Lentiviral Gene Therapy for CGD

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.

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.

Inclusion Criteria: 1. CGD patients \>= 0 years of age 2. Molecular diagnosis confirmed by DNA sequencing and supported by laboratory evidence for absent or significantly reduced biochemical activities of the NADPH-oxidase 3. Karnofsky-Index \> =70% 4. At least one prior, ongoing or refractory severe infection and/or inflammatory complications requiring hospitalization despite drug intervention 5. Written informed consent for adult patient, and assent for pediatric subjects seven years or older Exclusion Criteria: 1. Contraindication for leukapheresis (anaemia Hb \<8g/dl, cardiovascular instability, severe coagulopathy) or for administration of conditioning medication 2. Female patients who are pregnant or lactating as determined by history and/or positive pregnancy test