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

NCT06325709 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 10001580001580-I
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Chronic granulomatous disease (CGD) is a rare immune disorder caused by a mutation in the CYBB gene. People with CGD have white blood cells that do not work properly and are at greater risk of getting infections. Gene therapy using lentivector has helped people with CGD. Researchers want to know if the base-edited stem cells can improve the white cells' functioning and result in fewer CGD-related infections. Objective: To learn if base-edited stem cells will correct the white blood cells in people with CGD. Eligibility: Males aged 18 years and older with X-linked CGD. Design: This is a non-randomized study. Participants with the specific mutation under study will be screened during the initial phase. During the development phase, participants will undergo apheresis to collect stem cells for base-editing correction of the mutation. During the treatment phase, participants will receive the base-edited cells after chemotherapy with busulfan. Participants will remain in the hospital until their immunity recovers. Participants will be maintained on sirolimus to prevent an immune response to the new protein expressed by the base-edited cells. Follow-up visits will continue for 15 years.

Conditions

X-Linked Chronic Granulomatous Disease; Chronic Granulomatous Disease (CGD)

Keywords

base editing; Gene Editing

Outcome Measures

Primary Outcomes (2)

• To evaluate the safety of base-edited autologous CD34+ cells

  Safety of gene therapy using base-edited autologous hematopoietic stem and progenitor cells as measured by study agent related adverse events and serious adverse events

  Initiated from the time of the infusion of base-edited cells through 2 years post-infusion

• To evaluate the efficacy of base-edited autologous CD34+ cells

  Efficacy of gene therapy as determined by percentages ofparticipants who have \>= 10 percent oxidase-positive granulocytes

  Assessed 12 months post-infusion of base-edited cells

Secondary Outcomes (6)

• Evaluate the efficiency of base-editing.

  Assessed 12-24 months post-infusion of base-edited cells

• Evaluate the engraftment capability of base-edited hematopoietic stem progenitor cells.

  Assessed 12-24 months post-infusion of base-edited cells

• Evaluate the efficiency in restoring gp91phox expression.

  Assessed 12-24 months post-infusion of base-edited cells

• Evaluate efficacy in restoring NADPH oxidase function.

  Assessed 12-24 months post-infusion of base-edited cells

• Evaluate clinical efficacy

  Assessed through study completion

Study Arms (1)

Single Arm Study

EXPERIMENTAL

Drug: Plerixafor; Drug: Filgrastim; Drug: Palifermin; Drug: Busulfan; Biological: Base-edited hematopoietic stem and progenitor cells; Drug: Sirolimus

Interventions

Plerixafor DRUG

Stem Cell Mobilizing Agent: Subcutaneous administration for 2 consecutive days to improve stem cell collection.

Single Arm Study

Filgrastim DRUG

Stem Cell Mobilizing Agent: Subcutaneous administration for 6 consecutive days. It is necessary to mobilize stem cells for collection.

Single Arm Study

Palifermin DRUG

Mucositis Prophylaxis Agent: Intravenous infusion of keratinocyte growth factor (Palifermin) at 60 mcg/kg/day before (Days -7 to Day -5 administration of busulfan and (Days 1 to 3) post-busulfan administration to prevent oral mucositis.

Single Arm Study

Busulfan DRUG

Transplant Conditioning Agent: An alkylating chemotherapy drug to enhance engraftment of the study agent (base-edited stem cells). Conditioning will be given intravenously over 3 days with an approximate total dose of 12mg/kg. Drug levels obtained will be obtained to achieve the targeted total busulfan AUC of 65,000 ng/mL x hr.

Single Arm Study

Base-edited hematopoietic stem and progenitor cells BIOLOGICAL

Investigational/Study Agent: Base-edited autologous CD34 plus hematopoietic stem and progenitor cell product. The product is administered intravenously as a single infusion. This product is under an IND.

Single Arm Study

Sirolimus DRUG

Immunomodulating agent: Daily oral dosing beginning Day -1 for approximately 3 to 6 months to prevent an immune response to the protein expressed by the BE HSPCs.

Single Arm Study

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \>= 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Publications (3)

• Komor AC, Badran AH, Liu DR. Editing the Genome Without Double-Stranded DNA Breaks. ACS Chem Biol. 2018 Feb 16;13(2):383-388. doi: 10.1021/acschembio.7b00710. Epub 2017 Oct 9.

  PMID: 28957631 BACKGROUND

• Kuhns DB, Alvord WG, Heller T, Feld JJ, Pike KM, Marciano BE, Uzel G, DeRavin SS, Priel DA, Soule BP, Zarember KA, Malech HL, Holland SM, Gallin JI. Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med. 2010 Dec 30;363(27):2600-10. doi: 10.1056/NEJMoa1007097.

  PMID: 21190454 BACKGROUND

• Bzhilyanskaya V, Ma L, Liu S, Fox LR, Whittaker MN, Meis RJ, Choi U, Lawson A, Ma M, Theobald N, Burkett S, Sweeney CL, Lazzarotto CR, Tsai SQ, Lack JB, Wu X, Dahl GA, Malech HL, Kleinstiver BP, De Ravin SS. High-fidelity PAMless base editing of hematopoietic stem cells to treat chronic granulomatous disease. Sci Transl Med. 2024 Oct 16;16(769):eadj6779. doi: 10.1126/scitranslmed.adj6779. Epub 2024 Oct 16.

  PMID: 39413163 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Granulomatous Disease, Chronic

Interventions

plerixafor; Filgrastim; Fibroblast Growth Factor 7; Busulfan; Sirolimus

Condition Hierarchy (Ancestors)

Phagocyte Bactericidal Dysfunction; Leukocyte Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Immunologic Deficiency Syndromes; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Fibroblast Growth Factors; Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Macrolides; Lactones

Study Officials

• Suk S De Ravin, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Suk S De Ravin, M.D.

CONTACT

(301) 496-6772; sderavin@mail.nih.gov

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 21, 2024
• First Posted: March 22, 2024
• Study Start: April 17, 2024
• Primary Completion (Estimated): December 31, 2032
• Study Completion (Estimated): December 31, 2032
• Last Updated: June 11, 2026

Record last verified: 2026-01-30

Locations

US (1)