Base Editing for Mutation Repair in Hematopoietic Stem & Progenitor Cells for X-Linked Chronic Granulomatous Disease

Launched by NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES (NIAID) · Mar 21, 2024

Keywords

ClinConnect Summary

This clinical trial is investigating a new treatment for X-Linked Chronic Granulomatous Disease (CGD), a rare immune disorder that makes it hard for the body to fight infections. The study aims to see if a process called base editing can fix the genetic mutation responsible for CGD in a patient's own stem cells. By correcting this mutation, researchers hope to improve the function of white blood cells, which are crucial for fighting infections, and reduce the number of infections these patients experience.

To participate in the trial, men aged 18 and older with a specific mutation in the CYBB gene may be eligible. Participants will go through a procedure to collect their stem cells, which will then be treated with base editing. After receiving chemotherapy to prepare their bodies, they will receive their edited stem cells and stay in the hospital until their immune systems recover. Follow-up visits will continue for up to 15 years to monitor their health and the effectiveness of the treatment. It's important to note that participants must meet certain health criteria, and those with specific infections or health conditions may not be eligible.

Gender

MALE

Eligibility criteria

• * INCLUSION CRITERIA:
• • -\>= 18 years of age.
• • Confirmed CYBB c.676 C\>T mutation.
• • Male patients.
• • Clinically stable and eligible to undergo apheresis and conditioning chemotherapy.
• • -\>=5 x 10\^6 cryopreserved cells/kg body weight available for study product manufacturing.
• • History of at least one prior serious infection or inflammatory complication requiring hospitalization despite conventional therapy.
• • In the experience of a qualified clinical investigator, the patient has a poor prognosis.
• * Able and willing to use a highly effective method of contraception, AND partner has communicated her willingness through subject to do same, if engaging in potentially reproductive sex from the signing of the informed consent and for 6 months after IMP infusion. Acceptable methods of contraception include the following:
• • Hormonal contraception in continuously effective use by female partner.
• • Male or female condom with spermicide as indicated.
• • Diaphragm or cervical cap in consistent and effective pattern of use with a spermicide by female partner.
• • Intrauterine device in-situ throughout above period by female partner.
• EXCLUSION CRITERIA:
• Individuals meeting any of the following criteria will be excluded from study participation:
• • Untreated, acute infection.
• • Elevated anti-gp91 specific autoantibodies \>2 x ULN
• • Elevated anti-gp91 specific T cells (\>10 fold)
• • Anti-platelet antibody screening with \>1 anti-platelet antibody positive in the presence of an ongoing brain infection; OR \>1 anti-platelet antibody positive and considered unsafe for study participation after consultation with hematology specialist.
• • Known hypersensitivity to busulfan or any component of the product.
• • Contraindications for administration of busulfan.
• • Any current or pre-existing hematologic malignancy.
• • Chronic infections that are considered unsafe for participation in the study by Infectious Disease Consultant.
• • Cardiac abnormalities and neurological abnormalities that are deemed unsafe to participate in the study.
• • Childhood malignancy (occurring before 18 years of age) in the patient or a first degree relative, or previously diagnosed known genotype of the participant conferring a predisposition to cancer (no DNA or other testing for cancer predisposition genes will be performed as part of the screen for this protocol).
• • Hematological parameters unsafe for apheresis or above Grade 2 Common Terminology Criteria for Adverse Events (CTCAE) criteria until improved.
• • Hepatic dysfunction- alanine aminotransferase (ALT \>3.0 - 5.0 x upper limit of normal \[ULN\]), aspartate aminotransferase (AST \>3.0 - 5.0 x ULN), bilirubin (\>1.5 - 3.0 x ULN).
• • Renal dysfunction-serum creatinine \>1.5 - 3.0 x ULN or creatinine clearance 59-30 mL/min/1.73 m\^2.
• • Coagulation dysfunction- Prothrombin INR or Partial thromboplastin time \>2 x ULN (patients on controlled anticoagulation agents will not be excluded for therapeutic levels).
• • Uncontrolled hypertension- Systolic BP 140-159 mm Hg or diastolic BP 90-99 mm Hg.
• • Abnormal blood chemistries- Hyperkalemia (K \>5.5 - 6.0 mmol/L), Hypokalemia (\<LLN - 3.0 mmol/L and requiring intervention); OR Hypercalcemia (corrected serum calcium \>11.5 - 12.5 mg/dL), Hypocalcemia (corrected serum calcium \<8.0 -7.0 mg/dL)
• • These values exclude false abnormalities secondary to hemolysis.
• • Cytogenetic abnormalities evidenced on bone marrow aspirate.
• • Pulmonary dysfunction FEV1\<25% predicted.
• • Previous treatment with gene therapy or gene editing products.
• • Previous receipt of non-HLA matched donor granulocyte transfusions.
• • Any other condition that, in the opinion of the investigator, may unduly compromise the safety or compliance of the patient, or would make successful study completion highly unlikely.