Gene therapy restores immunity in infants with rare immunodeficiency disease

Press release

Wednesday, April 17, 2019

Scientists and NIH funding contributed to the development of an experimental treatment

A small clinical trial has shown that gene therapy can safely fix the immune system in infants newly diagnosed with a rare, life-threatening hereditary disorder in which immune cells fighting infection do not develop. or do not work normally. Eight infants with this disorder, called X-linked severe combined immunodeficiency (X-SCID), received experimental gene therapy developed jointly by scientists from the National Institutes of Health. They showed substantial improvements in the function of the immune system and developed normally up to two years after treatment. The new approach seems safer and more effective than previously tested gene therapy strategies for X-SCID.

Preliminary results of the clinical trial, supported in part by the NIH, were published today in The New England Medical Journal.

Infants with X-SCID, caused by mutations in IL2RG gene, are very susceptible to serious infections. If left untreated, the disease is fatal, usually in the first year or two years of life. Infants with X-SCID are usually treated with hematopoietic stem cell transplants, ideally from a sibling or genetically matched sister. However, less than 20% of infants with the disease have such a donor. Those who are not matched usually receive a transplant from a parent or other donor, which saves life, but often only partially restores immunity. These patients require lifelong treatment and may continue to suffer from complex medical problems, including chronic infections.

"A diagnosis of severe combined immunodeficiency linked to X can be traumatic for families," said Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH. "These exciting new findings suggest that gene therapy could be an effective treatment option for infants with this extremely serious disease, especially those who do not have an optimal donor for stem cell transplantation. This breakthrough offers them the hope of developing a fully functional immune system and the chance to lead a healthy and full life. "

To restore the immune function of people with X-SCID, scientists at NIAID and St. Jude's Children's Research Hospital in Memphis, Tenn., Have developed experimental gene therapy to insert a normal IL2RG gene in the patient's hematopoietic stem cells. The Phase 1/2 trial announced today included eight infants aged 2 to 14 months recently diagnosed with X-SCID and without a genetically matched sibling donor. The study was conducted at St. Jude Hospital and Benioff Children's Hospital at the University of California, San Francisco. Preliminary results encouraging a separate study conducted by NIAID at the NIH Clinical Center informed study design in infants. The NIH study evaluates gene therapy in older children and young adults with X-SCID who have previously undergone a stem cell transplant.

The approach of gene therapy first involves obtaining hematopoietic stem cells from the bone marrow of a patient. Then, an artificial lentivirus that can not cause disease is used as a vector, or "vector," to deliver the normal virus. IL2RGgene to the cells. Finally, the stem cells are reinjected into the patient, who has received a low dose of busulfan, a chemotherapy drug, to help genetically-corrected stem cells build up in the bone marrow and produce new blood cells.

A normal number of multiple types of immune cells, including T cells, B cells and natural killer cells (NK), developed three to four months after gene therapy in seven of eight infants. While the eighth participant initially had a low T cell count, this number increased dramatically as a result of a second infusion of genetically modified stem cells. The viral and bacterial infections that the participants had before the treatment disappeared afterwards. According to the researchers, experimental gene therapy was generally safe, although some participants presented with the expected side effects, such as a low platelet count after chemotherapy.

"The broad range of immune functions that our gene therapy approach has restored in infants with X-SCID – as well as in older children and young adults in our NIH study – is unprecedented," said Harry Malech. , MD, Head of the Department of Genetics Immunotherapy Section of the NIAID Laboratory for Clinical Immunology and Microbiology. Dr. Malech co-led the development of the lentiviral gene therapy approach with Brian Sorrentino, MD, of St. Jude, 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 played a key role in the development of this treatment and its integration 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 seems 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 present study, participants not only developed NK cells and B cells, but four infants were able to discontinue intravenous immunoglobulin therapy – infusions of antibodies to enhance their immunity . Three of the four people developed an antibody response to childhood vaccination – an indication of a robust B-cell function.

In addition, some participants in some early gene therapy studies eventually developed leukemia, which scientists suspect to be due to the fact that the vector has activated the genes that control cell growth. The lentiviral vector used in the study presented today is designed to avoid this result.

Researchers continue to monitor infants who have received lentiviral gene therapy to assess the durability of immune reconstitution and the potential long-term side effects of treatment. They also enroll additional children in the trial. The related NIH trial evaluating gene therapy in older children and young adults also continues to recruit participants.

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

NIAID conducts and supports research – at NIH, in the United States, and around the world – to investigate the causes of infectious and immune-mediated diseases and to develop better ways to prevent, diagnose and treat these diseases. NIAID press releases, fact sheets and other documents are available on the NIAID website.

About the National Institutes of Health (NIH):
The NIH, the country's medical research agency, has 27 institutes and centers and is part of the US Department of Health and Human Services. NIH is the lead federal agency that leads and supports basic, clinical and translational medical research. She studies causes, treatments and cures for common and rare diseases. For more information on NIH and its programs, visit www.nih.gov.

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