An Antibody-Oligonucleotide Conjugate for Myotonic Dystrophy Type 1.

The disease is caused by a trinucleotide repeat expansion in DMPK, which encodes myotonic dystrophy type 1 protein kinase and imparts a toxic gain of function to the transcribed messenger RNA (mRNA), resulting in dysregulated alternative splicing (missplicing).

该疾病是由DMPK基因中的三核苷酸重复扩展引起的，该基因编码肌营养不良症1型蛋白激酶，并赋予转录的信使RNA（mRNA）一种有毒的增益功能，导致调控失常的替代剪接（错配剪接）。

Delpacibart etedesiran (del-desiran [AOC 1001]) is a monoclonal antibody-oligonucleotide conjugate.

Delpacibart etedesiran (del-desiran [AOC 1001]) 是一种单克隆抗体-寡核苷酸偶联物。

The antibody component targets transferrin receptor 1, and the oligonucleotide component targets DMPK mRNA.

抗体部分靶向转铁蛋白受体1，而寡核苷酸部分靶向DMPK mRNA。

Methods

In this phase 1-2, multicenter, double-blind, randomized, placebo-controlledtrial, we assigned participants with myotonic dystrophy type 1 to receive del-desiran intravenously in a single dose (1 mg per kilogram of body weight) or three doses (2 mg or 4 mg per kilogram) or placebo.

在这项1-2期、多中心、双盲、随机、安慰剂对照试验中，我们将患有1型肌营养不良症的参与者分配接受del-desiran静脉注射单剂量（每公斤体重1毫克）或三剂量（每公斤体重2毫克或4毫克）或安慰剂。

The primary end point was safety, and secondary end points were the pharmacokinetic and pharmacodynamic profiles of del-desiran and changes in downstream aberrant splicing patterns at 43 days in the 1-mg group and at 92 days (49 days after the second dose) in the 2-mg and 4-mg groups.

主要终点是安全性，次要终点是del-desiran的药代动力学和药效学特征以及在1毫克组43天和2毫克组及4毫克组92天（第二次给药后49天）下游异常剪接模式的变化。

Results

Six participants received del-desiran at a dose of 1 mg per kilogram, 9 at a dose of 2 mg per kilogram, and 13 at a dose of 4 mg per kilogram; 10 participants received placebo.

六名参与者接受了每公斤体重1毫克的del-desiran剂量，9名参与者接受了每公斤体重2毫克的剂量，另外13名参与者接受了每公斤体重4毫克的剂量；10名参与者接受了安慰剂。

Mild or moderate adverse events occurred in 35 of the 38 participants who received an infusion.

在38名接受输液的参与者中，有35人出现了轻度或中度的不良事件。

Two severe, serious adverse events occurred in 2 participants in the 2-mg and 4-mg groups; 1 of these participants discontinued participation in the trial. The percent change in DMPK mRNA levels in muscle-biopsy samples was -46% in the 1-mg group, -44% in the 2-mg group, -37% in the 4-mg group, and 0.9% in the placebo group.

2-mg和4-mg组中有2名参与者发生了2起严重的不良事件；其中1名参与者退出了试验。肌肉活检样本中DMPK mRNA水平的百分比变化为1-mg组的-46%，2-mg组的-44%，4-mg组的-37%，安慰剂组的0.9%。

Maximum plasma concentrations of small interfering RNA (siRNA) and the area under the curve increased proportionally with dose escalation, and a minor fraction of siRNA was recovered in urine.

小干扰RNA（siRNA）的最大血浆浓度和曲线下面积随剂量增加而成比例增加，尿液中回收了少量的siRNA。

Reductions in the mean composite missplicing score from baseline were 3%, 17%, 16%, and 7%, respectively, consistent with amelioration of missplicing in the 2-mg and 4-mg groups.

从基线开始，平均复合错误剪接评分分别降低了3%，17%，16%和7%，这与2毫克和4毫克组中错误剪接的改善一致。

Conclusions

Our results are consistent with delivery of del-desiran to muscle and amelioration of aberrant alternative splicing in some patients with myotonic dystrophy type 1; two serious adverse events occurred.

我们的研究结果与del-desiran传递至肌肉并改善某些肌营养不良症1型患者的异常选择性剪接一致；发生了两起严重不良事件。

These data support further clinical investigation.

这些数据支持进一步的临床研究。

(Funded by Avidity Biosciences; ClinicalTrials.gov number, NCT05027269.).

(由Avidity Biosciences资助; ClinicalTrials.gov编号, NCT05027269。)