“It represents the first time an in vivo HSC-directed gene insertion therapy has been evaluated in a patient," said CEO Jim Burns in a statement.
Ensoma has officially dosed the first participant in its Phase 1/2 clinical trial of EN-374 for the treatment of X-linked chronic granulomatous disease (X-CGD) community, according to a press release from the company on December 1, 2025. EN-374 is the first in vivo hematopoietic stem cell (HSC)-directed gene insertion therapy to reach clinical evaluation, representing a potentially simpler and more accessible approach to addressing the root cause of X-CGD.1
The investigational therapy is designed as a one-time treatment designed to restore function of the infection-fighting NADPH oxidase enzyme complex, critical for immune defense in humans having an impaired CYBB gene. By engineering neutrophils arising from these HSCs to express the functional CYBB protein, EN-374 aims to correct the defective NADPH oxidase enzyme complex that drives vulnerability to life-threatening infections in X-CGD. Preclinical studies have demonstrated “therapeutic restoration of CYBB protein expression and NADPH oxidase activity in circulating neutrophils," according to Ensoma.
Jim Burns, CEO of Ensoma, emphasized both the scientific and clinical significance of this step forward, stating the dosing "represents the first time an in vivo HSC-directed gene insertion therapy has been evaluated in a patient, opening the door to a potentially simpler approach to addressing the root cause of this life-threatening disease."
The Phase 1/2 trial is an open-label, multicenter study designed to evaluate safety, tolerability, pharmacodynamics, and preliminary efficacy, with the goal of identifying a future development dose. Key safety outcomes include the incidence of treatment-emergent, treatment-related, and serious adverse events.
Efficacy will be assessed using biomarkers central to X-CGD, including:
Adult participants will be treated first in the dose-escalation phase, followed by a pediatric cohort once adult dosing is complete.
“People living with X-CGD are highly susceptible to recurrent, life-threatening bacterial and fungal infections, which can be severe and accompanied by lengthy hospitalizations," said Ahmad Rayes, MD, principal investigator, associate professor of pediatrics in the Pediatric Immunology and Hematopoietic Cell Transplantation/Cellular Therapy Program at the University of Utah and Intermountain Primary Children’s Hospital in Salt Lake City.
"Current treatment options may reduce infection risk but often fall short of meaningful immune restoration, particularly for children. Evaluating an in vivo HSC-directed gene insertion therapy offers real hope to families who have been waiting for safer, more accessible and more durable solutions," said Rayes.
X-CGD accounts for 60–70% of all chronic granulomatous disease cases and is caused by mutations in the CYBB gene. Individuals face a lifelong risk of recurrent, severe bacterial and fungal infections, chronic inflammation, and related complications, with a median life expectancy of approximately 45 years. Standard therapies—including antimicrobials, interferon gamma, and allogeneic stem cell transplantation—carry significant limitations and burdens.
Earlier this year, Ensoma received both rare pediatric disease and orphan drug designations for EN-374,
As detailed in that report, EN-374 is designed to deliver a functional CYBB gene in vivo using a promoter for selective expression in neutrophils—the primary dysfunctional cell type in X-CGD. Ensoma’s Drew Dietz, MD, MSCR, emphasized the importance of these designations, stating that they “highlight the significant medical need in chronic granulomatous disease.”
The rare pediatric disease designation offers the potential for a priority review voucher, while orphan drug designation provides benefits such as up to 7 years of market exclusivity, tax credits, and exemption from certain FDA fees.
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