英国伦敦大学学院Sarah J. Tabrizi课题组探讨了亨廷顿舞蹈症患者亨廷顿蛋白的表达。相关论文于2019年6月13日发表在《新英格兰医学期刊》杂志上。

IONIS-HTT_Rx(以下简称HTT_Rx)是一种反义寡核苷酸，旨在抑制HTT信使RNA，从而降低突变体亨廷顿蛋白的浓度。研究人员进行了一项随机、双盲、多上升剂量、1-2a期的试验，包括早期亨廷顿氏舞蹈症成人患者。 患者随机分成3:1的比例，每4周接受一次HTT_Rx或安慰剂包膜内注射，每次4次。剂量选择由小鼠和非人类灵长类动物的临床前模型指导，该模型将剂量水平与降低杭丁顿浓度相关。主要的目的是安全，次要目的为探索脑脊液HTT_Rx药代动力学。预先指定的探索性终点包括脑脊液中突变杭丁顿蛋白的浓度。在46名参与试验的患者中，34人被随机分配接受HTT_Rx(递增剂量为10至120毫克)，12人被随机分配接受安慰剂。每个病人都接受了全部四种剂量，并完成了试验。98%的患者报告了所有1级或2级不良事件。在接受HTT_Rx治疗的患者中未发现严重不良事件。 实验室变量无临床相关不良变化。 脑脊液中HTT_Rx的预剂量(谷)浓度在60 mg以下呈剂量依赖性。HTT_Rx治疗导致脑脊液中突变体浓度呈剂量依赖性降低(HTTRx 10-mg、30-mg、60-mg、90-mg和120-mg剂量组中突变体浓度与基线值的平均百分比分别为10%、20%、25%、28%、42%和38%)。 早期亨廷顿舞蹈症患者鞘内应用HTT_Rx并无严重不良反应。 该研究团队观察到亨廷顿突变体浓度呈剂量依赖性下降。

研究人员表示，亨廷顿氏舞蹈病是一种常染色体显性的神经退行性疾病，由HTT中CAG三核苷酸重复扩增引起，导致亨廷顿蛋白突变。

附：英文原文

Title: Targeting Huntingtin Expression in Patients with Huntington’s Disease

Author: Sarah J. Tabrizi, M.B., Ch.B., Ph.D., Blair R. Leavitt, M.D., C.M., G. Bernhard Landwehrmeyer, M.D., Edward J. Wild, M.B., B.Chir., Ph.D., Carsten Saft, M.D., Roger A. Barker, M.R.C.P., Ph.D., Nick F. Blair, M.B., B.S., David Craufurd, M.B., B.S., Josef Priller, M.D., Hugh Rickards, M.D., Anne Rosser, M.B., B.Chir., Ph.D., Holly B. Kordasiewicz, Ph.D., Christian Czech, Ph.D., Eric E. Swayze, Ph.D., Daniel A. Norris, Ph.D., Tiffany Baumann, B.S., Irene Gerlach, Ph.D., Scott A. Schobel, M.D., Erika Paz, B.S., Anne V. Smith, Ph.D., C. Frank Bennett, Ph.D., and Roger M. Lane, M.D.

Issue&Volume: VOL. 380 NO. 24, 2019

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-HTT_Rx (hereafter, HTT_Rx) 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 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.

Results

Of 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).

Conclusions

Intrathecal 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. Hoffmann–La Roche; ClinicalTrials.gov number, NCT02519036.)

DOI: 10.1056/NEJMoa1900907

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1900907