Gene Transfer for ADA-SCID Using an Improved Lentiviral Vector (TYF-ADA)

Gene Transfer for Adenosine Deaminase-severe Combined Immunodeficiency (ADA-SCID) Using an Improved Self-inactivating Lentiviral Vector (TYF-ADA)

This clinical trial will evaluate a safety and efficiency improved lentiviral vector system for delivering a therapeutic gene to patients with severe combined immunodeficiency (SCID) due to a defective adenosine deaminase (ADA) gene. This gene encodes for the adenosine deaminase enzyme, which is essential for the proper growth and function of infection-fighting white blood cells called T and B lymphocytes. Patients who lack this enzyme are vulnerable to frequent and severe infections. ADA-SCID patients are normally rescued by a bone marrow transplant (BMT) from a matched healthy donor. However, matched donors are difficult to find and donor BMT is associated with high risk. This trial aims to treat ADA-SCID using a safety and efficiency improved self-inactivating lentiviral vector carrying a functional ADA gene to correct the genetic defect. By collecting an individual's stem cells and modifying them with a lentivirus, the gene-corrected cells can be returned to the patient to help produce normal healthy immune cells.The primary objectives are to evaluate the safety of the improved self-inactivating lentiviral vector TYF-ADA, the ex vivo gene transfer clinical protocol and the efficacy of immune reconstitution in patients overcoming frequent infections present at the time of treatment. We will assess the lentiviral gene integration sites and the long-term effect of this gene transfer procedure.

Autologous hematopoietic and/or mesenchymal stem cells transduced with lentiviral vector carrying the ADA gene

Infusion of TYF-ADA-modified autologous stem cells at 1~10x10^6 gene-modified cells per kg body weight; or more infusions depending on the circumstances

Patient will be monitored for overall health condition, including immune cell assessments, blood biochemistry and metabolitic activities, metabolic detoxification, gene-modified cell percentage and vector copy number (VCN) in the blood, and continued follow-up for 15 years.

Immunological and metabolic values including all leukocyte counts (ALC), T, B and NK cell counts (CD3, CD4, CD8, CD19, CD56), T cell TREC levels, T cell repertoire diversity, PHA proliferation rate, immunoglobulins and dATP levels will be measured.

Immune recovery associated with reduction of infection episodes and frequencies, including viral, fungal and bacterial infections will be documented.

Inclusion Criteria: Diagnosis of classical ADA-SCID based on: A proven defective adenosine deaminase (ADA) gene as defined by direct sequencing of patient DNA. T-cell immune deficiency defined as one or more of the following: CD3+ autologous T cells < 300/ul, or less than 50% of normal value for in vitro mitogen stimulation, or absent proliferation in vitro to antigens. With severe infections, including but not limited to: pneumonitis; protracted diarrhea requiring total parenteral nutrition; infection with herpes viruses or adenovirus or fungus; disseminated BCG infection. No cytogenetic abnormalities (medullary karyotype) and no detection of main rearrangements associated with acute leukemia of children. No prior allogeneic stem cell transplantation. Life expectancy ≥ 2 months. Negative for HIV infection. Written, informed consent obtained prior to any study-specific procedures. Exclusion Criteria: None