Targeting Huntingtin Expression in Patients with Huntington’s Disease
Open accessAbstract
BACKGROUNDHuntington's disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein.IONIS-HTT Rx (hereafter, HTT Rx ) 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 HTT Rx 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 HTT Rx 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 HTT Rx (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 HTT Rx -treated patients.There were no clinically relevant adverse changes in laboratory variables.Predose (trough) concentrations of HTT Rx in CSF showed dose dependence up to doses of 60 mg.HTT Rx 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 HTT Rx 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively). CONCLUSIONSIntrathecal administration of HTT Rx 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.
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Dose-dependent reductions of mHTT concentrations in CSF have been observed with IONIS-HTTRx, with a 40% decrease in mHTT at the two highest medication dosages.
“Furthermore, dose-dependent reductions of mHTT concentrations in CSF have been observed, with a 40% decrease in mHTT at the two highest medication dosages,530”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [530]
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- Authors
- Tabrizi, S. J., Leavitt, B. R., Landwehrmeyer, G. B., Wild, E. J., Saft, C., Barker, R. A., Blair, N. F., Craufurd, D., Priller, J., Rickards, H., Rosser, A., Kordasiewicz, H. B., Czech, C., Swayze, E. E., Norris, D. A., Baumann, T., Gerlach, I., Schobel, S. A., Paz, E., Smith, A. V., Bennett, C. F., & Lane, R. M.
- Affiliations
- University of Cambridge (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 of Cambridge, Cambridge (R.A.B., N.F.B.), Manchester Centre for Genomic Medicine, St. Mary’s Hospital, Manchester University NHS Foundation Trust, and the Division of Evolution and Genomic Sciences, School...
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2019-06-13
- Volume
- 380
- Issue
- 24
- Pages
- 2307-2316
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2944628641
- Cited by
- 708
- References
- 25
- Citations by year
- 2026: 54 · 2025: 62 · 2024: 84 · 2023: 83 · 2022: 107 · 2021: 127 · 2020: 129 · 2019: 59 · 2018: 1 · 2017: 1
- FWCI
- 50.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- DZNE Pub (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Ionis Pharmaceuticals
- F. Hoffmann-La Roche
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- Huntington's disease, antisense oligonucleotides, huntingtin, mutant huntingtin, intrathecal administration, cerebrospinal fluid pharmacokinetics, dose dependence, safety, neurodegenerative diseases, CAG repeat expansion
- MeSH terms
- Huntingtin Protein, Adult, Dose-Response Relationship, Drug, Female, Humans, Huntington Disease, Injections, Spinal, Male, Middle Aged, Mutation, Nucleotides, Oligonucleotides
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