This study is NOT currently recruiting participants.
Background: Chronic granulomatous disease (CGD) affects the immune system. It is inherited, which means that people with this disease were born with a mutated gene. The infections and related illnesses CGD can cause can be controlled with lifelong drugs. But researchers are seeking a way to cure CGD by fixing the mutated gene.
To test a new treatment (PM359) in people with CGD.
People aged 6 years and older with CGD. They must have a specific mutated gene that causes CGD.
Participants will be screened with blood and urine tests. They will have tests of their heart and lung function.
Participants will receive drugs to release stem cells from their bone marrow into the blood stream. Then they will undergo apheresis: Blood will be taken from the body through a needle. The blood will pass through a machine that separates out the stem cells. The remaining blood will be returned to the body through a different needle. The collected stem cells will be edited in a lab to insert a healthy gene to create PM359.
Several weeks later, participants will enter the hospital for 3 to 4 weeks. In the first week, they will have drug treatments to prepare their bodies for the PM359. Then the PM359 will be administered into a vein. Participants will remain in the hospital until they are producing healthy new blood cells.
Participants will have follow-up visits for 3 years. Long-term follow-up will continue another 12 years.
INCLUSION CRITERIA:
Participants must meet the following criteria:
1. Autosomal recessive chronic granulomatous disease due to the delGT mutation in NCF1 causing dysfunction of p47phox, as determined by the following 3 criteria:
a. Medical history consistent with CGD
b. Laboratory evidence of compromised NADPH oxidase activity as measured by DHR assay
c. Genetic analysis confirming the c.75_76del (delGT) sequence in NCF1/B/C and excluding the presence of other (non-delGT) pathogenic variants in NCF1/B/C or in other-CGD-associated genes.
2. Treated and followed for at least the past 2 years in a specialized center that maintained detailed medical records on infections, autoimmune and inflammatory conditions, hospitalizations, and antimicrobial and immunomodulatory use (including IFN-gamma)
3. Karnofsky performance status of >= 60 for participants >= 16 years of age or a Lansky performance status of >= 60 for participants < 16 years of age (Note that the sentinel participants of each cohort must have a Karnofsky or Lansky score of at least 80)
4. 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 post-infusion
5. Well-documented within the individual s medical history, either or both 5a or 5b:
a. At least 1 prior severe infection characteristic of CGD requiring hospitalization and/or parenteral antimicrobial therapy OR current or ongoing presence of known, refractory, active severe infection characteristic of CGD requiring concurrent antimicrobial therapy or for which antimicrobial therapy is ineffective.* Organisms that are characteristic of CGD include, but are not limited to: Staphylococcus aureus, Nocardia spp., Serratia marcescens, Burkholderia cepacea, Salmonella spp, Aspergillus spp, and Klebsiella spp.
OR
b. Presence of an autoimmune or inflammatory complication of CGD that is active or requiring therapy to maintain remission
6.
a. For Cohort 1: Participants at least 18 years of age at the time of consent, and able to provide written consent.**
b. For Cohort 2: Participants aged 12 to 17, inclusive, at the time of consent or assent (as applicable), and able to provide written consent (adults, or legal guardians, as applicable) or assent (adolescents and pediatric participants).**
c. For Cohort 3: Participants aged 6 to 11, inclusive, at the time of consent or assent (as applicable), and able to provide written consent (legal guardians, as applicable) and assent (adolescents and pediatric participants)
*Note that treatment is staggered such that at least 1 participant who is free of active infection and severe inflammation has been treated in each cohort and meets criteria for safety and biological efficacy before participants with active infection and/or severe inflammation can proceed past Screening for eligibility. New infections or inflammatory conditions occurring between signing of the ICF and drug product infusion may delay study procedures, but will not disqualify eligible participants if they are treated successfully, and participants continue to meet other eligibility criteria.
**If approved by regional health authority and local IRB/EC, the second and subsequent participants in Cohort 1 may be aged 16 years and above, and Cohort 2 will include participants aged 12 to 15 years.
EXCLUSION CRITERIA:
1. For participants younger than 16: known, willing, and available 10/10 (A,B,C,DR,DQ) HLA-matched related donor (10/10 MRD)
2. Active bacteremia or fungemia (i.e., blood culture growth of bacteria or fungus), that is confirmed not to be due to specimen contamination.
3. Ongoing inflammatory condition that is >= CTCAE v5.0 Grade 3 despite high-dose steroids (>= 0.5 mg/kg/day of prednisone and/or equivalent).
4. Any contraindication which in the opinion of the transplant physician would make the participant ineligible to undergo autologous HSCT, including, but not limited to:
a. 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).
b. Contraindication to receipt of the conditioning agent, busulfan.
5.
a. 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). (Note that participants with positive hepatitis B core and/or hepatitis B-e antibodies are eligible provided viral load is negative by quantitative polymerase chain reaction [qPCR]. Also note that participants who are positive for anti-hepatitis C antibody are eligible as long as they have a negative HCV viral load by qPCR).
b. Where clinically and/or regionally indicated, other tests may be performed, in which case positive results may exclude the participant from participating. For example, and non-exclusively: human T-lymphotropic virus-1 (HTLV-1) or HTLV-2, syphilis (rapid plasma reagin [RPR]), tuberculosis, toxoplasmosis, Trypanosoma cruzi, West Nile Virus, or parvovirus. As applicable, should a potential study participant test positive for a clinically and/or regionally-specific viral infection, that participant may be re-screened after documented resolution of that infection, or after successful treatment of other pathogens and documented resolution of infection.
6. 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 (note: isolated laboratory abnormalities may be repeated if inconsistent with participant history):
a. Hematologic:
-Chronic anemia, defined as hemoglobin < 8 g/dL in the absence of packed red blood cell (pRBC) transfusions, or requirement of recurrent pRBC transfusions to sustain hemoglobin >= 8 g/dL.
-Neutropenia (ANC < 1.0 x 10^9/L).
-Thrombocytopenia (platelet count < 100 x 10^9/L).
-Uncorrected bleeding disorder. Prothrombin time (PT, and/or international normalized ratio, INR) or activated partial thromboplastin time (aPTT) > 2 x the upper limits of normal (ULN). Participants with a correctable deficiency controlled on medication will not be excluded.
-Unable to receive or intolerant of blood product transfusions despite appropriate pre-medication and blood product screening and treatment.
-History of significant immunodeficiency not due to CGD.
-Molecular or cytogenetic abnormalities known to be associated with hematopoietic defect or high risk of oncogenesis on peripheral blood or bone marrow. Assessments to evaluate this criterion may include karyotype on bone marrow to assess cytogenetic abnormalities or a next-generation sequencing (NGS) blood or bone marrow analysis on a panel of genes that may be responsible for myeloid or lymphoid malignancy development and frequently associated with leukemias, myeloid proliferative syndromes (MPS) or myeloid proliferative neoplasms (MPN).
b. Pulmonary:
-Resting oxygen saturation by pulse oximetry < 90% on room air.
-Diffusion capacity of carbon monoxide (DLCO) < 50% of predicted value after correction for anemia, if present, or FEV1 < 60% of predicted value. Younger participants who cannot cooperate or perform pulmonary testing can be assessed using pulse oximetry alone.
c. Cardiac:
-Clinically significant uncorrected congenital cardiac malformation.
-Unstable angina, clinical evidence of unstable coronary disease, or history of myocardial infarction within prior 2 years.
-Clinically evident, poorly controlled congestive heart failure, or left ventricular ejection fraction < 40% by echocardiogram.
-History of poorly controlled symptomatic atrial arrhythmia, or any history of unstable ventricular arrhythmia.
-Persistent hypotension or uncontrolled hypertension (adult hypotension defined as systolic blood pressure [SBP] < 80 mmHg, diastolic blood pressure [DBP] < 50 mmHg, or any requirement for medication to raise blood pressure; adult hypertension defined as SBP > 180 mmHg or DBP > 120 mmHg; for participants < 18 years of age, hypotension is defined as below the 5th percentile and hypertension is defined as above the 95th percentile, as per the National Heart, Lung, and Blood Institute [NHLBI] Blood Pressure Norms by Age/Height Percentiles .
-Clinically significant abnormality detected on electrocardiogram, confirmed by a cardiologist, that could pose elevated risk during HSCT.
d. Neurologic/ Psychiatric:
-Uncontrolled seizure disorder.
-Diagnosis of significant psychiatric disorder that could impede the ability to participate in the study.
e. Renal:
-Baseline estimated glomerular filtration rate < 50 mL/min/1.73 m^2, as determined using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation (http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm) for >= 18 years of age, and Bedside Schwartz equation or Chronic Kidney Disease in Children under 25 (U25 CKID) calculator (per institutional preference) for < 18 years of age.
-Recurrent or uncorrectable electrolyte abnormalities of Grade 3 or 4 by the CTCAE v5.0.
f. Hepatic:
-Persistent, recurrent aspartate transaminase or alanine transaminase value > 3 x the ULN or direct bilirubin value > 2 x the ULN. Bilirubin elevations that are due to a confirmed diagnosis of Gilbert Syndrome are not considered exclusionary.
-Known history of liver cirrhosis, nodular regenerative hyperplasia, or significant fibrosis. Potential participants suspected of having advanced liver disease should be assessed for the possibility of liver cirrhosis or significant fibrosis.
7. 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).
8. 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.
9. 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.
10. 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.
a. Administration of gamma-interferon within 30 days before initiation of mobilization and conditioning.
b. Receipt of granulocyte infusion within 6 months of initiation of conditioning.