The severe combined immunodeficiency syndromes (SCID) are a rare but lethal class of genetic disorders that result in patients being unable to form an immune system. The two most common types of SCID are SCID-X1 (also known as “bubble boy disease”) and ADA-SCID. While many patients can be cured using bone marrow transplantation (BMT), there are substantial limitations to this approach, notably that most patients do not have an ideal donor, that BMT has significant toxicities, and that the immune system after BMT is not always fully functional. The goal of this disease team is to develop gene targeting by homologous recombination as a novel form of gene therapy for this disease. Gene targeting is a technique in which precise changes are introduced into the genome of cells using a process called homologous recombination. In SCID our goal is to use gene targeting by homologous recombination to directly correct the mutations that cause the disease in blood stem cells. By using this approach we will be creating stem cells in which there is no remnant of the original disease. The advantages of this strategy are two-fold. First, we will be using homologous recombination--the most precise method of gene manipulation. Second, we will be doing the manipulations on the patient’s own stem cells so that the therapy would be available to all newly diagnosed patients with SCID-X1 and ADA-SCID.
In our pre-clinical work we have developed a number of different components in which we have demonstrated rates of gene targeting that would be sufficient to cure SCID if achieved in blood stem cells. The goal for the first two years of this disease team is to assemble these components into a process that can be translated to clinical use. We will work with regulatory agencies during these two years in order to perform the necessary studies for eventual approval of the process for a clinical trial. The third year will be focused on streamlining the approach developed in the first two years into a GMP grade process including developing GMP grade reagents. Finally, the fourth year will be to pilot the process by harvesting primary blood stem cells from patients, performing gene targeting/correction by homologous recombination in these cells, and then transplanting these cells into an animal model to demonstrate that the gene corrected cells are capable of forming an immune system. During all four years, we will continually assess the safety of this approach in preparation to present to the RAC and FDA that the overall procedure is safe for a clinical trial. Our goal by the end of the fourth year is to submit an IND to begin a clinical trial in SCID-X1 and ADA-SCID patients who do not have a matched sibling donor using homologous recombination to correct disease causing mutations in the patient’s own blood cells.
It is estimated that about a dozen children are born with severe combined immunodeficiency disorder (SCID) each year in California. Since ~60% of cases are caused by mutations in either the IL2RG or ADA gene, ~7 new cases of SCID-X1 and ADA-SCID are born in California each year. Clearly this disease is not a public health menace. On the other hand, for those children who do have SCID, the disease can be lethal, treatment options are sub-optimal, and improved therapies are needed. Moreover, the cost of treating each patient with SCID are substantial and can range from a one time cost of ~$200,000 for an uncomplicated matched sibling bone marrow transplant to an annual cost of greater than $100,000 for PEG-ADA enzyme replacement therapy for ADA-SCID. Thus, there are clearly both medical and economic benefits to the state of California and its citizens for the development of homologous recombination based gene therapy of autologous cells for SCID.
In addition, to the direct benefits for SCID, the development of homologous recombination based gene therapy for SCID would represent a first in kind clinical trial. That is, it would be the first attempt at using a potentially ideal approach to treating genetic diseases. The importance of this pioneering therapy for the state of the California and its citizens is multi-fold. It would serve to attract patients worldwide to enroll on the study. It would enhance the reputation of the state as a place where pioneering work to improve the lives of the most unfortunate is developed. Finally, it would serve as a paradigm for stem cell based therapies using homologous recombination for children and adults with both genetic and non-genetic diseases; a range of patients and diseases that would have an impact on the general health of the California citizenry.