Severe Combined Immune Deficiency (Bubble Boy Disease)

Overview

Severe Combined Immune Deficiency (SCID), also known as “bubble boy disease,” is a genetic, uniformly lethal disease that causes babies to be born without functioning immune systems. SCID can be caused by a number of mutations in genes required for the formation of lymphocytes: the immune cells in our body responsible for fighting off a variety of infections. Sometimes, bad copies of these genes are inherited from the parents; other times, they arise spontaneously. Because babies born with SCID do not produce functional lymphocytes, their ability to fight off infections or diseases is severely limited; therefore, even minor viral illnesses can be deadly. Left untreated, SCID-afflicted children die before age two. [1]

SCID affects approximately 1 in 58,000 newborns. [2] While SCID is an extremely rare condition, its prevalence is disproportionately higher in certain demographics; for instance, one in every 2,000 Navajo and Apache children are born with SCID. [3] SCID screening for all newborn infants has been mandatory in California since 2011.

Currently, the standard treatment for SCID babies is a bone marrow transplant, in which stem cells from a healthy donor—most often, a half-matched relative —replace the recipient’s dysfunctional lymphocytes. However, in order for the donor stem cells to be accepted by the patient’s bone marrow, “space” in the bone marrow niche needs to be created by eliminating the patient’s own blood-forming stem cells. Currently, the only way to eliminate the patient’s own blood-forming stem cells is through “conditioning” (treating the recipient to accept donor cells using toxic agents such as radiation and chemotherapy). Unfortunately, this aggressive procedure is extremely dangerous. Because bone marrow transplants often involve powerful, toxic agents, they carry great risk for SCID babies, most of whose immune systems are already significantly compromised. Tragically, the 5-year survival rate for SCID patients who undergo bone marrow transplants is only 75%. [4]

Gene therapy has been used to correct the mutation in certain types of SCID, but early techniques have proven risky for many patients. In gene therapy, scientists engineer blood cells to carry the gene that is missing or mutated in SCID; they then transplant these modified cells back into the patient, in hopes that the new cells will repopulate the patient’s immune system. Several of California’s foremost stem cell scientists, including Dr. Donald Kohn at UCLA, have pioneered safer gene therapy techniques. While these early results have shown promise, is important to remember these results are early, and these techniques have only been tested in in small patient populations. [5]

Progress towards a cure

California’s stem cell agency, the California Institute for Regenerative Medicine—formed in 2004, when voters passed Proposition 71—has awarded more than $110 million in funding to researchers studying Severe Combined Immune Deficiency (SCID).

One approach, taken by Dr. Inder Verma at the Salk Institute, is to obtain skin cells or fibroblasts from SCID patients and correct mutations that cause SCID. [6] Dr. Verma and colleagues were able to revert the patient cells to a pluripotent state, and then use gene-editing technology to actually correct the SCID-causing gene mutation. Once corrected, these cells were able to develop into functional lymphocytes that couldn’t be produced before. While this approach is still in its early stages of testing, the team’s results could lead to the development of a personalized therapy without the risks associated with gene therapy.

A new therapeutic approach for SCID, pioneered by Dr. Judith Shizuru at Stanford University and Dr. Morton Cowan at the University of California, San Francisco, shows tremendous potential to treat this devastating disease, and many other conditions. Their approach would replace existing, highly toxic bone marrow transplants with “chemotherapy-free” bone marrow transplants. The key is an antibody that recognizes the defective blood forming stem cells in SCID patients, and specifically eliminates them without killing other healthy cells. Targeting the stem cells of patients with SCID with this antibody would allow the patient to accept functional blood-forming stem cells from donors. Antibody targeting is substantially less toxic than standard treatments, and could result in safer bone marrow transplants. If successful, the applications of this work could extend not only to SCID, but to a multitude of other blood disorders and autoimmune diseases, including Type 1 Diabetes, Rheumatoid Arthritis and Multiple Sclerosis. Furthermore, this therapeutic approach could have critical implications for solid organ transplants, including kidney, heart, liver and lung transplants. The team hopes that this approach will become a revolutionary platform for all transplants.

In animal models, this procedure has allowed engraftment (acceptance) of donor stem cells at a high rate, and has rapidly replaced diseased blood cells with healthy blood cells. The result is a stronger blood system, with no need for chemotherapy, thus dramatically reducing the risk of bone marrow transplants.

Selected disease and research progress information provided by the California’s stem cell research funding agency, the California Institute for Regenerative Medicine (CIRM). Visit www.cirm.ca.gov for more updates.

Featured Image: Colton Ainslee, 5, And His Younger Sister, Abbygail, 14 Months: Patients in Dr. Donald Kohn’s SCID clinical trial at UCLA. Source.

Footnotes

[1] Author, No.  “SCID Fact Sheet.”  California Institute for Regenerative Medicine.  Web.  Accessed 4 February 2016.  https://www.cirm.ca.gov/our-progress/scid-fact-sheet

[2] Bock, Robert and Hillary Hoffman.  “Test Reliably Detects Inherited Immune Deficiency in Newborns.”  20 August 2014. National Institutes of Health.  Web.  Accessed 16 February 2016.  https://www.niaidnih.gov/news/newsreleases/2014/Pages/SCIDnewborns.aspx

[3] Kelly, Brian T et al. “Screening for Severe Combined Immunodeficiency in Neonates.” Clinical Epidemiology 5 (2013): 363–369. PMC. Web. 17 Feb. 2016.

[4] Buckley, Rebecca et al.  “Transplantation Outcomes for Severe Combined Immunodeficiency, 2000–2009.”  New England Journal of Medicine 371 (2014):434-446.  Web. 16 Feb. 2016.

[5] Id.

[6] Verma, Inder.  “Curing Hematological Diseases.”  California Institute for Regenerative Medicine.  Web.  Accessed 16 February 2016.  https://www.cirm.ca.gov/our-progress/awards/curing-hematological-diseases

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