a study of the safety and efficacy of prime editing (pm359) in participants with p47phox autosomal recessive chronic granulomatous disease (cgd )

Conditions: Chronic Granulomatous Disease; Granulomatous Disease, Chronic

Summary: 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.

Eligibility criteria:
inclusion criteria: * autosomal recessive chronic granulomatous disease due to the delgt mutation in ncf1 causing dysfunction of p47phox * treated and followed for at least the past 2 years in a specialized center * willingness to participate in this study as well as a long-term follow-up study with the understanding that the total participation is 15 years * at least 1 prior severe cgd-related infection or an ongoing severe cgd-related infection requiring therapy or that is refractory to standard therapy; or an autoimmune or inflammatory condition related to cgd that is active or requiring therapy to maintain remission. exclusion criteria: * for participants younger than 16 years of age: known, willing, and available 10/10 (a,b,c,dr,dq) hla-matched related donor (10/10 mrd) * active bacteremia or fungemia * ongoing inflammatory condition that is ≥ ctcae v5.0 grade 3 despite high-dose steroids (≥ 0.5 mg/kg/day of prednisone and/or equivalent). * any contraindication which in the opinion of the transplant physician would make the participant ineligible to undergo autologous hsct, including, but not limited to: 1. contraindication to mobilization and apheresis, including severe allergic reaction to receipt of any medication or other drug substance required for mobilization and apheresis (e.g., g-csf, plerixafor) or pm359 manufacture (e.g., dmso). 2. contraindication to receipt of the conditioning agent, busulfan. * positive for presence of human immunodeficiency virus (hiv)-1 or hiv-2, or active infection with hepatitis b virus (hbv), or hepatitis c virus (hcv). * inadequate organ function, including known chronic advanced end-organ damage which in the opinion of the investigator would put the participant at risk for undergoing hsct * prior or current malignancy or myeloproliferative disorder (excluding stage 1 or lower, fully treated/excised malignant and pre-malignant disease of the skin, cervix or colon). * any other condition that, in the opinion of the investigator, may compromise the safety or compliance of the participant or would preclude the participant from successful study completion, including participant/parent/guardian unable or unwilling to comply with the protocol requirements. * pregnancy or breastfeeding in a postpartum female or absence of adequate contraception for fertile participants. females of childbearing potential and non-sterile male participants who are or may become sexually active with female partners of childbearing potential are required to use highly effective contraception from screening through at least 12 months after drug product infusion. * participation in another clinical study with an investigational drug within 30 days of screening or at least 5 times the half-life of the investigational drug (whichever is longer), or any prior receipt of gene therapy or hematopoietic stem cell transplant.

Keywords: granulomatous disease, chronic chronic granulomatous disease autosomal recessive chronic granulomatous disease genetic therapy gene therapy gene editing genome editing stem cell transplantation transplantation, stem cell hematopoietic stem cell transplantation transplantation, hematopoietic stem cell