In a landmark moment for genetic medicine, researchers have reported the first peer-reviewed clinical use of prime editing to treat human patients. The New England Journal of Medicine article describes PM359, an autologous hematopoietic stem-cell (HSC) therapy that aims to correct the deletion of two base pairs, a guanine followed by a thymine (delGC), in NCF1, which is the primary cause of p47phox-deficient chronic granulomatous disease (p47-CGD). Both patients treated in this first-in-human study remained free of new CGD-related complications during the first few months of follow-up.

Two bases, two patients, two successes

CGD is a rare inherited immunodeficiency marked by defective NADPH oxidase activity, resulting in recurrent bacterial and fungal infections and chronic inflammation. About one quarter of all CGD cases in North America and Europe result in p47-CGD, of which about 80% can be attributed to variants in NCF1, which encodes the p47phox subunit of the NADPH oxidase complex. Most affected individuals carry the same two-base pair deletion, also present in two neighboring pseudogenes with over 99% sequencing homology. This implies that most individuals with p47-CGD have six potentially correctable delGT alleles.

PM359 uses prime editing to convert the delGT sequence to GTGT in NCF1 and, when present, its pseudogenes. Patients’ own CD34+ HSCs are electroporated to deliver the molecular machinery for prime editing ex vivo before being reinfused following busulfan conditioning. To test for safety and efficacy of PM359, the Prime Medicine researchers first performed preclinical studies using prime editing of CD34+ cells from four individuals with p47-CGD. PM359 yielded strong correction rates, with 82% of colony-forming cells carrying at least one repaired allele and fewer than two percent showing unintended edits.

When transplanted into immunodeficient mice, corrected cells persisted for at least 16 weeks and produced functional myeloid cells capable of generating reactive oxygen species—the antimicrobial activity missing in CGD. Unlike Cas9-nuclease editing, prime editing caused no detectable genome loss, chromosomal abnormalities, or off-target mutations. Edited cells showed normal engraftment and reduced the elevated interferon signaling characteristic of CGD.

Two men, aged 18 and 57, received PM359 after myeloablative conditioning. Both had longstanding CGD with complications such as pulmonary infections, hepatic abscesses, and CGD-associated colitis. Their PM359 products carried substantial levels of corrected alleles (68% and 91% of colony-forming cells).

Engraftment was rapid: neutrophils by days 14–16 and platelets by days 12–19, with no PM359-related serious adverse events. Within one month, both patients achieved near-normal neutrophil NADPH oxidative activity, with ?69% dihydrorhodamine-positive neutrophils at healthy-donor intensity. Restored NADPH oxidase activity levels remained stable for at least six months. Bone marrow testing confirmed durable correction, and p47phox protein was detected in circulating neutrophils. Clinically, both patients remained free of new infections or inflammatory complications; the younger patient discontinued antimicrobial prophylaxis, while the older patient showed improvements in biomarkers for inflammatory bowel disease.

A bittersweet milestone

The results provide the first demonstration that prime editing can precisely correct a disease-causing mutation in human HSCs and restore immune function without double-strand DNA breaks or donor transplantation. Although the study involved only two participants, the findings establish prime editing as a viable therapeutic platform with potential application across many monogenic diseases.

Despite this strong early data, Prime Medicine has decided to wind down its CGD program due to the small market size. “We may have effectively cured two patients, but the market is simply too small to sustain a company of our scale,” CEO Allan Reine told Inside Precision Medicine. The clinical trial remains active for long-term patient follow-up, but no additional participants will be enrolled.

Prime Medicine is now advancing programs targeting liver and lung diseases and immune-system cancers, with its Wilson’s disease program leading the pipeline. The company aims to leverage the modularity of prime editing to expand into a broad range of genetic, immunologic, infectious, and common diseases affecting millions.