SCID: A Genetic Disease that Can Be Treated with Gene Therapy
Gene Therapy for Severe Combined Immunodeficiency (SCID)
Severe combined immunodeficiency (SCID) is a rare genetic disorder that affects the development and function of the immune system. Infants with SCID are highly vulnerable to life-threatening infections and require prompt diagnosis and treatment to survive. In this article, we will explain what SCID is, what causes it, how it is diagnosed and treated, and how gene therapy can offer a potential cure for some types of SCID.
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What is SCID and what causes it?
SCID stands for severe combined immunodeficiency, which means that both the innate and adaptive branches of the immune system are severely impaired. The innate immune system consists of cells and molecules that provide a general defense against pathogens, while the adaptive immune system consists of cells and molecules that provide a specific and memory-based defense against pathogens. Both systems work together to protect the body from infections.
SCID is caused by mutations in different genes that are involved in the development and function of infection-fighting immune cells, such as T cells, B cells, and natural killer (NK) cells. These cells are produced in the bone marrow from stem cells and then mature in the thymus or other lymphoid organs. T cells help coordinate the immune response and kill infected cells, B cells produce antibodies that bind to pathogens and mark them for destruction, and NK cells kill abnormal or infected cells.
There are more than a dozen types of SCID, each caused by a mutation in a different gene. The most common type is X-linked SCID (XSCID), which affects only males and is caused by a mutation in the IL2RG gene on the X chromosome. This gene encodes a protein that is part of several receptors for cytokines, which are molecules that regulate the growth and activation of immune cells. Without this protein, T cells and NK cells cannot develop normally, and B cells cannot function properly.
Another common type of SCID is caused by a deficiency of an enzyme called adenosine deaminase (ADA), which is involved in purine metabolism. Purines are building blocks of DNA and RNA, and their excess accumulation can be toxic to cells. ADA converts adenosine to inosine, which can then be further metabolized or excreted. Without ADA, adenosine accumulates in the blood and lymphoid tissues, where it interferes with the survival and function of T cells, B cells, and NK cells.
A less common type of SCID is caused by a deficiency of another enzyme called Artemis, which is involved in DNA repair. DNA repair is essential for maintaining the integrity of the genetic material during cell division and after exposure to radiation or chemicals. Artemis helps repair double-strand breaks in DNA, which are particularly frequent during the rearrangement of genes that encode receptors for antigens on T cells and B cells. Antigens are molecules that trigger an immune response. Without Artemis, T cells and B cells cannot generate diverse receptors for antigens, which limits their ability to recognize and respond to pathogens.
Symptoms and diagnosis of SCID
Infants with SCID appear healthy at birth, but soon develop recurrent and severe infections, especially viral infections, which may result in pneumonia, meningitis, sepsis, or chronic diarrhea. They may also develop fungal infections, such as candidiasis of the mouth and diaper area, or pneumonia caused by Pneumocystis jirovecii. They may also develop bacterial infections, such as otitis media, sinusitis, or skin infections. These infections are often resistant to antibiotics and can be fatal if not treated promptly and aggressively.
Other symptoms of SCID may include failure to thrive, poor growth, weight loss, skin rashes, chronic cough, wheezing, or eczema. Some infants with SCID may also have other abnormalities, such as low levels of calcium in the blood (hypocalcemia), which can cause seizures or muscle spasms, or low levels of platelets in the blood (thrombocytopenia), which can cause bleeding or bruising.
The diagnosis of SCID is based on clinical signs and symptoms, family history, and laboratory tests. The most important laboratory test for SCID is the measurement of T cell receptor excision circles (TRECs), which are byproducts of T cell development. Because infants with SCID have few or no T cells, the absence of TRECs may indicate SCID. This test can be performed on a blood sample taken from the heel of a newborn as part of the routine newborn screening program. Newborn screening for SCID has been implemented in all 50 states in the United States since 2018 and has been shown to improve the survival and outcome of infants with SCID by allowing early diagnosis and treatment.
To confirm the diagnosis of SCID, a doctor will evaluate the numbers and types of T cells, B cells, and NK cells present in the blood and their ability to function. The doctor will also perform genetic tests to identify the specific gene mutation that causes SCID. This information is important for determining the best treatment option and providing genetic counseling to the family.
Conventional treatment options for SCID
The main goal of treatment for SCID is to restore the immune system and prevent infections. There are three conventional treatment options for SCID: antibiotics and immunoglobulins, enzyme replacement therapy, and stem cell transplantation.
Antibiotics and immunoglobulins
Antibiotics are drugs that kill or inhibit the growth of bacteria. They are used to treat bacterial infections that occur in infants with SCID. However, antibiotics do not treat the underlying cause of SCID and do not prevent viral or fungal infections. Therefore, antibiotics are only a temporary and supportive measure until a definitive treatment is available.
Immunoglobulins are proteins that contain antibodies that bind to pathogens and mark them for destruction by other immune cells. They are derived from the plasma of healthy donors who have been exposed to various antigens. They are given to infants with SCID by intravenous infusion every few weeks to provide passive immunity against common pathogens. However, immunoglobulins do not provide long-term immunity and do not stimulate the production of T cells or B cells. Therefore, immunoglobulins are also only a temporary and supportive measure until a definitive treatment is available.
Enzyme replacement therapy
Enzyme replacement therapy is a treatment that involves giving the missing or defective enzyme to patients who have a genetic deficiency of that enzyme. For example, patients with ADA deficiency SCID can receive injections of ADA every few days to lower the levels of adenosine in their blood and lymphoid tissues. This can improve their immune function and reduce their susceptibility to infections.
However, enzyme replacement therapy is not a cure for SCID and has several limitations. It is expensive, requires lifelong administration, does not correct the gene defect in the stem cells, does not restore normal T cell and B cell development, and may cause side effects such as allergic reactions or immune responses against the foreign enzyme.
Stem cell transplantation
Stem cell transplantation is a treatment that involves giving healthy stem cells from a donor to a patient who has defective stem cells. Stem cells are immature cells that can differentiate into various types of cells, such as blood cells or immune cells. Stem cell transplantation can potentially cure SCID by replacing the patient's defective stem cells with donor stem cells that can produce normal T cells, B cells, and NK cells.
and allowing them to produce normal T cells, B cells, and NK cells. Gene therapy can potentially cure SCID by restoring normal gene function in the patient's own stem cells and allowing them to produce normal T cells, B cells, and NK cells. Gene therapy has been developed and tested for several types of SCID, including X-linked SCID, ADA deficiency SCID, and Artemis deficiency SCID. Gene therapy has shown promising results in clinical trials, with most patients achieving immune reconstitution and being able to discontinue conventional treatments. However, gene therapy also has some limitations and challenges, such as high cost, complexity, potential side effects, and ethical issues. Therefore, gene therapy is not yet widely available or approved for all patients with SCID. Further research and development are needed to improve the safety, efficacy, durability, and accessibility of gene therapy for SCID.
FAQs
Here are some frequently asked questions about gene therapy for SCID:
What is the difference between gene therapy and stem cell transplantation?
Gene therapy involves correcting or replacing the defective gene that causes SCID in the patient's own stem cells and returning them to the patient. Stem cell transplantation involves giving healthy stem cells from a donor to a patient who has defective stem cells.
Is gene therapy a cure for SCID?
Gene therapy can potentially cure SCID by restoring normal gene function in the patient's own stem cells and allowing them to produce normal T cells, B cells, and NK cells. However, gene therapy is not yet widely available or approved for all patients with SCID. Gene therapy may also have some limitations and challenges, such as high cost, complexity, potential side effects, and ethical issues.
What are the risks of gene therapy for SCID?
Gene therapy involves risks of complications such as infection, bleeding, organ damage, or malignancy that may occur with conditioning or vector delivery. Gene therapy may also cause side effects such as allergic reactions or immune responses against the vector or the corrected cells. Gene therapy may also cause unintended consequences such as insertional mutagenesis, off-target effects, or germline transmission that may affect the safety or efficacy of gene therapy.
Who can receive gene therapy for SCID?
Gene therapy is currently only available for patients with SCID who participate in clinical trials or who have access to specialized centers that offer gene therapy. Gene therapy is not yet widely available or approved for all patients with SCID. Gene therapy may also not be suitable or effective for all types of SCID or all patients with SCID.
How can I find out more about gene therapy for SCID?
You can find out more about gene therapy for SCID by talking to your doctor or genetic counselor, who can provide you with more information and guidance about your condition and treatment options. You can also visit websites of organizations that support research and advocacy for SCID and gene therapy, such as the Immune Deficiency Foundation (https://primaryimmune.org/), the National Organization for Rare Disorders (https://rarediseases.org/), or the American Society of Gene & Cell Therapy (https://www.asgct.org/).
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