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

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. Researchers want to know if gene therapy using the patient's own 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 first receive Campath (alemtuzumab) to reduce the risk of an immune response to the new protein expressed by the base-edited cells. This will be followed by conditioning chemotherapy with busulfan and subsequent infusion of the base-edited stem cells. Participants will be maintained on sirolimus to further reduce the risk of an immune response to the new protein expressed by the base-edited cells.

Follow-up visits will continue for 15 years.

Conditions

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

Interventions

DRUG

Campath

Immunomodulating agent: Daily subcutaneous administration beginning Day -9 for 5 days to reduce the risk of an immune response to the protein expressed by the BE HSPCs.

DRUG

Sirolimus

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

BIOLOGICAL

Base-edited hematopoietic stem and progenitor cells

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.

DRUG

Busulfan

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.

DRUG

Palifermin

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.

DRUG

Filgrastim

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

DRUG

Plerixafor

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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

  lead NIH

Principal Investigators

• Suk S De Ravin, M.D. · National Institute of Allergy and Infectious Diseases (NIAID)

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Max Age

75 Years

Sex

MALE

Healthy Volunteers

No

Timeline & Regulatory

Start

2024-04-17

Primary Completion

2032-12-31

Completion

2032-12-31

FDA Drug

Yes

Countries

• United States

Study Locations