Targeting Huntingtin Expression in Patients with Huntington’s Disease
| Autor: | Tabrizi, Sarah J, Leavitt, Blair R, Rosser, Anne, Kordasiewicz, Holly B, Czech, Christian, Swayze, Eric E, Norris, Daniel A, Baumann, Tiffany, Gerlach, Irene, Schobel, Scott A, Paz, Erika, Smith, Anne V, Landwehrmeyer, G Bernhard, Bennett, C Frank, Lane, Roger M, Teams, Phase 1–2a IONIS-HTTRx Study Site, McColgan, Peter, Hensman, Davina, Ghosh, Rhia, Flower, Michael, Libri, Vincenzo, Saunders, Edwina, Raymond, Lynn, Wild, Edward J, Decolongon, Joji, Li, Tuan, Fathinia, Panteha, Lang, Christina, Lewerenz, Jan, Lindenberg, Katrin, Ludolph, Albert C, Schneider, Ariane, Trautmann, Sonja, Uhl, Stefanie, Saft, Carsten, Weydt, Patrick, Kaminski, Barbara, Kaminski, Daniela, Hoffmann, Rainer, von Hein, Sarah M, Muhlack, Siegfried, Gold, Ralf, Collins, Lucy, Mason, Sarah, Scott, Kirsten, Barker, Roger A, Stoker, Tom, Greenland, Julia, Andresen, Katie, Shanmugam, Mohan, Abdelghani, Mowafak, Turgut, Tolga, Peeren, Siofra, Colaco, Olga, Owens, Rebecca, Subin, Sujamole, Blair, Nick F, Spruth, Eike Jakob, Beckmann, Janna, Krug, Henriette, Langenfurth, Anika, Crossley, Diana, Akhtar, Nasreen, Gavin, Jennie, De Souza, Jenny, Massey, Thomas, McLauchlan, Duncan, Craufurd, David, Cousins, Rebecca, Shastin, Dmitri, Peall, Kathryn, Bhatt, Harsh, Davison, Andrew, Bagshawe, Joanne, Gunning, Belinda, Hamandi, Khalid, Priller, Josef, Rickards, Hugh |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male congenital hereditary and neonatal diseases and abnormalities Huntingtin Mutant HTT(RX) cerebrospinal fluid [Huntingtin Protein] Oligonucleotides Disease 030204 cardiovascular system & hematology HTT protein human medicine.disease_cause 03 medical and health sciences 0302 clinical medicine antagonists & inhibitors [Huntingtin Protein] Huntington's disease cerebrospinal fluid [Oligonucleotides] mental disorders Huntingtin Protein Medicine Humans In patient 030212 general & internal medicine ddc:610 Injections Spinal Mutation Dose-Response Relationship Drug business.industry Nucleotides genetics [Huntingtin Protein] General Medicine Middle Aged medicine.disease chemical synthesis [Nucleotides] nervous system diseases drug therapy [Huntington Disease] Huntington Disease therapeutic use [Oligonucleotides] nervous system Cancer research Female business Trinucleotide repeat expansion pharmacology [Nucleotides] |
| Zdroj: | 2019, ' Targeting Huntingtin Expression in Patients with Huntington’s Disease ', New England Journal of Medicine, vol. 380, no. 24, pp. 2307-2316 . https://doi.org/10.1056/NEJMoa1900907 The New England journal of medicine 380(24), 2307-2316 (2019). doi:10.1056/NEJMoa1900907 |
| ISSN: | 0028-4793 |
| DOI: | 10.1056/NEJMoa1900907 |
| Popis: | BACKGROUNDHuntington’s disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. IONIS-HTTRx (hereafter, HTTRx) is an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce concentrations of mutant huntingtin.METHODSWe conducted a randomized, double-blind, multiple-ascending-dose, phase 1–2a trial involving adults with early Huntington’s disease. Patients were randomly assigned in a 3:1 ratio to receive HTTRx or placebo as a bolus intrathecal administration every 4 weeks for four doses. Dose selection was guided by a preclinical model in mice and nonhuman primates that related dose level to reduction in the concentration of huntingtin. The primary end point was safety. The secondary end point was HTTRx pharmacokinetics in cerebrospinal fluid (CSF). Prespecified exploratory end points included the concentration of mutant huntingtin in CSF.RESULTSOf the 46 patients who were enrolled in the trial, 34 were randomly assigned to receive HTTRx (at ascending dose levels of 10 to 120 mg) and 12 were randomly assigned to receive placebo. Each patient received all four doses and completed the trial. Adverse events, all of grade 1 or 2, were reported in 98% of the patients. No serious adverse events were seen in HTTRx-treated patients. There were no clinically relevant adverse changes in laboratory variables. Predose (trough) concentrations of HTTRx in CSF showed dose dependence up to doses of 60 mg. HTTRx treatment resulted in a dose-dependent reduction in the concentration of mutant huntingtin in CSF (mean percentage change from baseline, 10% in the placebo group and −20%, −25%, −28%, −42%, and −38% in the HTTRx 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively).CONCLUSIONSIntrathecal administration of HTTRx to patients with early Huntington’s disease was not accompanied by serious adverse events. We observed dose-dependent reductions in concentrations of mutant huntingtin. (Funded by Ionis Pharmaceuticals and F. Hoffmann–La Roche; ClinicalTrials.gov number, NCT02519036. opens in new tab.) |
| Databáze: | OpenAIRE |
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