X-linked severe combined immunodeficiency (X-SCID, or SCID-X1), is an orphan monogenic disorder popularly known as ‘bubble boy disease’ that affects 1 in 50,000-100,000 live births. The most serious of all primary immunodeficiencies, X-SCID causes severe failure of the immune system, including a lack of T cells, natural killer (NK) cells, or functional B cells. For children affected by this disease, even an ordinary cold could be fatal. X-SCID is caused by mutations in the interleukin-encoding gene IL2RG located on the X chromosome. The standard treatment to restore immunity involves hematopoietic stem cell transplants from matched sibling donors, only available for about 1 in 5 patients, or transplants from other donors, which may not be as effective.
The rise of gene therapy has provided new hope for people affected by primary immunodeficiencies. The first gene-based treatment, using a gamma-retroviral vector, showed partial success in 1990 in the ultra-rare genetic disorder adenosine deaminase deficiency (ADA-SCID). Patients with this condition lack the ADA enzyme essential for maintaining lymphocyte health, and as a result their immune system falters. However, that approach received a battering when, in a trial at the Necker Hospital in Paris in X-SCID patients, four of the children receiving the treatment developed leukemias. Three of them recovered but one died. Despite major safety concerns, the study highlighted that gene therapy for immunodeficiency disorders could be efficacious, as five of the eight treated patients did not require subsequent immunoglobulin replacement therapy. In addition, it pointed the way towards safer and better gene therapies, including Strimvelis, a marketed gamma-retroviral gene therapy for ADA-SCID developed by GlaxoSmithKline and recently acquired by Orchard Therapeutics.
In the latest results from a Phase 1/2 gene therapy trial conducted at St. Jude Children’s Research Hospital and the University of California, San Francisco Benioff Children’s Hospital, eight infants with X-SCID and no matched sibling donor transplant were given lentiviral vector-based gene therapy jointly developed by the two institutions with support from the California Institute for Regenerative Medicine. The children in the new study also received a low dose of the chemotherapeutic busulfan to remove any immune cell precursors before treatment and reset the immune system.
According to the article detailing the results of this trial in the New England Journal of Medicine, seven of the eight infants achieved normal IgM levels after the gene therapy treatment, a sign that the therapy restored a functional immune system. Four patients no longer needed intravenous immunoglobulin supplementation, and, of these, three even responded to vaccines. All of the children, now toddlers, are growing normally with no serious infections. Each is building a complete set of immune cells of both the innate and adaptive immune systems, including T cells, B cells, and NK cells — a first time achievement for any SCID gene therapy.
“This treatment offers the first complete cure of babies with [X-SCID],” said Ewelina Mamcarz of St. Jude Bone Marrow Transplantation and Cellular Therapy in a statement. Mamcarz hopes that the combination of chemotherapy and lentiviral vector-based gene therapy will provide a template for curing other blood disorders.
The children will be monitored long-term to ensure that their immune system improvement is stable, and to keep an eye out for any side effects. So far, none of the patients have shown signs of leukemia up to two years after treatment. Notably, this lentiviral gene therapy delivery system has been in use in other research contexts for around a decade without any evidence of triggering leukemia-type symptoms.
Mustang Bio licensed the X-SCID gene therapy, now designated MB-107, from St Jude Children’s Research Hospital in August 2018. Another Phase 1/2 clinical trial of MB-107 in children over the age of two is ongoing with the National Institutes of Health. The company plans to start two pivotal trials for 2020 and 2021 in infants younger than two and children over two.
While Strimvelis has been available in Europe for ADA-SCID since 2016 and a number of other gene therapies for ADA-SCID are in development, gene therapy development for the more common X-SCID has lagged behind. French biotechnology company Genethon is developing a lentiviral vector-based X-SCID gene therapy product as part of a European consortium. If MB-107 or Genethon’s therapy, or any others earlier in development, manage to successfully enter the market, these treatments will give children born with SCID, and their parents, new hope.
These results are a significant step forward for gene therapy in a dramatically life-limiting orphan disease. Investigators are now hoping that the same lentiviral approach can work in less severe genetic disorders as well. While the risk/benefit ratio for gene therapies is often favorable for severe intractable orphan diseases like X-SCID, will gene therapy be safe enough to be applicable to more common disorders? And given the high price of gene therapies how will the costs be absorbed by health systems and payers if such treatments are more widely used?