Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector
Researchers are working on ways to treat SCID patients who don't have a matched brother or sister. One of the goals is to avoid the problems that happen with stem cell transplant from parents and unrelated people, such as repeat transplants, incomplete cure of the immune system, exposure to chemotherapy, and graft versus host disease.
The idea behind gene transfer is to replace the broken gene by putting a piece of genetic material (DNA) that has the normal gene into the child's cells. Gene transfer can only be done if we know which gene is missing or broken in the patient. For SCID-X1, gene transfer has been done in the laboratory and in two previous clinical trials by inserting the normal gene into stem cells from bone marrow. The bone marrow is the "factory" inside the bones that creates blood and immune cells. So fixing the gene in the bone marrow stem cells should fix the immune problem, without giving chemotherapy and without risk of graft versus host disease, because the child's own cells are used, rather than another person's. Out of the 20 subjects enrolled in the two previous trials, 18 are alive with better immune systems after gene transfer. Two of the surviving subjects received gene corrected cells over 10 years ago.
Gene transfer is still research for two reasons. One is that not enough children have been studied to tell if the procedure is consistently successful. Of the 20 children enrolled in the previous two trials, one child did not have correction of the immune system, and died of complications after undergoing stem cell transplant. The second important reason why gene transfer is research is that we are still learning about the side effects of gene transfer and how to do gene transfer safely. In the last two trials, 5 children have experienced a serious side effect. These children developed leukemia related to the gene transfer itself. Leukemia is a cancer of the white blood cells, a condition where a few white blood cells grow out of control. Of these children, 4 of the 5 have received chemotherapy (medication to treat cancer) and are currently in remission (no leukemia can be found by sensitive testing), whereas one died of gene transfer-related leukemia.
Severe Combined Immunodeficiency
Biological: Gene transfer
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Multi-institutional Phase I/II Trial Evaluating the Treatment of SCID-X1 Patients With Retrovirus-mediated Gene Transfer|
- CD3 cell count post transfusion [ Time Frame: 6 Months Post Gene Transfer ] [ Designated as safety issue: No ]Immunological reconstitution defined as absolute CD3 cells of >300/μl and PHA stimulation index >15 at 6 months post infusion
- Incidence of life-threatening adverse reactions related to the gene therapy procedure. [ Time Frame: Up to 15 years post gene transfer ] [ Designated as safety issue: Yes ]Incidence of life-threatening adverse reactions related to the gene therapy procedure.
- Molecular characterization of gene transfer. [ Time Frame: Up to 15 years post gene transfer ] [ Designated as safety issue: No ]
- Ability to mount antibody responses to vaccination. [ Time Frame: Within 18 Months post standard vaccination to tentanus ] [ Designated as safety issue: No ]
- Normalization of nutritional status, growth, and development [ Time Frame: Up to 15 years post gene transfer ] [ Designated as safety issue: Yes ]
|Study Start Date:||April 2010|
|Estimated Study Completion Date:||April 2030|
|Estimated Primary Completion Date:||April 2015 (Final data collection date for primary outcome measure)|
Experimental: Gene Transfer
open label single arm study
Biological: Gene transfer
Two procedures: 1) Bone marrow harvest from the patient's posterior iliac crests. 2)One time infusion of patient's transduced bone marrow cells.
Severe combined immunodeficiencies (SCID) are a heterogeneous group of inherited disorders characterized by a profound reduction or absence of T lymphocyte function. They arise from a variety of molecular defects which affect lymphocyte development and function. The most common form of SCID is an X-linked form (SCID-X1) which accounts for 40-50% of all cases. SCID-X1 is caused by defects in the common cytokine receptor chain, which was originally identified as a component of the high affinity interleukin-2 receptor (IL-2RG), but is now known to be an essential component of the IL-4, -7, -9 -15, and -21 cytokine receptor complexes. Classic SCID-X1 has an extremely poor prognosis without treatment. Death usually occurs in the first year of life from infectious complications unless definitive treatment can be administered. Until the recent advent of somatic gene therapy, hematopoietic stem cell transplantation (HSCT) offered the only curative option for patients with any form of SCID. If a genotypically matched sibling donor is available, HSCT is a highly successful procedure. However a genotypically matched family donor is only available for approximately 30% of patients. For the remaining individuals, alternative donor transplants, principally from matched unrelated or haploidentical parental donors have been performed. These approaches are still problematic with toxicity from ablative therapy, graft-versus-host disease and incomplete lymphoid reconstitution. Recent gene transfer trials have documented the efficacy of gene transfer in this disease, albeit with toxicity related to insertional mutagenesis. A new generation of self-inactivating (SIN) vectors has been developed which lack all enhancer-promoter elements of the LTR U3 region and are also devoid of all gammaretroviral coding regions. A SIN vector expressing the IL-2RG gene, pSRS11.EFS.IL2RG.pre* has been developed and has shown a reduction in mutagenic potential compared to LTR configuration in non-clinical studies. The current study is a phase I/II trial of somatic gene therapy for patients with SCID-X1.
|Contact: David A Williams, MDfirstname.lastname@example.org|
|Contact: Colleen H. Dansereau, RNemail@example.com|
|United States, California|
|Mattel Children's Hospital - UCLA||Recruiting|
|Los Angeles, California, United States, 90095|
|Contact: Donald B Kohn, MD 310-794-1964 DKohn@mednet.ucla.edu|
|Contact: Satiro De Oliveira, MD 310-794-1940 SDeOliveira@mednet.ucla.edu|
|Principal Investigator: Donald B Kohn, MD|
|United States, Massachusetts|
|Children's Hospital Boston||Recruiting|
|Boston, Massachusetts, United States, 02116|
|Contact: Luigi Notarangelo, M.D. 617-919-2276 Luigi.Notarangelo@Childrens.Harvard.edu|
|Contact: Sung-Yun Pai, M.D. 617-919-2508 Sung-Yun.Pai@Childrens.Harvard.edu|
|Principal Investigator: Luigi Notarangelo, MD|
|United States, Ohio|
|Cincinnati Children's Medical Center||Recruiting|
|Cincinnati, Ohio, United States, 45229|
|Contact: Alexandra H Filipovich, MD 513-803-3218 Lisa.Filipovich@cchmc.org|
|Contact: Punam Malik, MD 513-636-8588 Punam.Malik@cchmc.org|
|Principal Investigator: Alexandra H Filipovich, MD|
|Principal Investigator:||Luigi Notarangelo, MD||Children's Hospital Boston|