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iStock, alexkich As AAV9 and CRISPR programs navigate safety, delivery and scalability hurdles, small molecules offer a deployable, scalable bridge, complementing genetic approaches and accelerating meaningful impact for patients with Duchenne muscular dystrophy. The pursuit of a cure for Duchenne muscular dystrophy has long inspired some of the boldest scientific efforts in rare disease medicine. Fueled by urgency, innovation and hope, the field has made remarkable strides—from gene therapy to gene editing and beyond. Yet despite this promise, recent clinical setbacks remind us that no single modality will solve DMD. To truly deliver for patients, we must broaden our therapeutic toolkit, bringing forward small molecules, cell therapies and advanced biologics to complement, not replace, genetic approaches. As CEO of Sarcomatrix Therapeutics, I lead a team developing small molecule therapies for muscle-wasting diseases, including DMD. Based on my decades of experience in biotech, it is clear to me that small molecules deserve a seat alongside genetic and cell-based approaches in the battle against this formidable foe. Diversifying the Vector Toolbox First, let’s address gene therapy. Over the last several years, much of the field has rallied around AAV9-based gene therapy as a potential breakthrough for DMD. AAV9 vectors have clear strengths: they effectively target muscle tissue, cross the blood-brain barrier and enable systemic delivery of therapeutic genes such as microdystrophin. Companies like Pfizer, Sarepta and Solid Biosciences have led ambitious efforts in this space. But tragic clinical events —including multiple patient deaths across trials and with approved drugs —have revealed the limitations and risks of high-dose systemic AAV delivery in this population. While AAV9 has dominated the DMD gene therapy landscape, it is not the only option. Other adeno-associated virus serotypes, such as AAV8 and AAVrh74, offer different tissue tropism profiles and may improve transduction efficiency or safety in certain contexts. AAVrh74, for example, has shown promising muscle-targeting characteristics with potentially lower immunogenicity and is being evaluated in experimental gene therapies for multiple neuromuscular diseases. Sarepta’s other AAVrh74-based programs—including SRP-9003 for LGMD2E and SRP-9004 for LGMD2D—remain in clinical trials. Real progress in DMD will likely require synergy, not singularity. Beyond AAV vectors, lentiviral vectors—though more commonly used ex vivo —also represent another avenue for therapeutic delivery in select applications. And beyond viral systems altogether, several groups are advancing non-viral delivery platforms that may eventually bypass some of the safety and dose limitations of AAV. Lipid nanoparticles (LNPs), already clinically validated in mRNA vaccines, are being engineered for nucleic acid delivery to muscle. Polymeric nanoparticles, peptide-based delivery vehicles and exosome-like vesicles are also under active investigation. These technologies could enable redosing, reduce manufacturing bottlenecks and allow for modular payloads—including CRISPR components—without the long-term persistence associated with viral genomes. None of these alternatives are without their own challenges—whether it’s tissue targeting, endosomal escape or large-scale manufacturing—but diversifying the vector toolbox will be critical to building a sustainable gene delivery ecosystem for DMD. The ‘Trough of Disillusionment’ AAV9 isn’t inherently flawed—but it may not be sufficient on its own. Its use in DMD has shown the strain of trying to stretch a platform beyond its intended scope. We are asking it to transduce nearly every muscle in the body, across variable disease stages, in patients who often have pre-existing cardiac involvement and immune priming. This is a tall order for any delivery system. This moment represents a familiar stage in the Gartner Hype Cycle , a model used to describe the trajectory of emerging technologies. Gene therapy for DMD has crested the “Peak of Inflated Expectations” and now enters the “Trough of Disillusionment,” a phase where the technology’s promise is tested by real-world complexity, safety concerns and scalability challenges. This is not failure—it’s evolution. It’s an opportunity to step back, reassess and expand our approach. A similar trajectory played out with CAR T cell therapies in oncology. When early trials in refractory B cell leukemias and lymphomas reported unprecedented remission rates, CAR T was vaulted to the “Peak of Inflated Expectations.” Investor capital poured in, pipelines swelled and the technology was hailed as a paradigm-shifting cure. But real-world complexity quickly tempered the hype: severe toxicities like cytokine release syndrome and neurotoxicity emerged, efficacy in solid tumors proved elusive, and the logistical and manufacturing challenges of autologous cell therapy became clear. The field entered its “Trough of Disillusionment,” marked by program pauses, trial redesigns and more selective patient targeting. Through iterative advances in safety management, antigen targeting and manufacturing, CAR T has now moved into the “Slope of Enlightenment” with multiple approvals, broader indications and a more sustainable integration into cancer care. iStock, PeterHermesFurian Small Molecules—A Bridge to a Cure For patients with DMD, small molecules offer a critical, proven near-term bridge to the future. While gene editing may one day deliver a lasting solution, it’s still in its formative stages, and systemic delivery remains a limiting factor. In contrast, small molecule therapeutics are already deployable, scalable and well understood from both regulatory and clinical perspectives. These compounds can target pathways critical to muscle health—such as inflammation, regeneration, fibrosis and integrin signaling—while avoiding the risks associated with irreversible genome editing or immune activation. Oral small molecules can be titrated, paused and combined with other therapies. They are especially promising as a baseline treatment for all patients, including those not eligible for gene therapy or CRISPR trials. In this way, small molecules serve not as a competitor to gene editing but as a complement and a bridge, offering meaningful clinical impact while the field continues to mature more permanent and personalized therapies. Cell therapies also hold enormous potential. Satellite cell transplantation, stem cell–derived myoblasts and engineered muscle progenitors are making early clinical progress. These approaches may help rebuild damaged tissue or deliver supportive trophic factors—especially when used in tandem with pharmacological or genetic tools. And of course, gene editing platforms like CRISPR remain powerful. But they are also early. Delivery challenges persist, and systemic editing of muscle cells across the body is still years from being fully optimized. Most CRISPR-based programs still rely on AAV vectors for in vivo delivery—bringing us back to the same issues of dose, immunogenicity and off-target exposure. The future of DMD treatment isn’t about choosing between gene therapy or small molecules, editing or exon-skipping. It’s about combining these tools in thoughtful, patient-centered ways. Some patients may benefit from gene transfer early in life. Others may rely on a foundation of small molecule therapies to delay progression or complement other interventions. Still others, especially those with cardiac involvement, may need targeted, organ-specific solutions. Regulators, researchers and investors must embrace this complexity. A one-size-fits-all approach is no longer viable. We must fund and advance multiple modalities in parallel, recognizing that each brings unique advantages—and that real progress in DMD will likely require synergy, not singularity. DMD patients and their families have waited long enough. It’s time we stop searching for the one solution and instead commit to building a comprehensive arsenal of tools to treat—and ultimately overcome—this devastating disease.

The company staked its position shortly after the FDA asked Sarepta to voluntarily stop all shipments of Elevidys, which is being investigated by the U.S. drug regulator after two patients died following treatment with the therapy earlier this year. As the controversy over the safety of Sarepta Therapeutics’ gene therapies comes to a head, the biotech is standing firm behind its approved Duchenne muscular dystrophy (DMD) treatment.The FDA, for its part, is asking the company to pull the drug from the market.Sarepta will continue to ship its gene therapy Elevidys to DMD patients who can still walk independently, the company said in a statement late Friday, citing its own “comprehensive scientific interpretation of the data, which shows no new or changed safety signals in the ambulant patient population.”“We look forward to continued discussions and sharing of information with the FDA in order to advance our shared purpose of protecting patient safety and informed access to care,” Sarepta added.The company staked its position shortly after the FDA asked Sarepta to voluntarily stop all shipments of Elevidys, which is being investigated by the U.S. drug regulator after two patients died following treatment with the therapy earlier this year.At the same time, the FDA revoked Sarepta’s platform technology designation—which can help hasten the FDA review process for new products stemming from the same platform—and placed Sarepta’s investigational gene therapy trials in limb-girdle muscular dystrophy on clinical hold.Sarepta’s limb-girdle program was already greatly diminished after the company on Wednesday announced a pipeline shakeup and hundreds of layoffs in a bid to save $400 million annually.The new clinical hold affects four Sarepta gene therapy assets, three of which the company had already discontinued last week, Sarepta noted in a Securities and Exchange Commission filing Monday. Sarepta said it plans to discuss a potential biologics license application for the fourth asset, SRP-9003, with the FDA once the clinical hold is lifted.The FDA action—and Sarepta’s refusal to step down on Elevidys—capped off a whirlwind week for the company, with the restructuring announcement Wednesday quickly followed by the revelation of a third patient death late Thursday and a tense call with analysts Friday morning.The third death of a patient on a Sarepta therapy occurred in a 51-year-old man with limb-girdle muscular dystrophy type 2D/R3 who participated in a phase 1 trial. He had not received Sarepta’s approved treatment Elevidys, but rather an investigational gene therapy coded SRP-9004. As with the prior deaths of patients who'd received Elevidys, the SRP-9004 patient died from acute liver failure. Sarepta said it was pausing development of SRP-9004 and many other gene therapy programs on Wednesday, prior to news of the latest fatality breaking, and the company made no mention of the issue during a conference call that same day.“We recognize that the death of any patient is heartbreaking, including the recent death of a 51-year-old non-ambulant Limb-Girdle Muscular Dystrophy (LGMD) patient,” Sarepta said in its Friday press release. The company stressed that the investigational gene therapy was intended to treat a different disease, administered using a different dose and manufactured under a different process than Elevidys. Still, Sarepta’s platform is now steeped in scrutiny, with the FDA noting in its announcement that the three deaths of Sarepta patients that have been reported “appear to have been a result of acute liver failure in individuals treated with Elevidys or investigational gene therapy using the same AAVrh74 serotype that is used in Elevidys.”The FDA said it revoked Sarepta’s platform technology designation “because, among other things, given the new safety information, the preliminary evidence is insufficient to demonstrate that AAVrh74 Platform Technology has the potential to be incorporated in, or utilized by, more than one drug without an adverse effect on safety.”While Sarepta executives repeatedly stressed last week that the latest patient death was unrelated to Elevidys, analysts at Jefferies wrote in a Sunday note that doctors, patients and their families may “rethink” treatment with the approved gene therapy in light of the latest developments.“[W]e wouldn’t be surprised if the patient community grew more divided” around Elevidys, the analysts added.With Sarepta refusing to pull Elevidys in ambulatory patients, it remains unclear if the FDA has the power to force a market withdrawal, the Jefferies team noted. The drug boasts full approval in walking DMD patients, as opposed to an accelerated nod, which the FDA can revoke if a drug fails to impress in subsequent confirmatory studies.Word that the FDA was contemplating an Elevidys market pull surfaced shortly after Sarepta hosted a conference call Friday to discuss the third patient death. A federal official was said to be “taking a hard look at pulling [Elevidys] from the market,” according to a statement Fierce Pharma received from the agency late last week.“We first heard of this potential request earlier in the day at the same time the public and our patient communities did, through media reports,” Sarepta noted in its release on the status of Elevidys shipments. Elevidys was initially approved in June 2023 in ambulatory DMD patients before winning a label expansion to treat those who are non-ambulatory a year later. Sarepta reported the first death of an Elevidys patient in March and a second in June of this year, which prompted the company to suspend use of the gene therapy in the commercial setting for non-walking DMD patients.After the second death, Sarepta said it'd seek FDA approval of an enhanced mitigation measure leveraging the immunosuppressant sirolimus to help patients on the approved treatment manage liver toxicity.