Tracking Therapeutic Progress of Gene-Editing Agent PBGENE-DMD for Duchenne Muscular Dystrophy

Jeff Smith, PhD

Over the last few years, the therapeutic landscape for Duchenne muscular dystrophy (DMD) has expanded significantly, with several exon-skipping treatments and even a gene therapy available for patients with the disease. Despite these advancements, patients still struggle with obtaining durable functional muscle improvements, leading to further pursuit of new-age approaches. One such in development is Precision Biosciences’ PBGENE-DMD, a first-in-class in vivo gene editing method that utilizes a novel proprietary ARCUS platform.

At the recently concluded American Society of Gene and Cell Therapy (ASGCT) Annual Meeting, Precision shared new preclinical data surrounding PGGENE-DMD in humanized mouse models. In mice, adeno-associated-delivered PGBENE-DMD restored functional dystrophin expression across cardiac and skeletal muscles, leading to sustained muscle improvement over 9 months. Based on the totality of the preclinical data, the company is planning to file an investigational new drug application (IND) and/or clinical trial application in 2025, with clinical data expected in 2026.

For greater insights on the data presented at ASGCT 2025, as well as the mechanism and rationale behind PBGENE-DMD, NeurologyLive® sat down with Jeff Smith, PhD, cofounder and chief research officer at Precision. Smith explained how the ARCUS-based approach precisely excises a “hot spot” mutation region, potentially benefiting up to 60% of patients with DMD by restoring near full-length dystrophin production. Furthermore, he detailed the rigorous safety and efficacy considerations unique to gene-editing advancement, and how a growing understanding of DMD genetics—particularly from microdystrophin and exon-skipping therapies—has informed more targeted, durable solutions like PBGENE-DMD.

NeurologyLive: What were the biggest takeaways from the data presented at ASGCT 2025? From a clinical perspective

Jeff Smith, PhD: The biggest takeaway from the data we presented at ASGCT 2025 from a clinical impact perspective was the functional durability we demonstrated for our PBGENE-DMD program. Precision shared a poster showing that a one-time treatment with PBGENE-DMD produced a functional improvement in muscle strength and resistance to injury from 3 to 6 months in a DMD mouse model and, importantly, maintenance of that functional improvement from 6 to 9 months. PBGENE-DMD enabled the mice to produce a functional dystrophin protein that was naturally expressed within multiple muscles, including the skeletal muscles, heart, intercostal muscles and the diaphragm, at levels expected to provide therapeutic benefits. Over the 9-month study duration, PBGENE-DMD-treated mice showed a significant resistance to muscle injury compared to untreated mice and sustained up to 92% of a healthy mouse’s maximum tetanic force output, a measure used to evaluate muscle strength.We also showed that PBGENE-DMD-edited dystrophin mRNA was found in muscle satellite stem cells that give rise to new muscle fibers, which could contribute to prolonged durability of the therapeutic benefit. All of the presented data suggests the potential for long-lasting therapeutic effects compared to standard gene therapy approaches for patients.

How does PBGENE-DMD function? Describe the mechanism and rationale behind this approach

PBGENE-DMD is designed to be a one-time treatment that targets the root cause of DMD by permanently editing the patient’s own DNA to produce a meaningful and lasting improvement in muscle function. In PBGENE-DMD, genes encoding two ARCUS nucleases are co-delivered to muscle fibers in a single viral delivery vector, called an adeno-associated virus (AAV). When expressed, the two ARCUS nucleases work together in muscle tissue to excise a specific “hot spot” region of the dystrophin gene that contains mutations responsible for approximately 60% of DMD cases. ARCUS cuts DNA in a unique way, producing complementary 3’ overhangs, or “sticky ends”, that are more likely to come back together for a precise excision of the “hot spot” and perfect re-ligation of the dystrophin gene. Removing this “hot spot” from the dystrophin gene restores production of a nearly full-length dystrophin protein from the native locus which provides therapeutic benefit.

There is currently no cure for DMD. Dystrophin is one of the largest genes in the human genome which makes it impossible to deliver a full-length gene to muscle in a single delivery vector as a gene therapy. Thus far, treatment approaches have fallen into two categories: delivery of microdystrophin as a gene therapy or repeated delivery of an exon skipper for the few patients with a mutation at an addressable exon. Microdystrophin is a tiny, synthetic fusion of a small subset of domains from dystrophin that need to be constantly expressed from the viruses they were delivered on. Microdystrophins are less functional and less stable than full-length dystrophin due to the large number of missing domains. As a gene therapy, synthetic microdystrophins can be diluted or silenced as myofibers turn over or grow over time, reducing the therapeutic effect.

Part of the rationale behind PBGENE-DMD was to edit the native dystrophin gene in the patient’s genome so a near full-length dystrophin protein would be produced for potentially better therapeutic benefit. Directly editing the dystrophin gene within the genome at the native locus, especially in muscle satellite stem cells, will allow for propagation to new muscle fibers and prevent it from being diluted or silenced like a gene therapy for potentially better durability of therapeutic benefit.

Exon skipping therapies, similar to PBGENE-DMD, produce a fuller-length dystrophin protein but only address a mutation in a single exon. As such, only a small percentage of DMD patients can benefit from each product. The rationale for excising the exon 45-55 “hot spot” with PBGENE-DMD was to address up to 60% of the DMD patient population with one therapy. Additionally, we know that a dystrophin protein lacking exons 45-55 is functional in humans. Some Becker Muscular Dystrophy (BMD) patients have this same dystrophin deletion and often have a favorable prognosis, are asymptomatic, and are diagnosed later in adulthood.

What considerations go into advancing a gene-editing therapy through the pipeline?

The considerations boil down to the same as any other therapy - safety and efficacy - but how we evaluate these for a gene-editing treatment requires a much higher level of molecular detail.

For safety, we consider the characteristics of our AAV such as empty versus full ratio, quality, dose, and immunosuppression. As a gene editor, we also need to fully understand all possible off-targets edits, frequency of any off-targets edits related to dose and tissue, and the impact that any off-target edits could have on the cells. We also need to evaluate any potential germline delivery and editing. Fortunately, we have had numerous interactions with regulatory bodies and have reached agreement on our data package for safety.

For efficacy, we have evaluated the therapeutic benefits of PBGENE-DMD in disease model mice over multiple doses and demonstrated therapeutic benefits that improve from 3 to 6 months and remain durable to 9 months, which is a major portion of the mouse’s life. Histology measurements suggest that PBGENE-DMD is producing an edit that leads to dystrophin expression in a large number of myofibers and produces edits in satellite stem cells. As a gene editor, we also must consider at the DNA level how frequently PBGENE-DMD produces a productive edit that will result in dystrophin and how stable these gene edits are within the cells over time. We have demonstrated that the majority of the edits made by PBGENE-DMD would result in productive dystrophin production and that these edits remain stable over time.

How has our understanding of the genetic makeup of DMD evolved over the years?

It was not that long ago that we were completing the human genome project in the early 2000’s. I was already in the field of gene editing, and we were all very excited how a complete human genome sequence would change our understanding of genetic diseases and open new opportunities for treatment. The sequences of various dystrophin truncations in patients with Muscular Dystrophy suggested that smaller dystrophins could retain some function. The simultaneous development of AAV viral delivery helped the first attempts at gene therapy with a microdystrophin, but major gains against primary endpoints have remained elusive.

Exon skippers have been developed with the promise of a fuller-length dystrophin, but this approach comes with limitations - small percentages of addressable patients and the need for continual treatment. Both therapies, microdystrophins and exon skippers, have limitations as it relates to therapeutic benefit. These therapies were important advances, and a deeper understanding of their limitations provided key insights into an approach that may be more effective and more durable. For example, an understanding of the 45-55 deletion common to many mild or asymptomatic Becker Muscular Dystrophy patients and progress in gene editing has led to new learnings and potential new treatment approaches. More recently, gene editors like PBGENE-DMD are being tested with the potential advantages of durability and a more functional, fuller-length dystrophin protein. Considering the evolution of DMD therapies over the last 25 years, there are many reasons to be optimistic about treatments for DMD patients in the near future.