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Developmental Biology - Gene Therapy

Gene Therapy Corrects X-SCID

Gene therapy restores immunity in infants with rare immunodeficiency disease...

A small clinical trial shows that gene therapy can safely correct the immune systems of infants with a rare, life-threatening genetic disorder in which immune cells do not develop.

Eight infants with the disorder called X-linked severe combined immunodeficiency (X-SCID) — received an experimental gene therapy co-developed by National Institutes of Health scientists. The therapy substantially improved their immune system function, and they also grew normally for up to two years following treatment. The new approach appears safer and more effective than previously tested gene-therapy strategies for X-SCID.

These interim clinical trial results were supported in part by the National Institutes of Health (NIH) and are published in The New England Journal of Medicine.

X-SCID is caused by mutations in the IL2RG gene, making carriers highly susceptible to severe infections. Left untreated, the disease is fatal, usually within the first year or two of life. X-SCID infants are typically treated with blood-forming stem cell transplants, ideally from a genetically matched sibling. But, fewer than 20 percent of infants with the disease have such a donor. Without a donor matched sibling, X-SCID infants typically receive transplants from a parent or other donor, which can be lifesaving — but often only partially restores immunity. Such patients require lifelong treatment and may continue to experience complex medical problems, including chronic infections.

"A diagnosis of X-linked severe combined immunodeficiency can be traumatic for families," says Anthony S. Fauci MD, director of NIH's National Institute of Allergy and Infectious Diseases (NIAID). "These exciting new results suggest that gene therapy may be an effective treatment option for infants with this extremely serious condition, particularly those who lack an optimal donor for stem cell transplant. This advance offers them the hope of developing a wholly functional immune system and the chance to live a full, healthy life."

To restore immune function to those with X-SCID, scientists at NIAID and St. Jude Children's Research Hospital in Memphis, Tennessee, developed an experimental gene therapy that involves inserting a normal copy of the IL2RG gene into the patient's own blood-forming stem cells. The Phase 1/2 trial reported today enrolled eight infants aged 2 to 14 months who were newly diagnosed with X-SCID and lacked a genetically matched sibling donor. The study was conducted at St. Jude and the Benioff Children's Hospital of the University of California, San Francisco. Encouraging early results from a separate NIAID-led study at the NIH Clinical Center informed the design of the study in infants. The NIH study is evaluating the gene therapy in older children and young adults with X-SCID who previously had received stem cell transplants.
The gene therapy approach involves first obtaining blood-forming stem cells from a patient's bone marrow. Then, an engineered lentivirus that cannot cause illness is used as a carrier, or "vector," to deliver the normal IL2RG gene to the cells. Finally, the stem cells are infused back into the patient, who has received a low dose of the chemotherapy medication busulfan to help the genetically corrected stem cells establish themselves in the bone marrow and begin producing new blood cells.

Normal numbers of multiple types of immune cells, including T cells, B cells and natural killer (NK) cells, developed within three to four months in seven of the eight infants receiving gene therapy. While the eighth participant initially had low numbers of T cells, the numbers greatly increased following a second infusion of genetically modified stem cells. Viral and bacterial infections that participants had prior to treatment resolved afterwards. This experimental gene therapy was safe overall, researchers say, although some participants experienced expected side effects such as a low platelet count following chemotherapy.

"The broad scope of immune function that our gene therapy approach has restored to infants with X-SCID--as well as to older children and young adults in our study at NIH--is unprecedented," said Harry Malech, M.D., chief of the Genetic Immunotherapy Section in NIAID's Laboratory of Clinical Immunology and Microbiology. Dr. Malech co-led the development of the lentiviral gene therapy approach with St. Jude's Brian Sorrentino, MD, who died in late 2018. "These encouraging results would not have been possible without the efforts of my good friend and collaborator, the late Brian Sorrentino, who was instrumental in developing this treatment and bringing it into clinical trials," said Dr. Malech.

Compared with previously tested gene-therapy strategies for X-SCID, which used other vectors and chemotherapy regimens, the current approach appears safer and more effective. In these earlier studies, gene therapy restored T cell function but did not fully restore the function of other key immune cells, including B cells and NK cells. In the current study, not only did participants develop NK cells and B cells, but four infants were able to discontinue treatment with intravenous immunoglobulins — infusions of antibodies to boost immunity. Three of the four developed antibody responses to childhood vaccinations--an indication of robust B-cell function.

Moreover, some participants in certain early gene therapy studies later developed leukemia, which scientists suspect was because the vector activated genes that control cell growth. The lentiviral vector used in the study reported today is designed to avoid this outcome.

Researchers are continuing to monitor the infants who received the lentiviral gene therapy to evaluate the durability of immune reconstitution and assess potential long-term side effects of the treatment. They also are enrolling additional infants into the trial. The companion NIH trial evaluating the gene therapy in older children and young adults also is continuing to enroll participants.

Allogeneic hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency (SCID-X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high-dose chemotherapy is given. In previous studies, autologous gene therapy with ?-retroviral vectors failed to reconstitute B-cell and NK-cell immunity and was complicated by vector-related leukemia.

We performed a dual-center, phase 1–2 safety and efficacy study of a lentiviral vector to transfer IL2RG complementary DNA to bone marrow stem cells after low-exposure, targeted busulfan conditioning in eight infants with newly diagnosed SCID-X1.

Eight infants with SCID-X1 were followed for a median of 16.4 months. Bone marrow harvest, busulfan conditioning, and cell infusion had no unexpected side effects. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3 to 4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. The eighth infant had an insufficient T-cell count initially, but T cells developed in this infant after a boost of gene-corrected cells without busulfan conditioning. Previous infections cleared in all infants, and all continued to grow normally. IgM levels normalized in seven of the eight infants, of whom four discontinued intravenous immune globulin supplementation; three of these four infants had a response to vaccines. Vector insertion-site analysis was performed in seven infants and showed polyclonal patterns without clonal dominance in all seven.

Lentiviral vector gene therapy combined with low-exposure, targeted busulfan conditioning in infants with newly diagnosed SCID-X1 had low-grade acute toxic effects and resulted in multilineage engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK-cell counts during a median follow-up of 16 months. (Funded by the American Lebanese Syrian Associated Charities and others; LVXSCID-ND ClinicalTrials.gov number, NCT01512888.)

Ewelina Mamcarz MD, Sheng Zhou PhD, Timothy Lockey PhD, Hossam Abdelsamed PhD, Shane J. Cross PharmD, Guolian Kang PhD, Zhijun Ma MD, Jose Condori PhD, Jola Dowdy MS, Brandon Triplett MD, Chen Li MS, Gabriela Maron MD, Juan C. Aldave Becerra MD, Joseph A. Church MD, Elif Dokmeci MD, James T. Love MD PhD, Ana C. da Matta Ain MD, Hedi van der Watt MD, Xing Tang PhD, William Janssen PhD, Byoung Y. Ryu PhD, Suk See De Ravin MD PhD, Mitchell J. Weiss MD, Ph.D., Benjamin Youngblood PhD, Janel R. Long-Boyle PharmD PhD, Stephen Gottschalk MD, Michael M. Meagher PhD, Harry L. Malech MD, Jennifer M. Puck MD, Morton J. Cowan MD and Brian P. Sorrentino, MD.

Supported by the American Lebanese Syrian Associated Charities; by grants from the California Institute of Regenerative Medicine (CLIN2-09504), the National Heart, Lung, and Blood Institute (P01 HL053749), the National Cancer Institute (CA21765), the intramural program of the National Institute of Allergy and Infectious Diseases (NIAID) (Z01-AI-00988, to Drs. De Ravin and Malech), and the NIAID (U54-AI082973, to Drs. Cowan and Puck); and by the Assisi Foundation of Memphis.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this SCID-X1 gene therapy.

We recognize the major contributions of our deceased colleague, Dr. Brian P. Sorrentino, who initiated this work and brought it to fruition with a successful clinical trial. We thank Dr. Arthur Nienhuis for his long-term support, inspiration, and discussions; the staff at the Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, and the staff at the Bone Marrow Transplant Program, University of California, San Francisco, Benioff Children’s Hospital, for their care of these children and support of this study; Dr. Don Kohn for his discussions about and help with establishing the bone marrow harvest procedure; Drs. Mary Ellen Conley and Andrew Scharenberg for their help and insights in planning and designing the study and Dr. Robert Throm from the Vector Production and Development laboratory at St. Jude Children’s Research Hospital for his discussions about and work in vector production and cell transduction; Drs. Taihe Lu and Soghra Fatima from the Department of Hematology at St. Jude Children’s Research Hospital and Dr. Jean-Yves Metais, Ms. Sara Schell, and Ms. MaCal Tuggle from the Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, for their technical assistance in analyzing patient samples; Dr. Thasia Leimig and Ms. Suzette Wingo from the Department of Therapeutics Production and Quality, St. Jude Children’s Research Hospital, for their work in cell production; Ms. Jane Stringfellow and Ms. Terri Davis for their administrative support of the St. Jude investigative team; Drs. Christine Narrin-Talbot and Wayne Wolfrey for their contributions to recruiting patients for the study; and, most of all, the families that participated in our study.


The gene therapy trial in infants is funded by the American Lebanese Syrian Associated Charities (ALSAC), and by grants from the California Institute of Regenerative Medicine and the National Heart, Lung, and Blood Institute, part of NIH, under award number HL053749. The work also is supported by NIAID under award numbers AI00988 and AI082973, and by the Assisi Foundation of Memphis. More information about the trial in infants is available on ClinicalTrials.gov using identifier NCT01512888. More information about the companion trial evaluating the treatment in older children and young adults is available using ClinicalTrials.gov identifier NCT01306019.

Reference: E Mamcarz et al. Lentiviral gene therapy with low dose busulfan for infants with X-SCID. The New England Journal of Medicine DOI: 10.1056/NEJMoa1815408 (2019).

NIAID conducts and supports research--at NIH, throughout the United States, and worldwide--to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

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