2012 Aug 17;337(6096):816-21 PubMed

Nat Rev Mol Cell Biol. 2019 Jul;20(7):406-420 PubMed

Neurology. 2000 Jan 25;54(2):452-8 PubMed

Front Neurosci. 2018 Feb 26;12:75 PubMed

Adv Drug Deliv Rev. 2015 Jun 29;87:46-51 PubMed

Nat Biotechnol. 2017 Mar;35(3):238-248 PubMed

Hum Mol Genet. 2003 Dec 15;12(24):3359-67 PubMed

Hum Gene Ther. 2018 Jun;29(6):663-673 PubMed

Mol Ther Methods Clin Dev. 2017 May 11;5:259-276 PubMed

Mol Ther. 2015 Nov;23(11):1759-1771 PubMed

Hum Mol Genet. 2007 May 15;16(10):1133-42 PubMed

Front Aging Neurosci. 2014 Apr 22;6:78 PubMed

Nat Rev Drug Discov. 2018 Oct;17(10):729-750 PubMed

Mol Ther. 2008 May;16(5):947-56 PubMed

Curr Biol. 2009 May 12;19(9):774-8 PubMed

Mol Ther. 2017 Jan 4;25(1):12-23 PubMed

Mol Ther. 2018 Sep 5;26(9):2163-2177 PubMed

N Engl J Med. 2019 Jun 13;380(24):2307-2316 PubMed

Lancet Neurol. 2015 Nov;14(11):1135-42 PubMed

Cell. 2000 Mar 31;101(1):57-66 PubMed

Lancet Neurol. 2009 Sep;8(9):791-801 PubMed

J Clin Invest. 2017 Jun 30;127(7):2719-2724 PubMed

Cell. 2019 Aug 8;178(4):887-900.e14 PubMed

Nat Biotechnol. 2019 Aug;37(8):884-894 PubMed

Annu Rev Pharmacol Toxicol. 2010;50:259-93 PubMed

Physiol Rev. 2010 Jul;90(3):905-81 PubMed

Nat Med. 2014 May;20(5):536-41 PubMed

Cell. 1993 Mar 26;72(6):971-83 PubMed

Hum Gene Ther. 2014 May;25(5):461-74 PubMed

RNA Biol. 2009 Jul-Aug;6(3):329-34 PubMed

Science. 1997 Sep 26;277(5334):1990-3 PubMed

Science. 2013 Feb 15;339(6121):819-23 PubMed

Sci Rep. 2017 May 2;7(1):1307 PubMed

Psychosocial Impact of Huntington's Disease and Incentives to Improve Care for Affected Families in the Underserved Region of the Slovak Republic