Lentiviral Gene Therapy for CGD

Study Overview
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Brief Summary
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This is a Phase I/II clinical trial of gene therapy for treating Chronic Granulomatous Disease using a high-safety, high-efficiency, self-inactivating lentiviral vector TYF to functionally correct the defective gene. The objectives are to evaluate the safety and efficacy of the TYF-CGD gene transfer clinical protocol.

Detailed Description
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Chronic granulomatous disease (CGD) is a rare disorder caused by inherited defects in the NADPH oxidase multienzyme complex. It is associated with severe and life-threatening bacterial and fungal infections. Approximately two-thirds of all CGD cases result from mutations within the X-linked gp91phox gene (CYBB), followed by the autosomal recessive forms of CGD, with defects in the gene coding for p47phox (NCF1) accounting for 10-30% of all CGD cases. The primary objectives are to evaluate the safety of the advanced self-inactivating lentiviral vector TYF-CYBB and TYF-NCF1, the ex-vivo gene transfer clinical protocol and the efficacy of immune reconstitution in patients overcoming frequent infections present at the time of treatment, assessment of vector integration sites, and finally the long-term correction of immune dysfunctions.

Official Title
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Lentiviral Gene Therapy for Chronic Granulomatous Disease (CGD)

Conditions
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Chronic Granulomatous Disease

Intervention / Treatment
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* Genetic: Infusion of lentiviral TYF-CGD-modified autologous stem cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CGD patients >= 0 years of age Molecular diagnosis confirmed by DNA sequencing and supported by laboratory evidence for absent or significantly reduced biochemical activities of the NADPH-oxidase Karnofsky-Index > =70% At least one prior, ongoing or refractory severe infection and/or inflammatory complications requiring hospitalization despite drug intervention Written informed consent for adult patient, and assent for pediatric subjects seven years or older Exclusion Criteria: Contraindication for leukapheresis (anaemia Hb <8g/dl, cardiovascular instability, severe coagulopathy) or for administration of conditioning medication Female patients who are pregnant or lactating as determined by history and/or positive pregnancy test
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lentiviral TYF-CGD-modified autologous stem cells<br>Autologous hematopoietic stem cells transduced with lentiviral TYF vector carrying the functional gene | Genetic: Infusion of lentiviral TYF-CGD-modified autologous stem cells<br>* Infusion of lentiviral TYF-modified autologous stem cells at 1 10x10^6 gene-modified cells per kg body weight<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Patient will be monitored for overall health condition, including immune cell assessments, blood biochemistry and metabolitic activities, metabolic detoxification. | 15 year follow up | 
| Gene marking in bone marrow cells | Gene-modified cells in the bone marrow will be measured by vector-specific quantitative PCR of colony-forming cells. Patient overall survival will be followed up for 15 years. | 15 year follow up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in infection frequency |  | 1 year after treatment by clinical history, complete physical examination, haematological and microbiological tests | 
| Recovery of immune function | Whole blood cell counts (WBC), including CD3+ CD4, CD8 T cells, CD19+ B cells and CD16/CD56 NK cells, and absolute neutrophil counts (ANC), the percentage of NADPH oxidase positive cells, and the kinetics of transduced cells as determined by dihydrorhodamine (DHR) assay, will be measured. | 1 year follow up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic granulomatous disease, Lentiviral vector