FDA Clears ARCUS Editor for Duchenne Hot-spot

DMD is caused by disruptive variants in the X-linked DMD gene that eliminate functional dystrophin, a large cytoskeletal protein that stabilises muscle fibres during contraction; without it, muscle damage accumulates from early childhood, with progressive weakness and cardiopulmonary complications. Current genetic strategies mostly work around the problem rather than fixing it. Exon-skipping drugs restore some dystrophin by redirecting RNA splicing, but require repeat dosing and tend to yield modest protein levels.

Microdystrophin gene therapies take a different route, delivering a shortened synthetic construct via AAV, yet the protein must be continually expressed from vector DNA that may dilute as muscle grows and regenerates – and in a minority of patients, the approach has triggered clinically significant immune toxicities. The recently approved microdystrophin construct from Sarepta Therapeutics has not been demonstrated to produce significant functional improvements in clinical studies.

PBGENE-DMD is pitched as a different bet: instead of adding a new gene cassette, it rewrites the patient's own dystrophin locus so the corrected gene can keep producing a functional protein as muscle turns over.

Dual ARCUS cuts delete exons 45–55 to restore the reading frame

Mechanistically, PBGENE-DMD uses Precision's ARCUS platform – engineered from a homing endonuclease originally derived from I-CreI – to cut DNA at chosen genomic sites. The therapy is delivered by a single AAV encoding two ARCUS nucleases designed to cut on either side of the exon 45–55 region; the intervening stretch is excised, and the chromosome rejoined, bringing upstream and downstream exons back into an in-frame transcript.

The edit effectively links exon 44 to exon 56, removing a segment that harbours many DMD-causing deletions and duplications and converting a Duchenne-style frameshift into a Becker-like, internally truncated but functional dystrophin – one that retains approximately 80% of the native sequence, compared with around 34% for current approved microdystrophin constructs. This “genomic exon-skipping” idea is grounded in human genetics: some people with Becker muscular dystrophy carry large in-frame deletions across this region and still have relatively mild symptoms, suggesting that a shorter dystrophin – so long as it keeps the key functional domains – can still stabilise muscle. It is also consistent with clinical-pathology observations that very low dystrophin amounts can meaningfully shift disease severity, underscoring why even partial restoration might matter.

What has made the company emphasise durability is not only the permanence of a chromosomal edit, but where the edit lands. Skeletal muscle relies on satellite cells – resident stem cells that continuously fuse into damaged fibres to repair them – and any therapy that edits only mature myofibres risks being gradually diluted as those fibres are replaced by new ones grown from unedited progenitors. Precision reports the detection of dystrophin mRNA in PAX7-positive cells, a satellite-cell marker, suggesting that at least some of the stem and progenitor compartments are being reached. Whether that degree of satellite-cell editing is sufficient for multi-year clinical durability will be a key question the trial will need to answer.

Mouse data suggest durable force preservation across key muscles

The most detailed efficacy readout disclosed to date comes from mouse work presented ion a poster at the World Muscle Society meeting in October 2025. In a humanised DMD model (hDMDdel52/mdx) dosed at three weeks of age – framed as roughly analogous to treating boys aged four to seven – Precision reports restoration of dystrophin across multiple skeletal muscles and the heart, with dystrophin-positive fibres detectable by immunofluorescence and protein restoration quantified by capillary western blotting.

Functionally, in vivo muscle testing indicated that treated mice retained 81–84% of the maximal force and 89–92% of the tetanic force observed in healthy animals for up to 9 months after dosing. Surprisingly, performance was actually stronger at six months than at three. This is an unexpected pattern in a degenerative model that the team reads as a gradually accruing benefit as corrected dystrophin becomes established across the muscle. The poster also points to effects in the heart and diaphragm – tissues that often shape long-term outcomes in DMD. It argues that editing is not confined to a single limb muscle but extends to multiple clinically relevant targets.

The FDA clearance opens the door to the first human test

With the FDA now allowing the programme to proceed, Precision plans to initiate the Phase 1/2 study in ambulant patients whose mutations fall within the exon 45–55 region – the largest molecular subset, potentially covering approximately 60% of boys with DMD. The trial will assess safety and tolerability while also looking for early signs of biological activity – such as near full-length dystrophin in muscle biopsies and changes in functional measures – alongside an immune-modulation regimen informed by what systemic AAV programmes have taught the field about managing immune responses.

Initial data from multiple patients are expected by year-end 2026; following supportive results from at least 10 patients, the company plans to meet with the FDA to agree on a regulatory path forward. PBGENE-DMD has already received both Rare Paediatric Disease and Orphan Drug Designations from the FDA, the former potentially entitling Precision to a Priority Review Voucher on approval – an asset of considerable commercial value in the rare disease field – and the latter providing up to seven years of market exclusivity.

PBGENE-DMD is Precision's second wholly owned programme to reach the clinic, following PBGENE-HBV for chronic hepatitis B, which is currently in the global Phase 1/2a ELIMINATE-B trial with multiple dosing cohorts underway. The company has stated its current cash position is sufficient to advance both programmes through Phase 1 readouts. In the near term, the key translational test will be whether the gene excision can be delivered at sufficient efficiency in human skeletal and cardiac muscle – without unacceptable immune toxicity – and whether edited fibres and edited progenitors together translate into sustained functional stabilisation.

This article is based on a press release from 11 February 2026 and a poster presented at the World Muscle Society Conference on 7–11 October 2025 in Vienna, Austria.