Background: Myotonic dystrophy type 1 (DM1) is caused by expansion of CUG repeats in the 3’-UTR of the dystrophia myotonica protein kinase (DMPK) RNA. The expanded CUG repeats form hairpin-loop structures that sequester splicing regulators into toxic nuclear foci, leading to a spliceopathy that drives DM1 clinical manifestations. No disease-modifying treatments are available, limiting treatment to symptom management. We developed the FORCETM platform, which harnesses the natural expression of transferrin receptor (TfR)1 on muscle cells for targeted delivery of oligonucleotide payloads. DYNE-101 is a TfR1-targeting antigen-binding fragment conjugated to a gapmer antisense oligonucleotide (ASO) that targets nuclear DMPK RNA. Data show that DYNE-101 reduces mutant DMPK RNA, foci formation, and corrects splicing defects in preclinical models of DM1, suggesting a potential effect in individuals with DM1. Objectives: The ACHIEVE trial is a randomized, double-blinded, placebo-controlled, multiple ascending dose (MAD) Phase 1/2 study assessing safety, tolerability, pharmacodynamics, efficacy, and pharmacokinetics of DYNE-101 administered intravenously to adults with DM1 aged 18-49 years (NCT05481879). The study consists of a MAD/placebo-controlled period (24 weeks), open-label extension (OLE, 24 weeks), and long-term extension (LTE) period (96 weeks). The primary outcome is the number of participants with treatment-emergent adverse events. Change from baseline in splicing index in skeletal muscle is a secondary outcome. Results: The study will enroll ~64 participants across 4 cohorts of ascending doses of DYNE-101 (1.8, 3.4, 6.8, and 10.2 mg/kg approximate ASO equivalent doses). Participants who receive 1.8 and 3.4 mg/kg DYNE-101 will follow an every 4 weeks (Q4W) dosing regimen, whereas participants who receive 6.8 and 10.2 mg/kg DYNE-101 will follow a Q4W dosing regimen or a Q8W regimen. All participants will receive the highest safe and tolerable dose of DYNE-101 during the OLE and LTE periods. Conclusions: The study will inform further development of DYNE-101 for the treatment of DM1.