New England Journal of Medicine最新文献

Background: Myotonic dystrophy type 1 is a rare, dominantly inherited, progressive, disabling, neuromuscular disease that leads to decreased life expectancy and has no approved therapies. 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). Delpacibart etedesiran (del-desiran [AOC 1001]) is a monoclonal antibody-oligonucleotide conjugate. The antibody component targets transferrin receptor 1, and the oligonucleotide component targets DMPK mRNA.

Methods: In this phase 1-2, multicenter, double-blind, randomized, placebo-controlled trial, 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. 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.

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

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. These data support further clinical investigation. (Funded by Avidity Biosciences; ClinicalTrials.gov number, NCT05027269.).

Background: Cystinosis is a multisystemic lysosomal storage disorder caused by pathogenic variants in CTNS, the gene encoding cystinosin, a lysosomal transmembrane cystine transporter. In patients with cystinosis, cystine accumulates within lysosomes in all organs. The cystine-depleting agent cysteamine delays but does not prevent disease progression.

Methods: In this phase 1-2, open-label, ongoing clinical study, we performed a preliminary assessment of CTNS-RD-04, which consists of autologous CD34+ cells transduced with lentiviral vectors carrying CTNS complementary DNA, in patients with cystinosis. The primary end points were the safety and the side-effect profiles of CTNS-RD-04. Secondary end points were measures of efficacy, including white-cell cystine levels and cystine storage depletion. Oral cysteamine was withdrawn before CTNS-RD-04 infusion, and cysteamine eyedrops were withdrawn 1 month after myeloablation.

Results: Six participants (20 to 46 years of age) received CTNS-RD-04 and were followed for 29 to 63 months. CTNS-RD-04 doses ranged from 3.63×10⁶ to 9.59×10⁶ CD34+ cells per kilogram of body weight, and vector copy numbers ranged from 0.59 to 2.91 copies per diploid genome. All the patients had sustained and highly polyclonal hematopoietic reconstitution; vector copy numbers at 24 months ranged from 0.51 to 2.67 copies per diploid genome. A total of 217 adverse events occurred, most of which were mild or moderate in severity and largely consistent with the procedures and underlying disease. No evidence of monoclonal expansion was noted. White-cell cystine levels decreased from baseline except in Patient 4, who had the lowest vector copy number.

Conclusions: In this small study, CTNS-RD-04, an ex vivo gene therapy for cystinosis, had adverse effects that were largely consistent with the myeloablative regimen and underlying disease profile. White-cell cystine levels decreased after therapy. (Funded by the California Institute for Regenerative Medicine and others; ClinicalTrials.gov number, NCT03897361.).