Severe combined immunodeficiency, most commonly known as SCID, consists of a group of rare diseases caused by mutations in different genes during the development of the immune cells that combat infections. As a result, people with this disease have an inefficient immune system. SCID can be recognized by its serious, even life-threatening infections (most predominantly viral infections) which may cause in the patient, as an example, pneumonia (caused by different pathogens such as the fungus Pneumocystis jirovecii) and chronic diarrhea, as well as candidiasis around the mouth and diaper area. If untreated, life expectancy for people with this disease is very short.
Although the most common treatment for this genetic disorder is enzyme replacement therapy with Adenosine Deaminase with polyethylene glycol (known as PGE ADA), a new innovative method of treatment which involves gene therapy to treat X linked SCID (SCID-X1, which is the most common type of SCID) has been proposed. The problem with previous attempts using gene therapy was that, although it was able to successfully restore children’s T cell function, leukemia cases have been reported in approximately one quarter of the children two to five years after treatment.
This new innovative gene therapy is based on the human immunodeficiency virus vector. This is a lentivirus which is able to infect cells that are not dividing. Researchers of the St. Jude’s Children's Hospital and UCSF (University of California- San Francisco) have been able to redesign the lentivirus to transport the normal copy of IL2RG gene (which encodes the protein IL-2 receptor gamma, a cytokine receptor subunit common to the receptor complex of different interleukins) to the stem cells of patients’ blood. The vector included isolators in order to block the possible activation of adjacent genes where IL2RG is inserted, as a method to prevent patients from developing leukemia by activation of an oncogen in the stem cells. This was the reason why two of the patients who underwent the previous treatment, PGE ADA, developed leukemia; in both patients, the corrected gene activated an oncogen known as LMO-2.
This approach led to a successful immune recovery of eight patients under treatment. The vector could be efficiently transduced in many cell lineages, including T cells, B cells, NK cells, myeloid cells and bone marrow progenitors after 3 months. Furthermore, immunoglobulin levels were normalized and the patients gained the capacity of developing normal antibody response, which had never been achieved before in patients with SCID-X. In addition, none of the patients has suffered a potentially mortal infection since they underwent this therapy and the ones who had previous infections successfully recovered from them. These great advances were achieved with just one dose of treatment by all patients except one, who required a second dose.
No secondary effects of this treatment have been described yet, and so, it is unknown how it will affect patients during their lives. The results obtained seem to suggest that most of the patients will develop a durable full immune response without adverse effects.
By Yiaza Anido and Iara Inés Méndez
Second year Degree in Biotechnology. Faculty of Pharmacy. Universidad CEU San Pablo.
Citations:
I., R. “Una Innovadora Terapia Génica Cura a Los 'Niños Burbuja' Sin Efectos Adversos.” Abc, ABC.es, 17 Apr. 2019, https://www.abc.es/salud/enfermedades/abci-innovadora-terapia-genica-cura-ninos-burbuja-sin-efectos-adversos-201904172308_noticia.html.
Medicina, Salud y. “¿Qué Es El ‘Síndrome Del Niño Burbuja’?” Salud y Medicina | Inicio, 20 Sept. 2016, https://www.saludymedicina.org/post/que-es-el-sindrome-del-nino-burbuja.
“Severe Combined Immunodeficiency (SCID).” National Institute of Allergy and Infectious Diseases, U.S. Department of Health and Human Services, https://www.niaid.nih.gov/diseases-conditions/severe-combined-immunodeficiency-scid.
Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1. 18 Apr. 2019, https://www.nejm.org/doi/full/10.1056/NEJMoa181540
Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1. 18 Apr. 2019, https://www.nejm.org/doi/full/10.1056/NEJMoa1815408.
http://www.medisur.sld.cu/index.php/medisur/announcement/view/142
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