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September is Muscular Dystrophy Awareness Month. The treatment of Duchenne muscular dystrophy (DMD) highlights both the urgent need for effective therapies and the evolving technologies behind oligonucleotide drug development. Phosphorodiamidate morpholino oligomers (PMOs) are a key modality for DMD, and conjugated therapies such as peptide-conjugated PMOs (PPMOs) and antibody–oligonucleotide conjugates (AOCs) have improved the delivery of PMOs to muscle tissue in recent studies. To meet rising industry demand, WuXi TIDES offers integrated CRDMO services from discovery through development to commercial manufacturing for oligonucleotide therapeutics, including PMOs and PPMOs, helping clients accelerate the development of innovative therapies and bring them to patients.
Muscle is relatively difficult to target with nucleic acid drugs. DMD exemplifies this challenge and has become an important focus of research into new delivery technologies. Several companies have chosen DMD as the lead indication for their delivery platforms, and successful muscle delivery platforms could be adapted for other neuromuscular and cardiac indications.
DMD is a rare muscle-wasting disease caused by mutations in the gene encoding dystrophin. About 20,000 new DMD diagnoses occur worldwide each year, and most patients do not live beyond their 40s.
To date, eight DMD therapies have been approved by the U.S. FDA, five of which target the underlying genetic defect, and these include four therapies based on PMO technology. Still, PMO delivery to skeletal and cardiac muscle remains limited, which has driven new development strategies. Publicly available data show roughly 50 clinical-stage DMD candidates globally, with about one-quarter based on oligonucleotides. Next-generation cyclic-peptide PPMOs and AOCs are generating promising clinical data.
Several currently approved DMD therapies are based on PMOs. PMOs are synthetic molecules based on an RNA framework. Their bases are linked to morpholine rings via phosphorodiamidate bonds rather than the ribose–phosphate bonds of natural RNA. This structure enables PMOs to bind target pre-mRNA and resist degradation in vivo. In DMD, PMOs bind dystrophin pre-mRNA to skip mutated exons and modify splicing, producing truncated dystrophin proteins that retain partial function.
PMOs nonetheless have poor uptake into muscle cells and limited endosomal escape. Peptide-conjugated PMOs (PPMOs) were developed to address these delivery challenges. Cell-penetrating peptides (CPPs) can carry cargo across membranes and increase tissue penetration. However, many early PPMOs used linear CPPs with strong cationic properties, which can promote renal accumulation and raise safety concerns.
Cyclic peptides offer a new route. Entrada Therapeutics is pursuing this approach. The company has developed a cyclic CPP-based endosomal escape vehicle (EEV) delivery platform. The EEV’s cyclic structure ensures rigidity and stability and helps it evade cellular clearance to reach disease-causing targets. In preclinical models, EEV improved PMO delivery to skeletal and cardiac muscle, and early clinical data indicate an acceptable renal safety profile.
In May 2026, Entrada announced top-line results from cohort 1 of the DMD patients treated with ENTR-601-44 in the Phase 1/2 ELEVATE-44-201 study. ENTR-601-44 is an EEV‑PPMO designed for exon 44 skipping. The trial showed favorable safety and tolerability, and the renal function in treated patients remained within normal limits. Treated participants showed a 2.36% increase in dystrophin levels over a 4% baseline expression. The functional measure time to rise velocity also improved versus placebo. ENTR-601-45, an EEV‑PMO designed to induce exon 45 skipping, entered Phase 2 in June, and two additional candidates are progressing in preclinical studies.
Another strategy to achieve tissue‑selective delivery of PMOs is to conjugate them to antibodies that recognize specific receptors, forming AOCs.
In DMD, Avidity Biosciences and Dyne Therapeutics have recently made notable progress. Both companies use antibodies targeting transferrin receptor 1 (TfR1) to deliver PMOs into muscle. Clinical data showed marked increases in muscle dystrophin when treated by AOC versus unconjugated PMOs.
In Q2 2026, Avidity submitted a Biologics License Application (BLA) to the U.S. FDA for delpacibart zotadirsen (del‑zota), seeking accelerated approval for DMD patients amenable to exon 44 skipping. In the Phase 1/2 EXPLORE44 study and its open-label extension, del-zota treatment was associated with improvements in key functional outcomes compared to natural history data, and del-zota demonstrated an acceptable safety and tolerability profile.
In July 2026, the U.S. FDA accepted Dyne’s BLA for z‑rostudirsen for patients eligible for exon 51 skipping. The BLA is primarily supported by data from the registrational expansion cohort of the Phase 1/2 DELIVER trial. After six months of treatment, the adjusted mean dystrophin expression reached 5.46% of normal levels, a 7-fold increase from baseline. Signals of improvement across multiple functional endpoints were also observed, along with favorable safety and tolerability.
Exon skipping strategies typically use PMO backbones, delivered via PPMOs or AOCs. Developing PMO-based therapies demands highly complex processes because the PMO backbone does not map directly to standard oligonucleotide synthesis methods, posing significant challenges for synthetic efficiency. Moreover, the added chemical complexity of conjugation and extensive modifications makes impurity profiles harder to predict. Kilogram scale, regulatory grade PMO and conjugate manufacturing capacity remains limited across the industry.
Integrated capabilities from sequence design through development and manufacturing are critical to improving R&D efficiency and success rates. Building on two decades of experience in chemistry, WuXi AppTec has established systematic capabilities for the development of next‑generation PMOs and other oligonucleotide therapies. The WuXi TIDES platform focuses on providing integrated, end‑to‑end CRDMO services for oligonucleotides, peptides, and related synthetic conjugated drugs.
WuXi TIDES supports conjugation of oligonucleotides to peptides, lipids, small molecules and toxins. With fully integrated capabilities from PMO monomers, PMOs, and peptides to PPMO conjugation and formulation development, WuXi TIDES delivers a truly one-stop PMO/PPMO development platform that is rarely available in the industry. WuXi TIDES’s high‑loading solid‑phase PMO synthesis process can achieve yields of more than 50%, crude purity above 75%, and final product purity exceeding 90%, while supporting large‑scale manufacturing.
The WuXi TIDES team currently operates more than 10 R&D and manufacturing sites. Multiple sites can simultaneously provide both oligonucleotide and peptide services, offering global partners flexible options. This footprint and capability are particularly well-suited for the development and manufacturing of oligonucleotide‑peptide conjugates, especially PPMOs. For example, the Changzhou site houses capabilities in PMO, peptide, and PPMO drug substance process development and manufacturing from preclinical through commercial stages, facilitating efficient process and material handoffs and accelerating projects for partners. As of H1 2026, the WuXi TIDES team is supporting development of more than 20 PMO/PPMO molecules.
Beyond conjugated PMOs, a range of other approaches delivered encouraging DMD updates this year.
Some companies modify the oligonucleotide backbone to improve delivery. Wave Life Sciences’ ASO WVE‑N531 incorporates phosphoryl guanidine (PN) backbone chemistry and is designed to induce exon 53 skipping. The company reported positive Phase 2 results in March 2026, and it plans to submit a New Drug Application (NDA) to the U.S. FDA later this year.
In the field of cell and gene therapy, Capricor Therapeutics is continuing discussions with the FDA regarding the potential approval of deramiocel, with improvements in upper-limb function serving as key supporting evidence; REGENXBIO’s gene therapy RGX‑202 produced positive results in a Phase 3 study, with 93% of participants reaching >10% microdystrophin expression at week 12; and Genethon reported positive two‑year durability data for its candidate GNT0004, with sustained clinical signals and an acceptable safety profile.
Non-dystrophin-based strategies are also being pursued. Satellos Bioscience is developing the oral small molecule SAT‑3247, an AAK1 inhibitor designed to promote skeletal muscle regeneration. AAK1 is implicated in muscle repair and is dysregulated in DMD. Early study data in four adults (ages 21–28) showed reduced muscle fat fraction, increased effort, stable strength, lower creatine kinase and a favorable safety profile.
Collectively, these approaches for DMD share a single aim: preserve more muscle function and expand life’s possibilities. As therapeutic boundaries shift, more innovations may change the course of DMD and open paths for other diseases. WuXi AppTec will continue strengthening its platform capabilities in oligonucleotides and related emerging therapeutic modalities to help global partners accelerate development and advance treatments for DMD and beyond.