Why Delivery Is Defining The Next Era Of Neuromuscular Therapeutics

By Ranjan Batra, Ph.D., Chief Scientific Officer, and Doug Kerr, MD, Ph.D., Chief Medical Officer, Dyne Therapeutics

For more than two decades, oligonucleotide therapeutics have held enormous promise for neuromuscular diseases. The field has produced remarkable advances in oligonucleotide chemistry, RNA biology, and target selection. Today, we can modulate splicing, silence disease-causing transcripts, and restore expression of critical proteins with unprecedented precision. Despite these advances, one challenge has consistently limited the full potential of RNA medicines: delivery.

As modalities become more sophisticated, success will be determined not only by what a therapy is designed to do, but whether it can get to disease-relevant tissues safely, consistently, and deeply and achieve sufficient intracellular delivery to truly modulate biological pathways and disease processes. Emerging therapies have been designed to safely deliver oligonucleotides to multiple cells in disease-relevant tissues at effective concentrations to engage the target with the goal of altering the course of disease.

On this basis, neuromuscular disease has become a proving ground for a broader shift across drug development. The next wave of innovation will be defined by programs that integrate delivery from the outset, align design with distribution, and generate clinical evidence that connects tissue exposure to meaningful functional change. In this context, delivery is no longer a technical hurdle to overcome but a strategic lever that will separate promising science from a potentially transformative medicine.

The Biodistribution Challenge: Overcoming The Multisystemic Complexity Of Neuromuscular Diseases

Neuromuscular diseases are multisystemic and often affect skeletal, smooth, and cardiac muscle, as well as the central nervous system (CNS), which leads to widespread clinical manifestations.² Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1) are two multisystemic neuromuscular diseases that have become key targets for therapeutic oligonucleotide development over recent years.^3,4 DMD is a progressive and fatal disease caused by mutations in the DMD gene that lead to total absence or nearly undetectable levels of the dystrophin protein.⁴ DMD manifests as progressive muscle weakness, which results in loss of ambulation and upper limb function, cardiomyopathy, respiratory decline, and CNS issues, such as cognitive impairment and neuropsychiatric manifestations.

DM1 is a spliceopathy caused by cytosine-thymine-guanine (CTG) repeat expansions in the DMPK gene, which leads to compromised function of the Muscleblind-like (MBNL) family of splicing factors and widespread dysregulated gene transcript splicing in multiple tissues.⁵ DM1 is therefore associated with diverse clinical manifestations, including myotonia (inability to relax muscles), progressive muscle weakness, cardiac arrhythmias, gastrointestinal dysfunction, and CNS manifestations.^3,5

For diseases like DMD and DM1, even though the therapeutic target is known, multisystemic delivery and distribution are required to potentially optimize outcomes. The challenge is to efficiently deliver adequate amounts of drug to various affected tissues while maintaining an acceptable safety profile. Historically, for oligonucleotides, this has required high systemic doses and/or frequent administration to overcome tissue penetration barriers, which has caused dose-limiting toxicities leading to a limited therapeutic window.⁶ As a result, the field has often been constrained not by biology but by biodistribution, leading to limited clinical impact that at best slows disease progression, but without improving the functional abilities of individuals living with neuromuscular disease. Consistent exposure across multiple tissues is required to achieve sufficient and effective genetic correction to drive optimal biological and clinical outcomes.

Drug Delivery As A Design Imperative: Delivery Is Not A Downstream Optimization, It Is An Upstream Design Choice

The growing emphasis on consistent and targeted drug delivery is evident across the neuromuscular field.^4,7 Gene therapies are being engineered to improve tissue tropism and transduction efficiency.⁸ Cell therapies seek to enhance homing, engraftment, and persistence within diseased muscle.⁹ Oligonucleotide therapeutics are being conjugated to targeting ligands to improve uptake into specific cell types.⁷

Although these modalities differ substantially in their mechanisms, they share a common objective: maximizing exposure in disease-relevant tissues while minimizing exposure elsewhere. The realization that therapeutic efficacy is determined not only by the therapeutic payload but by the ability to deliver that payload efficiently to the cells that matter most has had important implications for drug development. Programs that do not optimize for delivery may demonstrate compelling biology in preclinical models but fall short in the clinic due to insufficient drug delivery to target tissues.

As an example, baliforsen, a naked oligonucleotide targeting DMPK mRNA tested in a Phase 1/2 clinical trial in patients with DM1, failed to show sufficient skeletal muscle drug concentrations or substantial target reductions.¹⁰ In neuromuscular diseases, delivery cannot be a secondary consideration. Skeletal muscle alone represents a formidable target due to the large volume of tissue distributed throughout the body, and neuromuscular disease pathology often extends beyond skeletal muscle to smooth muscle and to the CNS as well. It is therefore critical to incorporate delivery from the very earliest stages of therapeutic drug design.

Delivery must be balanced with safety/efficacy (therapeutic index), distribution, durability, dosing frequency, target modulation, and the ability to efficiently scale manufacturing. Incorporating these principles from the earliest stages of development is essential, as both the extent and pattern of tissue distribution can have important implications for efficacy and safety. For example, mosaic patterns of delivery (within a tissue) and off-target tissue expression are key concerns as they may lead to unfavorable safety and suboptimal efficacy.^6,11

Achieving delivery to the CNS in neuromuscular diseases is also an important and long-standing objective of drug developers, due to the limitations of intrathecal delivery and the challenge of traversing the blood–brain barrier, a difficult obstacle for the delivery of most large molecule therapeutics.¹² For multisystemic indications, such as DM1, where CNS manifestations are frequent, therapeutics that can achieve CNS distribution represent a major unmet need for patients.¹³

When Targeting The Genetic Cause Of Neuromuscular Disease, The Quantity, Quality, And Distribution Of RNA Modulation Matters

Clinical experience across multiple therapeutic modalities has reinforced the idea that therapeutic payload and delivery strategy cannot be developed independently.^6,14 A potent payload cannot compensate for heterogeneous and inadequate delivery. Indeed, first-generation unconjugated oligonucleotides have failed to show functional improvements in patient outcomes in clinical trials for both DMD and DM1.^10,15

Clinical success requires alignment between mechanism of action and the quantity, quality, and distribution of its effect throughout the body. As an example, in DMD, the presence of even very low dystrophin levels is associated with delayed clinical progression milestones in individuals living with the disease. Compared with no detectable dystrophin, levels <5% are associated with a milder clinical DMD phenotype, including delayed loss of ambulation, greater cardiorespiratory function, reduced need for rescue treatment (i.e., spinal surgery, ventilation, tracheostomy), and increased survival.¹⁶ The quality of dystrophin may also play a role in DMD severity, with specific regions of the protein required for normal muscle and CNS function.^17,18

Currently available dystrophin-producing therapies for individuals with DMD are associated with low quantity, quality, and/or distribution of dystrophin that may limit their functional benefit, as well as having potential safety concerns.¹⁸ Unconjugated oligonucleotides show inadequate uptake and mostly modest increases in dystrophin levels in skeletal muscle.¹⁹ Gene therapy produces micro-dystrophin that lacks key functional domains and has current limitations on its use due to safety concerns.¹⁸ The goal of new dystrophin-producing genetic therapies for DMD is therefore to achieve more efficient muscle delivery and greater dystrophin restoration than first-generation exon-skipping oligonucleotides, while restoring as much of the function of endogenous dystrophin as possible when compared to micro-dystrophin constructs.

Navigating Delivery And Distribution Challenges With Targeted Drug Delivery Is Finally Within Reach For Neuromuscular Disease Therapeutics

Importantly, the industry has moved beyond theoretical discussions of targeted delivery in neuromuscular disease. One example of this is receptor-mediated delivery of RNA-targeted oligonucleotides and small interfering RNA (siRNA). These approaches leverage naturally occurring cellular transport pathways to enhance uptake into target tissues. Transferrin receptor 1 (TfR1) has emerged as a particularly compelling delivery target in neuromuscular diseases because it is expressed across multiple disease-relevant tissues, including skeletal, cardiac, and smooth muscle, the blood–brain barrier, and cells within the CNS.

Conjugated therapeutics that leverage TfR1 can achieve widespread and effective intracellular delivery compared with unconjugated (naked) payloads, with the potential for greater pharmacologic activity and broader therapeutic impact across multisystemic diseases.^12,20 This precision delivery approach has been associated with significant improvements in functional outcomes in patients with neuromuscular disease, with less frequent dosing as compared to naked oligonucleotides.²¹

Platforms that target TfR1 have been refined significantly in the past decade. When targeting via TfR1, it is important not to interfere with endogenous transferrin cellular levels and function and to reduce the potential for anemia via impact on reticulocytes, which may limit therapeutic dose and thus efficacy.²²

Conjugates that have abrogated Fc effector function and do not interfere with endogenous transferrin binding and function may have reduced impact on hematologic function²² and this has been borne out in clinical trials with TfR1-targeted monovalent antibody fragment (Fab) based therapies, which have yet to show any signs of persistent anemia or thrombocytopenia.^21,23 Monovalent TfR1-targeted platforms have also been recognized as an important approach for delivering oligonucleotide therapies across the blood–brain barrier to the CNS. TfR1-binding platforms with bivalent target engagement and high binding affinity have been shown to form clusters in the blood–brain barrier that accumulate in the endolysosomal compartment, resulting in degradation; however, monovalent binding platforms with optimized affinity for TfR1 reduce clustering and favor exocytosis and release into the brain interstitium.^12,24,25

The ability to target delivery of therapeutics, both to muscle and the CNS, could substantially enhance the treatment of multisystemic neuromuscular diseases and may potentially expand opportunities in other neurological conditions as well.

Next-Generation Oligonucleotide Therapeutics Stand To Redefine Expectations In Neuromuscular Disease

Oligonucleotide targeting platforms that can achieve a high quality and quantity of RNA modulation, coupled with broad uptake in muscle and the CNS, represent a meaningful step change in therapeutics for neuromuscular diseases.

In DMD, it is beginning to redefine expectations for what constitutes a meaningful therapeutic effect, moving the field from modest molecular changes toward levels of target engagement that may be more closely linked to functional benefit. In DM1, advances in delivery are creating the possibility of treating multiple affected tissues, including both muscle and the CNS, with a single therapeutic approach.

Together, these developments highlight a broader shift in neuromuscular medicine: delivery may no longer simply be a means of transporting a therapy to its target but a key determinant of the outcomes that therapies can ultimately achieve.

References

1. Rinaldi C, Wood MJA. Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat Rev Neurol. 2018;14(1):9-21. doi:10.1038/nrneurol.2017.148
2. Muntoni F, Wood MJA. Targeting RNA to treat neuromuscular disease. Nat Rev Drug Discov. 2011;10(8):621-637. doi:10.1038/nrd3459
3. Rahm L, Hale MA, Raaijmakers RHL, et al. Myotonic dystrophy type 1: clinical diversity, molecular insights and therapeutic perspectives. Nat Rev Neurol. 2025;21(11):623-641. doi:10.1038/s41582-025-01139-x
4. Duan D, Goemans N, Takeda S, Mercuri E, Aartsma-Rus A. Duchenne muscular dystrophy. Nat Rev Dis Primer. 2021;7(1):13. doi:10.1038/s41572-021-00248-3
5. López-Martínez A, Soblechero-Martín P, de-la-Puente-Ovejero L, Nogales-Gadea G, Arechavala-Gomeza V. An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I. Genes. 2020;11(9):1109. doi:10.3390/genes11091109
6. Hammond SM, Aartsma-Rus A, Alves S, et al. Delivery of oligonucleotide-based therapeutics: challenges and opportunities. EMBO Mol Med. 2021;13(4):e13243. doi:10.15252/emmm.202013243
7. Torres-Masjoan L, Aguti S, Zhou H, Muntoni F. Clinical applications of exon-skipping antisense oligonucleotides in neuromuscular diseases. Mol Ther. 2025;33(6):2689-2704. doi:10.1016/j.ymthe.2025.04.038
8. Suarez-Amaran L, Song L, Tretiakova AP, Mikhail SA, Samulski RJ. AAV vector development, back to the future. Mol Ther. 2025;33(5):1903-1936. doi:10.1016/j.ymthe.2025.03.064
9. Biressi S, Filareto A, Rando TA. Stem cell therapy for muscular dystrophies. J Clin Invest. 130(11):5652-5664. doi:10.1172/JCI142031
10. Thornton CA, Moxley RT, Eichinger K, et al. Antisense oligonucleotide targeting DMPK in patients with myotonic dystrophy type 1: a multicentre, randomised, dose-escalation, placebo-controlled, phase 1/2a trial. Lancet Neurol. 2023;22(3):218-228. doi:10.1016/S1474-4422(23)00001-7
11. van Westering TLE, Lomonosova Y, Coenen-Stass AML, et al. Uniform sarcolemmal dystrophin expression is required to prevent extracellular microRNA release and improve dystrophic pathology. J Cachexia Sarcopenia Muscle. 2020;11(2):578-593. doi:10.1002/jcsm.12506
12. Zanotti S, Martinez-Montero S, Correia S, Yoder N, Batra R, Beskrovnaya O. Reaching the CNS with therapeutic oligonucleotides via TfR1: navigating delivery and distribution challenges. Nucleic Acid Insights. 2026;3:23-35. doi:10.18609/nuc.2026.005
13. White M. Patient Input to Inform the Development of Central Nervous System Outcome Measures in Myotonic Dystrophy. Ther Innov Regul Sci. 2020;54(5):1010-1017. doi:10.1007/s43441-020-00117-3
14. Kakkar A, Traverso G, Farokhzad OC, Weissleder R, Langer R. Evolution of macromolecular complexity in drug delivery systems. Nat Rev Chem. 2017;1(8):63. doi:10.1038/s41570-017-0063
15. Muntoni F, Ciafaloni E, Chloca F, et al. Efficacy and Safety of Golodirsen and Casimersen Compared With Placebo in Duchenne Muscular Dystrophy (ESSENCE): Phase 3 Topline Results. In: MDA Clinical & Scientific Conference 2026. Presentation 22S. 2026. Accessed July 10, 2026. https://www.mdaconference.org/abstract-library/efficacy-and-safety-of-golodirsen-and-casimersen-compared-with-placebo-in-duchenne-muscular-dystrophy-essence-phase-3-topline-results/
16. De Feraudy Y, Ben Yaou R, Wahbi K, et al. Very Low Residual Dystrophin Quantity Is Associated with Milder Dystrophinopathy. Ann Neurol. 2021;89(2):280-292. doi:10.1002/ana.25951
17. Waldrop MA, Lucas KK, Martin AS, et al. Clinical Phenotypes of DMD Exon 51 Skip Equivalent Deletions: A Systematic Review. J Neuromuscul Dis. 2020;7(3):217-229. doi:10.3233/JND-200483
18. Duan D. Systemic AAV Micro-dystrophin Gene Therapy for Duchenne Muscular Dystrophy. Mol Ther. 2018;26(10):2337-2356. doi:10.1016/j.ymthe.2018.07.011
19. Chwalenia K, Wood MJA, Roberts TC. Progress and prospects in antisense oligonucleotide-mediated exon skipping therapies for Duchenne muscular dystrophy. J Muscle Res Cell Motil. 2025;46(4):293-300. doi:10.1007/s10974-024-09688-2
20. Desjardins CA, Yao M, Hall J, et al. Enhanced exon skipping and prolonged dystrophin restoration achieved by TfR1-targeted delivery of antisense oligonucleotide using FORCE conjugation in mdx mice. Nucleic Acids Res. 2022;50(20):11401-11414. doi:10.1093/nar/gkac641
21. Flanigan K, Deconinck N, De Waele L, et al. Zeleciment rostudirsen significantly increased dystrophin protein levels and led to functional improvement in clinical measures in the DELIVER trial. In: MDA Clinical & Scientific Conference 2026. Presentation O442. 2026. Accessed July 10, 2026. https://www.mdaconference.org/abstract-library/zeleciment-rostudirsen-significantly-increased-dystrophin-protein-levels-and-led-to-functional-improvement-in-clinical-measures-in-the-deliver-trial/
22. Couch JA, Yu YJ, Zhang Y, et al. Addressing Safety Liabilities of TfR Bispecific Antibodies That Cross the Blood-Brain Barrier. Sci Transl Med. 2013;5(183):183ra57-183ra57. doi:10.1126/scitranslmed.3005338
23. Lilleker JB, Bassez G, Diaz-Manera J, et al. Safety and Efficacy of DYNE-101 in Adults With DM1: Phase 1/2 ACHIEVE Trial Data. In: MDA Clinical & Scientific Conference 2025. Presentation O44. 2025. Accessed July 10, 2026. https://www.mdaconference.org/abstract-library/safety-and-efficacy-of-dyne-101-in-adults-with-dm1-phase-1-2-achieve-trial-data/
24. Shen X, Li H, Zhang B, Li Y, Zhu Z. Targeting Transferrin Receptor 1 for Enhancing Drug Delivery Through the Blood-Brain Barrier for Alzheimer’s Disease. Int J Mol Sci. 2025;26(19):9793. doi:10.3390/ijms26199793
25. Niewoehner J, Bohrmann B, Collin L, et al. Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron. 2014;81(1):49-60. doi:10.1016/j.neuron.2013.10.061

About The Authors

Ron Batra is a leading expert in RNA biology and therapeutics. Before joining Dyne, he was vice president of discovery and translation at Lexeo Therapeutics and served as a senior vice president of R&D at LocanaBio, where he advanced RNA-targeted therapies for rare disorders including Duchenne muscular dystrophy and myotonic dystrophy. His work earned him the Biocom Catalyst Award (2019), Endpoints News 20 Under 40 (2021), and recognition as one of San Diego’s Top 25 Health Care Leaders (2022). Batra earned a Ph.D. in genetics from the University of Florida, where he studied RNA biology and gene therapy for neuromuscular diseases.

Doug Kerr brings more than 25 years of expertise in early- and late-stage clinical development, with deep experience in neurology. Before joining Dyne, he was a venture partner at Atlas Venture. From 2017 to 2023, he was an integral member of Generation Bio, joining initially as the head of research and development and most recently serving as its CMO. Kerr holds a B.A. in biochemistry from Princeton University and an M.D. from Jefferson Medical College, as well as his Ph.D. in molecular biology from Thomas Jefferson University. He obtained his MBA, with a specialization in entrepreneurship and finance from Northeastern University and completed his medical residency at Johns Hopkins School of Medicine and served on their faculty for 10 years.