Christopher C. Porter, MD
During yesterday’s plenary scientific session, Dr. Christoph Klein reported on behalf of an international collaborative group the early results from 10 patients in a gene therapy trial aimed at replacing the abnormal gene in the hematopoietic cells of patients with Wiscott-Aldrich syndrome (WAS). Dramatically, nine of the patients had evidence of engraftment of gene-corrected cells and notable clinical benefit.
WAS is a life-threatening disease with the classic triad of micro-thrombocytopenia, immune deficiency, and eczema and is caused by mutations in a gene called WAS protein (WASP). The X-linked syndrome is at the severe end of a spectrum of disorders due to abnormal expression of the WASP, which is exclusively expressed in the cytoplasm of hematopoietic cells. The protein is a scaffold protein critical in the transduction of signals from the cell surface to the cytoskeleton. Without curative therapy by allogeneic hematopoietic stem cell transplantation (HSCT), patients with WAS typically die early in childhood.
The data presented yesterday afternoon, though, suggest that introducing the WASP gene in autologous HSC is feasible and effective. The group, headed by Dr. Klein, used a retrovirus to introduce the normal WASP gene into the HSC of 10 affected patients. Engraftment of gene-corrected cells failed in only one patient, apparently due to insufficient numbers of harvested CD34+ cells. In the nine patients with successful engraftment of gene-corrected cells, an early increase in platelet counts was seen, and by three months the majority of platelets expressed WASP. By 12 months after treatment, the percentage of WASP-expressing lymphoid cells surpassed 80 percent. Most importantly, in these nine patients, symptoms of WAS were improved with less observed eczema, bleeding, and immunodeficiency. The investigators also reported an association between WASP reconstitution in regulatory T cells and resolution of auto-immune symptoms.
The promising results from this trial demonstrate again the potential of gene therapy to cure hematopoietic diseases caused by mutation in a single gene. Patients with two types of severe combined immunodeficiency (SCID) and chronic granulomatous disease have also had evidence of efficacy from gene therapy, but these early gene-therapy trials highlighted the potential danger of integrating retroviruses. Some of the patients in these trials had evolution of clonal hematopoiesis and leukemia as a result of vector integrations resulting in abnormal gene expression. Unfortunately, acute T-cell leukemia has developed in one patient in this trial, confirming the potential danger of retroviral-mediated introduction of genes. As with the patients with SCID, the integration of the vector near LMO2 appears to have caused the leukemia. Studies with vectors thought to be safer are planned.
The possibilities of gene therapy were proposed more than 35 years ago. Substantial technical and regulatory hurdles have delayed the full realization of the potential of gene therapy. The data from this trial renew the promise of gene therapy for WAS patients.
Dr. Porter indicated no relevant conflicts of interest.