X-linked severe combined immunodeficiency (XSCID) is a rare genetic disorder that occurs in 1-2 per 100,000 births. It is characterized by the absence or lack of function of key immune cells, resulting in a severely compromised immune system and death by one year of age if untreated. Patients with XSCID, also known as bubble boy disease, have no T cells or natural killer cells; although their B cells are normal in number, they are not functional. As a result, XSCID patients are usually affected by severe bacterial, viral, or fungal infections early in life and often present with interstitial lung disease, chronic diarrhea, and failure to thrive.
The specific genetic disorder that causes XSCID is a mutation in the gene coding for the common gamma chain (γc), a protein that is shared by the receptors for at least 6 interleukins. These interleukins and their receptors are critical for the development and differentiation of immune cells. The gene coding for γc is known as IL-2 receptor gamma, or IL2RG; since IL2RG is located on the X-chromosome, XSCID is inherited in an X-linked recessive pattern, resulting in almost all patients being male.
Ideally, for earliest treatment and best clinical outcome, XSCID is diagnosed by newborn screening or family history, rather than by symptoms. Standard of care for XSCID is hematopoietic stem cell transplantation (HSCT), which has been successful using either a matched related or unrelated donor, or a half-matched donor, who would be either parent. The half-matched type of transplant is called haploidentical. Physicians have also had success by using umbilical cord blood, which is rich in stem cells. Overall survival for the 10% of patients who have matched sibling donors is up to 95%; however, it falls to 60-75% with other types of transplant, with over 50% of these patients requiring lifelong intravenous immunoglobulin therapy. In addition, 28% experience acute graft-vs-host disease (GvHD), 15% experience chronic GVHD, and T-cell immunity may decrease over time. Twenty-six percent of patients require a second HSCT due to poor T-cell reconstitution.
For almost 20 years, investigators have been conducting clinical trials with ex vivo gene therapy for XSCID either as an alternative to HSCT or following a poor outcome post-HSCT. Transduction of normal copies of the mutated IL2RG gene into hematopoietic stem cells using a gamma-retroviral vector has resulted in reconstitution of NK and T cells in most patients, but without generation of functional B cells. Furthermore, in early trials, treatment resulted in vector-induced leukemia in 25% of patients due to insertion of the gene-carrying retrovirus near an oncogene.
St. Jude Children’s Research Hospital has developed a safety modified lentiviral (LV) vector which is currently being investigated in a multicenter clinical trial in conjunction with reduced-exposure busulfan conditioning for newly diagnosed infants with XSCID. Eight patients have been treated to date, and the therapy has been well tolerated. Six patients have achieved reconstituted immune systems within three to four months following treatment, with the remaining two patients continuing to progress favorably in earlier stages of recovery. Two of these six patients have discontinued monthly infusions of intravenous immunoglobulin – an indication that their B cells are now functional – and the remaining patients, at earlier stages of recovery, continue to progress favorably.
A similar trial is being conducted with this vector at the National Institutes of Health (NIH) in patients over the age of two with persistent disease after one or more haploidentical HSCTs. In this trial, five patients aged 10 to 23 years have been treated and, again, the therapy appears to be safe. Follow-up data from two older patients have demonstrated immune system reconstitution and clinical improvement at 2 to 3 years following treatment. In three younger patients, similar levels of gene-modified immune cells have also been observed at 6 to 9 months following treatment.
Both trials continue to accrue patients, with patients under the age of two being treated at St. Jude, UCSF Benioff Children’s Hospital San Francisco and Seattle Children’s Hospital, and older patients being treated at the NIH.