History
1990
Dr. William French Anderson and Michael Blaese performed the world’s first officially approved gene therapy by manipulating human genes on 1990. The patient was a four-year-old girl named Ashanti DeSilva. She inherited a defective gene from both parents and suffered from ADA (adenosine deaminase) deficiency. The scientists introduced millions of Ashanthi’s own white blood cells into her bloodstream that were extracted from Ashanthi’s blood and genetically engineered to contain a corrected copy of the adenosine deaminase gene. The scientists hope these cells will restore Ashanthi’s immune function by producing a normal version of the defective enzyme. The treatment has been a success. Ashanti is alive and well today.
1971 - 1983
The first known case of SCID was David Phillip Vetter in Texas (United States of America). He was born in 1971 and died 12 years later, the only treatment for this boy was isolation in a sterile environment until a bone marrow donor was identified and a successful bone marrow transplant performed. The unique chance for all babies that were born with Severe Combined Immunodeficiency Disease to survive was a transplantation of HLA-identical bone marrow cells. In the absence of an HLA-identical donor the survival chances were very low till 1990.
Between 1999 and 2006, 20 subjects with SCID-X1 were treated in two trials in Paris and then London. The leaders from each clinical trial are Marina Cavazzana-Calvo and Alain Fischer from Hôpital Necker in Paris and Adrian Thrasher from the Institute of Child Health in London.
All the subjects lacked an HLA-identical donor and received ex vivo-transduced CD34+ cells in the absence of any additional therapy. The efficiency of γc gene transfer has been clearly demonstrated. The results on these clinical trials were: full or nearly full correction of the T-cell immunodeficiency, NK cell counts fell very low values, the B ells were poorly transduced. Five of the 20 subjects developed T-cell leukemia 2.5-5 years after gene therapy. In four cases, chemotherapy was easily able to destroy abnormal clones. However, on of them died.
It was found that proliferative clones carried V integrations within oncogene loci. LMO2 had been targeted in four out the five cases. It became clear that RV-mediated gene transfer could deregulate proto-oncogen expression through the LTR’s enhancer activity. After these results an ongoing international trail is using a self-inactivating (SIN) RV vector that should reduce the risk of insertional mutagenesis. Alternative approaches based on gene correction and targeted integrations using nucleases have achieved so far relatively low levels of correction in hematopoietic.
