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Targeting Huntingtin Expression in Patients with Huntington's Disease.
Tabrizi, Sarah J; Leavitt, Blair R; Landwehrmeyer, G Bernhard; Wild, Edward J; Saft, Carsten; Barker, Roger A; Blair, Nick F; Craufurd, David; Priller, Josef; Rickards, Hugh; 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; Bennett, C Frank; Lane, Roger M.
Afiliação
  • Tabrizi SJ; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Leavitt BR; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Landwehrmeyer GB; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Wild EJ; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Saft C; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Barker RA; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Blair NF; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Craufurd D; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Priller J; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Rickards H; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Rosser A; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Kordasiewicz HB; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Czech C; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Swayze EE; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Norris DA; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Baumann T; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Gerlach I; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Schobel SA; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Paz E; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Smith AV; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Bennett CF; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
  • Lane RM; From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University o
N Engl J Med ; 380(24): 2307-2316, 2019 06 13.
Article em En | MEDLINE | ID: mdl-31059641
ABSTRACT

BACKGROUND:

Huntington'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.

METHODS:

We 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 31 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.

RESULTS:

Of 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).

CONCLUSIONS:

Intrathecal 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.).
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oligonucleotídeos / Doença de Huntington / Proteína Huntingtina / Nucleotídeos Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oligonucleotídeos / Doença de Huntington / Proteína Huntingtina / Nucleotídeos Idioma: En Ano de publicação: 2019 Tipo de documento: Article