Severe combined immunodeficiency (SCID), also known as the “bubble boy disease,” is a rare genetic disease that affects people around the world. Characterized by gross deficiencies in the immune system, the disease is so dubbed colloquially because a child with SCID in the 1970s and 80s famously lived in a plastic bubble to protect himself from opportunistic infections. He was the longestliving child with SCID at the time, when the plastic bubble was the only treatment option available. While SCID used to be a fatal disease with no real treatments, it can now be managed by enzyme replacement and bone marrow transplants. Promising research has recently shown that gene therapy may soon replace these traditional therapies.
The Immune System
SCID generally affects the patient’s B and T cells. B and T cells are the main components of the adaptive immune system that works in conjunction with the innate immune system to protect the body from foreign pathogens. The innate immune system recognizes and attacks invading cells, which may destroy invading pathogens but may not completely fight off the infection alone. The adaptive system then helps the innate by recognizing pathogens and responding specifically to each one. In addition, the adaptive immune system remembers each pathogen it has encountered and can launch a faster, more effective response against the same pathogen in the future.
What is ADA-SCID?
One of the more common forms of SCID is ADA-SCID, so named because the mutation affects the formation of the enzyme adenosine deaminase (ADA). Adenosine deaminase breaks down byproducts of DNA formation in the cell. When the enzyme is not working, as in ADA-SCID patients, these byproducts accumulate in the cell. This accumulation creates a toxic environment that kills emerging immune system cells before they can mature. With almost no B or T cells, people with ADA-SCID essentially have no adaptive immune system.
Treating ADA-SCID: Traditional Methods
Traditionally, ADA-SCID has been managed with enzyme replacement therapy. Doctors inject the ADA-SCID patients with the missing adenosine deaminase, but this treatment can be problematic. As Associate Professor of Immunobiology Eric Meffre says, “You can detoxify the cell serum, but it is not as efficient as healthy systems because the enzyme that you give intravenously does not get into the cells themselves. Although it improves the patients’ conditions, it still does not reconstitute the immune system.” This treatment is not considered a cure, and other options are usually explored as long-term options for ADA-SCID patients.
One accepted cure for ADA-SCID is a bone marrow transplant. If the transplant is accepted by the patient’s immune system, no other treatments are needed. However, donors must be biological matches with recipients, which are usually limited to family members, so marrow transplants are often unavailable.
Treating ADA-SCID: New Options
Recent research has shown that gene therapy may be a viable alternative to the traditional transplant. Currently, it is available at a select number of institutions including the National Institutes of Health (NIH). So far, 20-30 individuals have been treated and all have survived. A multi-institutional research team led by Meffre is working to better understand the implications of this treatment. To perform gene therapy for ADA-SCID, doctors first isolate stem cells from the patients. They then transform these cells into functional bone marrow cells by infecting the stem cells with a retrovirus whose genome contains a functional version of ADA. These cells then have normal metabolic function and can be re-injected into the patient, who will then express normal ADA function and no longer be immunodeficient. So far, ADA gene therapy has been the only successful gene therapy trial. Some patients have been followed for more than ten years, and no significantly problematic side effects have been observed. As Meffre says, “The patients are alive and have normal lives. The kids go to school.” Though not life-threatening, autoimmune reactions have sometimes been observed as a side effect from ADA gene therapy.
Understanding the Side Effects
Because the autoimmune side effects are not fully understood, Meffre and his team examined this phenomenon in greater detail. Meffre says, “What we think is happening is that you get a system that is just partially fixed. When you do gene therapy, not all the stem cells in gene therapy may be corrected. This means that, at the end, you may still have a patient that is a mosaic.” Meffre thinks that the toxic accumulation of metabolites signals a receptor, which then block receptors for autoreactive B cells. When doctors artificially give adenosine deaminase, B and T cells develop and proliferate, but nearly all the B cells that exit the bone marrow are autoreactive. This problem affects patients treated with enzyme injections as well as gene therapy patients.
Finding Children with SCID
Due to these potential side effects, gene therapy is only considered for life-threatening diseases that affect children early in life. Most SCID patients are diagnosed at birth or shortly after because of noticeable immune problems. Some states mandate screening for SCID diseases at birth, including Connecticut, where Yale-New Haven Hospital serves as the center for SCID screening. Early diagnosis also gives doctors a longer window to look for a bone marrow donor; there are no side effects from bone marrow transplant if it occurs before the child’s first birthday. Unfortunately, high costs have prevented SCID blood screenings from achieving universal adoption.
The Future of Gene Therapy
While ADA gene therapy has been initially successful, Meffre says that expanding the treatment to other diseases is not viable until gene therapy technology improves. In another gene therapy trial, doctors treated four patients, and two of these patients died from lymphoma. In this trial, overexpression of the gene caused unrestrained proliferation of T-cells and lymphoma. Overexpression resulted because when the retrovirus infected the genome with the corrected gene, it inserted itself into a more active area of the genome. Scientists cannot yet target the location of this retroviral insertion and instead use a completely random process. Technology to target the retrovirus to infect specific areas of the genome, preferably at the exact place where the gene is normally located in the human genome, must be developed before gene therapy can be applied to other diseases.
Despite these difficulties, gene therapy will always be an attractive treatment possibility for gene-related diseases because it is truly à la carte medicine. Once technology is developed, the treatment has the potential to cure any genetic disease, even ones caused by rare or de novo mutations. Of course, some diseases will be easier to treat than others, such as those in which the body tissue of interest (in this case, bone marrow) is easier to isolate and target. Clinical trials for ADA-SCID have provided the first successful, safe use of this exciting technology in the process of saving lives. For those still struggling with other genetic diseases, treatment is not yet possible, but relief may soon come.
About the Author
Elisa Visher is a junior in Trumbull College double majoring in Anthropology and Biology. She works in the Yale Molecular Anthropology Lab and Paul Turner Lab.
Acknowledgements
The author would like to thank Professor Eric Meffre for his time, patience, and comprehensive explanation of ADA-SCID and its treatment.
Further Reading
Sauer, AV, H Morbach, I Brigida, A Aiuti, and E Meffre. “Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy.” Journal of Clinical Medicine 2012; 122 (6): 2141–2152.