Manuel Litchman, MD, President, Chief Executive Officer at Mustang Bio discusses his company’s X-linked severe combined immunodeficiency (SCID) program.

X-linked SCID is an inherited disorder of the immune system that occurs almost exclusively in males. Boys with X-linked SCID are prone to recurrent and persistent infections because they lack the necessary immune cells to fight off certain bacteria, viruses, and fungi. Many infants with X-linked SCID develop chronic diarrhea, a fungal infection called thrush, and skin rashes. Affected individuals also grow more slowly than other children. Without treatment, males with X-linked SCID usually do not live beyond infancy.

X-linked SCID is the most common form of severe combined immunodeficiency. Its exact incidence is unknown, but the condition probably affects at least 1 in 50,000 to 100,000 newborns.

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.

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.

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