ORLANDO – – Gene therapy can help restore immune function to older children and young adults with X-linked severe combined immunodeficiency, a team of US investigators reports.
“This is the first demonstration of the use of gene therapy to salvage failed allogeneic hematopoietic stem cell transplants in older SCID-X1 patients,” said Dr. Suk See De Ravin from the Laboratory of Host Defenses at the National Institutes of Health in Bethesda, Maryland.
Although allogeneic hematopoietic stem cell transplantation (HSCT) from a matched sibling donor can be curative, transplants using parental bone marrow or genetically modified autologous transplants without myeloconditiong restore T-cell-mediated immunity but not humoral immunity, Dr. De Ravin said at the American Society of Hematology annual meeting.
Frontline Medical News
Dr. Suk See De Ravin
Additionally, transplants in older children with SCID-X1 who have persistent immune system defects – despite having received a transplant from a haploidentical donor in infancy – leave the patients with serious medical problems, including the life-long need for immunoglobulin G (IgG) supplementation, recurrent and chronic infections, warts, malnutrition, growth failure, and progressive diseases of the gut and lung.
Previous attempts at using gene therapy to correct mutations in IL2RG, the cause of SCID-X1, used mouse retroviral vectors to insert normal IL2RG into autologous hematopoietic stem cells without chemotherapy conditioning. This treatment restored T-cell immunity, but not B-cell- or natural killer (NK)-cell immunity
Of even greater concern is the fact that among infants with SCID-X1 who received autologous stem cells transduced with murine gamma retrovirus carrying the common gamma chain, 25% developed vector-associated leukemia.
To overcome these problems, investigators in the current study used a lentiviral vector containing an insulator fragment from a chicken beta-globin gene. The insulator fragment allows expression of the gamma chain complementary DNA while protecting against up-regulation of neighboring oncogenes.
Dr. De Ravin reported data on five patients from the ages of 7 to 24 years who had worsening immune dysfunction and complex medical problems, including dependence on immunoglobulin G (IgG) supplementations. All of the patients had previously undergone one or more HSCT from haploidentical donors.
The patients were treated with granulocyte-colony stimulating factor and plerixafor to mobilize peripheral blood cells, and then underwent apheresis to isolate CD34 cells. The cells were transduced in vitro with a lentiviral vector, and reinfused into patients after conditioning with low-dose busulfan (6 mg/kg). The vector was developed by researchers at St Jude Children’s Hospital in Memphis, Tennessee.
At the most recent follow-up, the first two patients treated with the protocol had stable engraftment of gamma-chain expressing cells gene with enhanced expression of B, T, and NK cells, with the cells continuing to show improvements, Early data on the remaining four patients indicates a similar positive trend.
Chimerism studies of the patients’ T-cells showed that the host cells were continuing to increase their contribution, suggesting gradual replacement over time of the T-cell graft, Dr. De Ravin said.
In the second patient treated, an increase in NK cells corresponded with an improvement in chronic warts. In addition, the first two patients began to produce both IgG and antigen-specific responses to vaccination, clearance of chronic norovirus infections, and resolution of their protein-losing enteropathy.
“Gene therapy does not appear to reverse prior organ damage, supporting early intervention to improve immunity in these patients before such damage occurs,” Dr. De Ravin said.
The study was supported by the National Institutes of Health. The viral vector was developed at St. Jude Children’s Research Hospital in Memphis, Tennessee. The authors reported no relevant conflicts of interest.