Stem-cell gene therapy resulted in marked clinical improvement for two patients with the rare Wiskott-Aldrich syndrome, researchers reported.
After treatment, the two patients -- both young boys -- saw resolution of symptoms that included eczema, autoimmunity, and predisposition to severe infection, according to Christoph Klein, MD, PhD (pictured), of Hannover Medical School in Hannover, Germany, and colleagues.
The therapy also resulted in sustained expression of the WAS protein in a range of cell types, Klein and colleagues reported.
The syndrome is an X-linked recessive primary immunodeficiency disorder -- caused by mutations in the WAS gene -- that is associated with thrombocytopenia, eczema, a tendency to bleeding, and autoimmunity, the researchers noted. Because of the X-link, it is almost always seen in boys, but it is also rare, occurring in about 1 in 4 million live male births.
The WAS protein plays a role in signaling, cell locomotion, and immunologic-synapse formation in hematopoietic cells, Klein and colleagues noted. Its absence leads to multiple dysfunctions in leukocytes, including defective function of T and B cells, disturbed formation of the NK-cell immunologic synapse, and impaired migratory responses in all leukocyte subgroups.
The disease is a "promising candidate" for gene therapy, Klein and colleagues argued, because the WAS protein is only expressed by cells of the hematopoietic system.
In this study, the researchers treated two boys, who were diagnosed with the condition soon after birth, using their own hematopoietic stem cells that had been genetically altered so they expressed the WAS protein.
Within 6 months of the gene transfer, both boys saw sharp increases in the proportion of leukocytes that were positive for the WAS protein, including CD8-positive and CD4-positive T cells, and NK cells. The proportion of monocytes expressing the protein has ranged between 7% and 28%.
The boys also saw increased platelet counts, starting 6 to 9 months after gene therapy, which ended episodes of clinical bleeding. Two and half years after the therapy, they reported, one patient had a platelet count of 256,000 per microliter of blood, while the other had 88,000 per microliter.
The proportion of B cells expressing the WAS protein rose over time, to between 57% and 69%, two and a half years after the treatment, the researchers reported. As well, abnormal immunoglobulin levels normalized, although not to a protective level in one patient who had had his spleen removed earlier.
The symptoms of autoimmunity vanished within a year of the therapy, Klein and colleagues reported, including hemolytic anemia, thrombocytopenia, and neutropenia in one patient and severe eczema in the other.
The study shows that gene therapy for the condition is "feasible," the researchers argued, especially since no treatment-limiting adverse events have been seen during the follow-up. Specifically, the study shows that the therapy can correct the thrombocytopenia that is the most common cause of death and complications in patients with Wiskott-Aldrich syndrome, they reported.
The findings warrant follow-up with more patients, they concluded.
Illustration: Hannover Medical School.
MedPage Today (11/10/10)
Abstract (The New England Journal of Medicine; 363, 1918-1927 (11/11/10))