This is an open-label, single-arm, multicenter Phase 1/2 study evaluating the safety and efficacy of gene therapy by transplantation of Prime Edited autologous CD34+ stem cells modified ex vivo (PM359) in participants with autosomal recessive Chronic Granulomatous Disease (CGD) caused by mutations in the NCF1 (Neutrophil Cytosolic Factor 1) gene.
Chronic Granulomatous Disease (CGD) is a rare genetic disease affecting the white blood cells, leading to failure of innate immunity against a variety of human pathogens and is also associated with autoimmune and inflammatory conditions. Approximately 20-25% of people with CGD inherit a mutation commonly known as "delGT" in both copies of the NCF1 gene, which encodes the p47phox protein. This study seeks to understand the safety and efficacy of a new gene editing technology, known as Prime Editing, in participants with autosomal recessive CGD caused by the delGT mutation in NCF1. Autologous CD34+ cells are collected from the participant via mobilization and apheresis, shipped to a central manufacturing facility and modified using Prime Editing to 'correct' the delGT mutation causing p47phox CGD. After manufacture, the Prime Edited stem cells (PM359) will be shipped to the study site, where they will be infused back into the participant following a preparative procedure known as conditioning. The study will initially enroll adult participants (aged ≥ 18) and plans to then move into adolescents aged 12 - 17, followed by children aged 6 - 11.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
12
Single dose of PM359 administered autologously by intravenous (I.V.) infusion following myeloablative conditioning with busulfan
University of California Los Angeles Medical Center
Los Angeles, California, United States
NIH Clinical Center
Bethesda, Maryland, United States
The Children's Hospital at Tristar Medical Group/Sarah Cannon Center for Blood Cancers
Nashville, Tennessee, United States
CHU - Sainte Justine Hospital
Montreal, Quebec, Canada
Safety of administration of PM359, as quantified by frequency of adverse events (AEs) after drug product infusion
Time frame: PM359 infusion through Month 12 after PM359 infusion
Percentage of participants with sustained reconstitution of NADPH oxidase activity in neutrophils
Time frame: At Month 6 and Month 12 after PM359 infusion, as compared to baseline
Frequency of all drug product-related AEs, ≥ Grade 3 AEs, and serious adverse events (SAEs)
Time frame: Signing of ICF through Month 36 following PM359 infusion
Time to neutrophil engraftment
Time frame: From PM359 infusion through engraftment, typically within 2-3 weeks but assessed up to 36 months
Transplant related mortality
Time frame: From PM359 infusion, assessed at 100 Days and 1 Year post-PM359 infusion
Overall survival
Time frame: From PM359 infusion, assessed at 1 Year and 3 Years post-PM359 infusion
Incidence of acute graft-versus-host disease (GvHD)
Time frame: From PM359 infusion through Month 36
Incidence of graft failure or rejection
Time frame: From PM359 infusion through Month 36
Durability of multi-lineage hematopoietic cell reconstitution
Time frame: Assessed at 12, 24 and 36 months following PM359 infusion
Percentage of participants with clinical evidence of malignancy, pre-malignancy or myelodysplasia
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University College of London Hospital
London, England, United Kingdom
Time frame: From PM359 infusion through Month 36
Percentage of participants with sustained reconstitution of NADPH oxidase activity
Time frame: Assessed at Month 6 and Month 12 after PM359 infusion
Percentage of participants with sustained reconstitution of NADPH oxidase activity
Time frame: Assessed at Months 3, 18, 24 and 36 after PM359 infusion
Reconstitution of NADPH oxidase activity in peripheral granulocytes, as measured by DHR assay
Time frame: Months 1, 2, 3, 6, 12, 18, 24, and 36 after PM359 infusion
Frequency of new or worsening severe bacterial or fungal infections requiring anti-microbial therapy, as compared to baseline
Time frame: From Month 6 following PM359 infusion through Month 36
Frequency of any new or worsening moderate or greater CGD associated infection requiring anti-microbial therapy with confirmed microbiology demonstrating bacterial or fungal origin consistent with CGD-related pathology, as compared to baseline
Time frame: From Month 6 following PM359 infusion through Month 36
Frequency of autoimmune or inflammatory, non-infectious processes consistent with CGD, with symptom severity moderate or greater, as compared to baseline
Time frame: From 1 Year following PM359 infusion through Month 36
Resolution of pre-existing active infections (defined as infection present at time of study enrollment and ongoing at time of PM359 infusion) following PM359 infusion
Time frame: From PM359 infusion until resolution of active infection, assessed up to Month 36
Resolution of pre-existing autoimmune or inflammatory (non-infectious) processes (defined as autoimmune or inflammatory processes present at time of study enrollment and ongoing at time of PM359 infusion) following PM359 infusion
Time frame: From PM359 infusion until resolution of autoimmune or inflammatory process, assessed up to Month 36