Children born with Severe Combined Immunodeficiency Disease (SCID) are unable to fight common infections and often die within the first 6 months of life. These children have a defect in white blood cells called T and B lymphocytes which are essential for fighting bacterial, viral and fungal infections. The most severe form of SCID is the result of an inherited deficiency of an essential chemical in the body called Artemis (SCID-A) without which T and B cells are unable to develop. Artemis is an essential component of a process which repairs DNA (the instructions in cells which make us who we are) when it is damaged or cut during normal metabolic activities. Because of this, children with SCID-A are also more sensitive to typical chemotherapeutic drugs used for bone marrow stem cell transplant (BMT). The only cure for SCID is a BMT but for children with SCID-A, a successful BMT is often more difficult to achieve and usually only restores T lymphocyte function so that children remain dependant on supplemental therapy called gammaglobulin for the rest of their lives. Also children with SCID-A who are exposed to high doses of chemotherapy necessary for a successful BMT are more likely to die following a BMT and if they do survive, these children do not grow well, have more difficulty in school, and fail to develop normal permanent teeth. For these reasons, if the patient’s own blood stem cells could be corrected by inserting a normal human Artemis gene into their DNA and these cells put back into the patient’s bone marrow to grow and restore normal T and B lymphocyte function, many if not all of the problems associated with BMT would be eliminated. We have developed a novel way of inserting the normal human Artemis gene into the DNA of mouse blood stem cells and have been able to cure Artemis-deficient mice that we created. We propose to complete the necessary studies for obtaining approval from the FDA for an IND and to initiate a clinical trial of gene-corrected blood stem cells in children with Artemis-deficient SCID.
Statement of Benefit to California:
Artemis-deficient severe combined immunodeficiency (SCID-A) is a rare disease. However, the results of this study will advance the field not only for gene therapy using vectors which are more efficient and less toxic that the first generation of retroviral vectors, but also for our understanding of niche space in the marrow and the degree of open niches needed to achieve durable engraftment and correction of hematopoiesis without using full myeloablative pre-conditioning. The results of this study will apply not only to children with SCID but also to those with other disorders including hemoglobinopathies (thalassemia and sickle cell disease), which can be corrected without the need for full donor chimerism. The State of California was among the first states to initiate newborn screening for SCID and patients diagnosed with SCID-A in California (as well as elsewhere) will benefit from this therapeutic approach.