This article is more than 5 years old. Information may no longer be current.
Gene therapy shows promise in Wiskott-Aldrich syndrome
Click Here to Manage Email Alerts
Gene therapy conferred sustained benefit in pediatric patients with Wiskott-Aldrich syndrome, according to results of a small study conducted in Europe.
The approach also appeared safe, demonstrating its potential viability for this patient population, researchers wrote.
Wiskott-Aldrich syndrome is an immunodeficiency associated with severe microthrombocytopenia. Eczema and recurrent infections also frequently occur, according to study background.
“In the absence of definitive treatment, patients with classic Wiskott-Aldrich syndrome do not survive beyond their second or third decade of life,” Marina Cavazzana, MD, PhD, of the biotherapy department at Necker Children’s Hospital in Paris, and colleagues wrote. “Although hematopoietic stem cell (HSC) transplantation is usually curative, the use of partially HLA antigen-matched HSCs is associated with a high risk of complications.”
Cavazzana and colleagues assessed the efficacy and safety of autologous HSC gene therapy in seven pediatric patients with severe Wiskott-Aldrich syndrome. The mean age was 7 years (range, 10 months to 15.5 years), and all patients lacked an HLA antigen-matched hematopoietic stem cell donor. Patients were enrolled in hospitals in England and France, and treatment occurred between December 2010 and January 2014.
Patients were infused with genetically modified hematopoietic stem cells collected from bone marrow or mobilized peripheral blood. Patients were confined to a sterile environment during treatment and received a low-intensity conditioning procedure of busulfan (4 mg/kg daily) and fludarabine (40 mg/m2 daily) for 3 days. Converted cells were infused without cryopreservation, with anti-CD20 and/or alemtuzumab administered to patients if autoimmune disease was detected.
Improvement in clinical manifestation — evaluated by incidence and severity of infections, bleeding, eczema and autoimmune manifestations following gene therapy — served as the primary endpoint. Safety served as the secondary endpoint.
Median follow-up was 27 months.
One patient died 7 months after treatment due to septic shock, which was related to a pre-existing drug-resistant herpes virus infection, according to researchers.
However, the investigators observed a continued clinical response in the other six patients. Eczema and vulnerability to recurrent infections were resolved in all evaluable patients, though two patients developed minor, non-recurring infections. Researchers reported no severe bleeding incidents following treatment, and autoimmunity improved in all five effected patients. Additionally, no blood product support or thrombopoietic agonists were detected in the surviving patients.
Patient hospitalization was reduced from a median of 25 days in the 2 years prior to treatment to a median of 0 days in the 2 years following treatment. Functional and high-level engraftment of the corrected lymphoid cells were detectable in all six evaluable patients. Normal absolute T cell levels were attained in four patients, with normal T cell counts observable in the remaining two patients. The degrees of platelet reconstitution were associated with the administered dose of corrected cells.
Researchers detected no vector-related toxicity in the six surviving patients, either through clinical observation or molecular analysis.
“[This study] is the first to our knowledge to demonstrate clinical improvement after autologous gene therapy using a lentiviral vector in severely affected children and young adult patients in whom more pronounced procedure-related complications would be expected,” Cavazzana and colleagues wrote.
“Interpretation of the results of this type of study is constrained by the small number of patients and the difficulty in performing randomized trials in severe orphan diseases,” they wrote. “We therefore cannot draw conclusions on long-term outcomes and safety. Controlled studies with larger numbers of patients are necessary to assess long-term outcomes and safety.”
The results of this study and prior investigations suggest gene therapy can confer “substantial sustained clinical benefit” in patients with certain diseases, Harry L. Malech, MD, of the National Institute of Allergy and Infectious Diseases and the NIH, and Hans D. Ochs, MD, of the department of pediatrics at the University of Washington and Seattle Children’s Research Institute, wrote in an accompanying editorial.
“Correction of immune deficiencies, thalassemia and metabolic disorders with integrating vectors is only one area of success,” Malech and Ochs wrote. “Chimeric T-cell receptor gene therapy is successfully treating B-cell malignancies. Gene therapy with adeno-associated virus vectors has been used to restore vision to patients with an inherited abnormality of the retina and to correct a rare type of hemophilia. Virus vectors are not likely to be the last word in gene therapy…At a time when many are championing personalized medicine, no advance is as representative of that fundamental biological approach as gene therapy.” – by Cameron Kelsall
Disclosure: Cavazzana reports no relevant financial disclosures. Ochs reports consulting fees from CSL Behring and grants from the Jeffrey Modell Foundation. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Click Here to Manage Email Alerts