Breakthrough treatment in genetic condition

Data presented at The American Society of Hematology (ASH) Annual Meeting, has opened the possibility of new treatment for infants with the devastating genetic condition X-SCID.

Interim Results from a Phase I/II Clinical Gene Therapy Study for Newly Diagnosed Infants with X-Linked Severe Combined Immunodeficiency Using a Safety-Modified Lentiviral Vector and Targeted Reduced Exposure to Busulfan [523]

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 percent 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 percent 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 percent of patients. The remaining 80 percent 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.

This study was supported by The Assisi Foundation of Memphis, Inc. and the California Institute of Regenerative Medicine (CIRM).

Ewelina Mamcarz, MD, of St. Jude Children’s Research Hospital, will present this study during an oral presentation on Sunday, December 10, at 4:30 p.m. EST in Auditorium C101 of the Georgia World Congress Center.

The American Society of Hematology (ASH) is the world's largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 50 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. The Society publishes Blood®, the most cited peer-reviewed publication in the field, as well as the online, open-access journal, Blood Advances®.