A new form of gene therapy for boys with X-linked severe combined immunodeficiency syndrome (SCID-X1), a life-threatening condition also known as “bubble boy” disease, appears to be both effective and safe, according to an international clinical trial with sites in Boston, Cincinnati, Los Angeles, London, and Paris. 

Early data published in the New England Journal of Medicine suggests that the therapy may avoid the late-developing leukemia seen in a quarter of SCID-X1 patients in previous gene-therapy trials in Europe that took place more than a decade ago. Left untreated, boys with SCID-X1 usually die of infection before their first birthday. 

The lab of coauthor Frederic Bushman, PhD, professor of Microbiology, from the Perelman School of Medicine at the University of Pennsylvania, carried out the deep DNA sequencing on patient specimens to track and verify distributions of integration sites of the vector. The vector used in the new trial was engineered to remove molecular signals implicated in cancers in the first trial. 

Eight of nine boys recruited to date to the present trial are alive between 12 and 38 months after treatment, with no SCID-X1-associated infections. The gene therapy alone generated functioning immune systems in seven of eight boys. Genetic studies showed that the new viral vector did not lead to vector insertions near known cancer-causing genes, raising cautious hopes about the vector's long-term safety. 

“We showed that fewer cells accumulated with integration sites near cancer genes in the second trial, suggesting that the adverse properties had indeed been engineered out,” explains Bushman “So far there are no clinical adverse events in the present trial -- the integration site data has suggested improved safety.” 

The modified vector created for the current trial is a self-inactivating gammaretrovirus, designed to deliver its payload effectively while minimizing the chance of inadvertently turning on oncogenes that could lead to leukemia.