Lentiviral Gene Therapy for X-Linked Chronic Granulomatous Disease (X-CGD)

Phase I/II Gene Therapy Protocol for X-Linked Chronic Granulomatous Disease

Chronic Granulomatous Disease (CGD) is a rare inherited disorder in which patients suffer from severe infection and inflammation. The first indication of disease usually appears in early childhood. The basic defect found to be lie in specialised white blood cells called phagocytic cells, which are responsible for engulfing and destroying germs. In CGD, there is a defect in an enzyme (known as NADPH-oxidase) that is responsible for generating bleach like substances that are important for killing some important germs. In the form of the disease known as X-CGD (which accounts for two thirds of patients), there are defined mistakes in a gene called gp91-phox, which is a key part of the NADPH-oxidase.

In many cases, patients can be protected from infection by constant intake of antibiotics. However, in others potential life-threatening infections break through. In some cases patients also develop serious inflammation requiring high doses of drugs such as steroids. CGD can be cured by bone marrow transplant, but the best results are available when there is matched donor available. Transplant from unmatched donor have a much worse outcome.

Gene therapy of CGD can be performed by introducing a normal copy of human gp91-phox gene into the blood forming stem cells of patients' bone marrow by using a gene carrier (in this study called lentiviral vector). After treatment of the bone marrow cells in a specialised laboratory are given back to the patient and will grow into functional phagocytic cells.

Study Overview

• Status: Withdrawn
• Conditions: Granulomatous Disease, Chronic, X-linked, Variant
• Intervention / Treatment: Genetic: pCCLchimGp91s lentiviral vector transduced CD34+ cells infusion

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital for Children NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 30 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• History of at least one severe infection requiring hospitalisation despite standard antimicrobial prophylaxis and/or inflammation complications including one of the following: Oesophageal obstruction, gastric outlet obstruction, bladder outlet obstruction or colitis
• Molecular diagnosis confirmed by DNA sequencing and supported by laboratory evidence for absent or significantly reduced biochemical activities of the NADPH-oxidase
• Parental/Guardian and where appropriate Child's signed consent/assent

Exclusion Criteria:

• 10/10 HLA identical (A,B,C,DR,DQ) family or unrelated or cord blood donor unless there is deemed to be an unacceptable risk associated with an allogeneic procedure
• Contraindication for leukapheresis (anaemia Hb <8g/dl, cardiovascular instability, severe coagulopathy) or for administration of conditioning medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: pCCLchimGp91s lentiviral vector transduced CD34+ cells; pCCLchimGp91s lentiviral vector transduced CD34+ cells will be infused in a volume of 50-100 mls intravenously over 30-45 minutes	Genetic: pCCLchimGp91s lentiviral vector transduced CD34+ cells infusion; pCCLchimGp91s lentiviral vector transduced CD34+ cells will be infused in a volume of 50-100 mls intravenously over 30-45 minutes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall survival following gene therapy	3 years follow up

Secondary Outcome Measures

Outcome Measure	Time Frame
Reduction in frequency of infections	evaluated from 1st year after treatment by clinical history, complete physical examination, haematological and microbiological tests
Long term immune reconstitution	3 years follow up

Collaborators and Investigators

• Sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust
• Investigators: Principal Investigator: Adrian Thrasher, Professor, Great Ormond Street Hospital For Children NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (Anticipated): November 1, 2016
• Study Completion (Anticipated): November 1, 2016

Study Registration Dates

• First Submitted: June 23, 2011
• First Submitted That Met QC Criteria: June 23, 2011
• First Posted (Estimate): June 27, 2011

Study Record Updates

• Last Update Posted (Estimate): June 4, 2012
• Last Update Submitted That Met QC Criteria: June 1, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: Chronic Granulomatous Disease; Gene therapy; X-CGD; NADPH-oxidase; gp91-phox
• Additional Relevant MeSH Terms: Pathologic Processes; Immunologic Deficiency Syndromes; Immune System Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Leukocyte Disorders; Phagocyte Bactericidal Dysfunction; Granuloma; Granulomatous Disease, Chronic
• Other Study ID Numbers: 11-MI-03