Efficacy of gene therapy in treating Wiskott-Aldrich Syndrome

Gene therapy has shown to be effective in treating Wiskott-Aldrich Syndrome (WAS), a potentially fatal, rare genetic condition that affects blood cells, by reducing severe infections and bleeding. Strengthening the current body of evidence on gene therapy’s potential effectiveness in treating WAS are the interim results of the registrational clinical trial published today in Lancet Haematology* and coordinated by Alessandro Aiuti, professor of Pediatrics at the Vita-Salute San Raffaele University, and vice director of the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) at San Raffaele Hospital in Milan. The study which involved 8 patients and started in 2010, was possible thanks to the strategic and pioneering alliance between the San Raffaele Research Hospital, Fondazione Telethon and GlaxoSmithKline, which moved to Orchard Therapeutics in 2018, and is based on over 20 years of cutting-edge research at the SR-Tiget laboratories.


WAS is a condition caused by mutations in the WAS protein (WASP) coding gene. The effects of this mutation are mainly seen at platelet level and in the immune system, resulting in low counts and abnormal function. Patients suffer serious consequences - abnormal bleeding, infections, tumours, autoimmune disorders, and widespread chronic eczema. To date, the only curative treatment available has been a bone marrow transplantation, which is not an option for everyone and carries its own risks. However, the results of the clinical study suggest that gene therapy may be an alternative. Eight patients with WAS were treated successfully using a gene therapy protocol that was optimised in the SR-Tiget laboratories.


Researchers took blood stem cells from the 8 patients and inserted the correct version of the WASP gene into them, so they are able to differentiate into healthy white cells and platelets. To insert the gene into the diseased cells correctly, researchers used what is known as a lentiviral vector - a modified virus belonging to the HIV family and rendered safe in the laboratory, which exploits the natural ability of the virus to penetrate the cells and transfer the genetic material contained within them.

In addition to the gene, a 'natural promoter' is also inserted into cells, whose task is to control protein synthesis. This ensures that the patient's cells, once treated, produce WASP physiologically in the correct amount", explains Francesca Ferrua, the leading paediatrician publishing the study along with Maria Pia Cicalese. "This aspect is fundamental for reducing the risk of side effects”.


The results show sustained clinical benefit. “The first patient was treated in 2010 and the last in 2015, and all the patients involved are well and no longer suffer from the ongoing infections, autoimmune disorders, and serious bleeding associated with the condition” explains Alessandro Aiuti. “Their immune system has started functioning again and producing antibodies. The platelet count has increased and the platelets are normal. Even though platelet numbers remain lower than normal, patients can still lead a normal life. In an effort to make the treatment more widely available if approved by regulatory bodies, a new clinical study started recently, which involves freezing the stem cells after modification with viral vectors”, adds Aiuti.


The research group originally benefited from funding received from Fondazione Telethon.

Francesca Ferrua, MD; Maria Pia Cicalese, MD; Stefania Galimberti, PhD; Stefania Giannelli, PhD; Francesca Dionisio, MSc; Federica Barzaghi, MD; Maddalena Migliavacca, MD; Maria Ester Bernardo, MD; Valeria Calbi, MD; Andrea A Assanelli, MD; Marcella Facchini, PhD; Claudia Fossati, MSc; Elena Albertazzi, PhD; Samantha Scaramuzza, PhD; Immacolata Brigida, PhD; Serena Scala, PhD; Luca Basso-Ricci, MSc; Roberta Pajno, MD; Miriam Casiraghi, RN; Daniele Canarutto, MD; Federica A Salerio, MSc; Michael H Albert, MD; Antonella Bartoli, MScPharm; Hermann M Wolf, MD; Rossana Fiori, MD; Paolo Silvani, MD; Salvatore Gattillo, MD; Anna Villa, MD; Luca Biasco, PhD; Christopher Dott, PhD; Emily J Culme-Seymour, PhD; Koenraad van Rossem, MD; Gillian Atkinson, PhD; Maria Grazia Valsecchi, PhD; Maria Grazia Roncarolo, MD; Fabio Ciceri, MD; Luigi Naldini, MD; Alessandro Aiuti, M.D., Ph.D, Lentiviral haematopoietic stem/progenitor cell gene therapy for the treatment of Wiskott-Aldrich syndrome: interim results of a nonrandomized, open-label, phase 1/2 clinical study, The Lancet Hematology, April 2019