NEJM has published a successful phase I/II trial of a lentiviral gene therapy for the treatment of infants with XSCID (bubble boy disease)

Mustang Bio, Inc. announced that the New England Journal of Medicine has published data from St. Jude Children’s Research Hospital the nation’s leading hospital dedicated to understanding, treating and curing childhood cancer and other life-threatening diseases. The data comes from a Phase 1/II clinical trial of a lentiviral gene therapy for the treatment of newly diagnosed infants under two years old with XSCID, also referred to as SCID-X1 and commonly known as bubble boy disease. Under a licensing agreement with St. Jude, Mustang will develop the lentiviral gene therapy for commercial use as MB-107.

The multi-center Phase 1/II clinical trial is evaluating the safety and efficacy of a lentiviral vector to transfer a normal copy of the IL2RG gene to bone marrow stem cells in newly diagnosed infants under the age of two with XSCID, preceded by low exposure-targeted busulfan conditioning. A total of 10 infants have received the therapy to date in this clinical trial. The published data covers eight infants with XSCID who were treated at St. Jude and at UCSF Benioff Children’s Hospital and followed for a median of 16.4 months.

Data Highlights: Bone marrow harvest, busulfan conditioning and cell infusion were well tolerated. In seven of the eight cases, normalization of CD3+, CD4+ and CD4+ naïve T-cell and natural killer (“NK”) cell numbers occurred within three to four months after treatment, accompanied by vector marking in T, B, NK and myeloid cells and marrow progenitors. The eighth infant had insufficient T cells initially, but normalization of T cells occurred following an unconditioned boost of gene-corrected cells, and the patient is progressing favorably. All patients cleared previous infections and are growing normally. Seven of the eight infants treated have developed normal IgM levels to date. Four of these seven infants have discontinued monthly infusions of intravenous immunoglobulin (IVIG) therapy to date. Three of those four infants that discontinued monthly IVIG infusions have responded to vaccines to date. Most patients were discharged from the hospital within one month.

The gene therapy was developed in the laboratory of the late Brian Sorrentino, M.D., formerly of the St. Jude Department of Hematology, and produced in the St. Jude Good Manufacturing Practice facility. The multi-center Phase 1/II clinical trial is led by Ewelina Mamcarz, M.D., assistant member at St. Jude. Other participating sites and key collaborators are at UCSF Benioff Children’s Hospital, the National Institutes of Health (NIH) and Seattle Children’s Hospital.

“The results have been very good thus far. We’ve been able to restore a full immune system pretty quickly,” Mamcarz said. “All of these patients were able to come off of isolation and they’ve returned home with immune systems that were fully functional. We had patients come to us with very severe infections and they cleared them through the emergence of this newly developed immune system.” For additional information, visit ClinicalTrials.gov: NCT01512888.

X-linked severe combined immunodeficiency (XSCID) is a rare genetic disorder that occurs in approximately 1 per 200,000 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 (yc), a protein that is shared by the receptors for at least six interleukins. These interleukins and their receptors are critical for the development and differentiation of immune cells. The gene coding for yc 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.

See- "Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1."_ Ewelina Mamcarz, M.D., Sheng Zhou, Ph.D., Timothy Lockey, Ph.D., et al. April 18, 2019N Engl J Med 2019; 380:1525-1534 DOI: 10.1056/NEJMoa1815408.