Interim results from a phase I/II clinical gene therapy study for newly diagnosed infants with X-linked severe combined immunodeficiency (SCID) using a safety-modified lentiviral vector and targeted reduced exposure to busulfan.
Infants with the devastating genetic condition X-SCID were able to produce all three major immune cell types with no major side effects after receiving an investigational gene therapy in a phase-I/II-trial. The preliminary results suggest a substantial breakthrough for a therapeutic area that has encountered significant safety hurdles in the past, according to investigators.
X-SCID is an inherited condition in which the body cannot produce the cells responsible for defending against infection: T-cells, B-cells, and natural killer (NK) cells. The disease is rare, but devastating. Without treatment, babies born with SCID succumb to infections and die by age two. Of those who receive a stem cell transplant, the best-available treatment, approximately 30% die by age 10. Previous experimental gene therapies for X-SCID have only been able to restore T-cell function, and in some cases have caused treated infants to develop leukemia.
In developing this new gene therapy, researchers at St. Jude Children’s Research Hospital and the University of California, San Francisco used an inactivated form of HIV as a vector to introduce genetic modifications into the patients’ bone marrow cells. HIV was chosen as the delivery vehicle given the virus’ ability to better infiltrate cells compared to previously-used gene therapy vectors. The team used low doses of chemotherapy to prepare the patients’ bone marrow to receive this therapy.
To date, the researchers have tested their new gene therapy in seven infants, tracking outcomes for up to 12 months. Preliminary results reveal evidence of T-cell, B-cell, and NK cell production in some of the treated infants, with no major side effects. Unprecedentedly high levels of the vector were seen in all types of blood cells, and in some cases, more than 60% of all bone marrow stem cells contained the corrective gene for X-SCID. All of the treated babies have so far appeared to benefit from the therapy.
„It is very exciting that we observed restoration of all three very important cell types in the immune system,“ said lead study author Ewelina Mamcarz, MD, assistant professor in the bone marrow transplant department at St. Jude Children’s Research Hospital. „This is something that’s never been done in infants and a huge advantage over prior trials. The initial results also suggest our approach is fundamentally safer than previous attempts.“
The researchers are continuing to track the infants’ immune activity and their ability to respond to vaccination, which will take more time to establish. The current standard of care for SCID is a stem cell transplant from a matched sibling donor, but that treatment is only possible for about 20% of patients. The remaining 80% of patients typically receive a stem cell transplant from a parental donor, but continue to suffer from life-threatening infections and require monthly immunoglobulin infusions. If gene therapy proves successful and safe for SCID, it could potentially cure many more patients, reduce dependency on immunoglobulin, and avoid the serious risks associated with stem cell transplantation, such as graft-versus-host disease.
Several genetic mutations can cause SCID. The new therapy is designed for those with a type known as X-linked SCID, which comes from a mutation in the IL2RG gene found on the X chromosome. Researchers say the same approach could be adapted for any type of SCID, and indeed many other genetic disorders, as well.
ASH Annual Meeting 2017, abstract #523