Adenosine Deaminase Deficiency: Treatment, Bone Marrow Transplant, Gene Therapy

Adenosine Deaminase Deficiency, commonly called ADA deficiency, is a very rare genetic disorder, documented as occurring in fewer than one in 100,000 live births worldwide. This disease is also quite lethal, leading to death in virtually all those afflicted if not treated. The disease is an autosomal recessive disease caused by receiving a deficient ADA gene from both parents. The ADA gene codes for the enzyme Adenosine Deaminase which is essential for the proper functioning of the human body's immune system. People afflicted with this disease often have to live in a sheltered or enclosed environment, so that they're not exposed to infectious agents. Individuals with ADA deficiency inherit defective ADA genes and are unable to produce the enzyme adenosine deaminase in their cells. This enzyme is needed to break down metabolic byproducts that become toxic to T cell lymphocytes. Most of the body's cells have other means of removing the metabolic byproducts that ADA helps break down and remain unaffected by ADA deficiency

Without ADA, the toxins derived from the metabolic byproducts kill the T cells shortly after they are produced in the bone marrow. Instead of having a normal life span of a few months, T cells of individuals with ADA deficiency live only a few days. Consequently, their numbers are greatly reduced, and the body's entire immune system is weakened. The body's immune system includes T cell lymphocytes and B cell lymphocytes; these lymphocytes play different roles in fighting infections. B cells produce antibodies that lock on to disease-causing viruses and bacteria, thereby marking the pathogens for destruction. Unlike B cells, T cells cannot produce antibodies, but they do control B cell activity. T cell helpers enable antibody production, whereas T cell suppressors turn off antibody production. Another T cell subtype kills cancer cells and virus-infected cells.

Because T cells control B cell activity, the reduction of T cells results in an absence of both T cell and B cell function, culminating in a condition known as severe combined immunodeficiency (SCID). Individuals with SCID are unable to mount an effective immune response to any infection. Therefore, exposures to organisms that normal, healthy individuals easily overcome may result in deadly infections in SCID patients. Prior to present-day treatments, most ADA-deficient SCID victims died from infections ADA and Depression ADA plays an essential role in the functioning of the immune systems. Depression has been shown to accompany individuals with immune issues. Individuals with ADA, are often cut off from other individuals and the environment around them, this increases their chances of becoming depressed. Most depressed individuals have a greater likelihood of developing some type of immune illness. As depression lowers your ability to do the healthy things in your life, your body reacts to these things and many times your immune system begins to suffer.

Treatment

Bone marrow transplant

Bone marrow transplantation (BMT) or hematopoietic stem cell transplantation

(HSCT) is a medical procedure in the field of hematology and oncology that involves transplantation of hematopoietic stem cells (HSC). It is most often performed for people with diseases of the blood or bone marrow, or certain types of cancer. E. Donnall Thomas whose work was later recognized with a Nobel Prize in Physiology and Medicine pioneered bone marrow transplantation in the 1970's. Dr. Thomas' work showed that bone marrow cells infused intravenously could repopulate the bone marrow and produce new blood cells. His work also reduced the likelihood of developing a life-threatening complication called Graft-versus-host disease (GVHD). However it remains a risky procedure and it is reserved for patients with life threatening diseases.

Side effects and complications

Bone marrow transplantation is associated with a fairly high mortality (10% or higher), which limits its use to conditions that are themselves essentially life-threatening. Major causes of complications are sepsis, graft-versus-host disease and veno-occlusive disease.

Regimen-related toxicity

Regimen-related toxicities are side effects of the high dose chemotherapy or irradiation used in ablative HSCT. Severe liver injury is termed hepatic veno-occlusive disease (VOD). Elevated levels of bilirubin, hepatomegaly and fluid retention are clinical hallmarks of this condition. Initially thought to be a specific form of Budd-Chiari syndrome (i.e. thrombosis of the liver veins). There is now a greater appreciation of the generalized cellular injury and obstruction in hepatic vein sinuses, and it has thus been referred to as sinusoidal obstruction syndrome (SOS). Severe case are associated with a high mortality. Anticoagulants or defibrotide may be effective in reducing the severity of VOD but may also increase bleeding complications. Ursodiol has been shown to help prevent VOD, presumably by helping the flow of bile. Mucositis is the injury of the mucosal lining of the mouth and throat and is a common regimen-related toxicity following ablative HSCT regimens. It is usually not life-threatening but is very painful, and prevents eating and drinking. Mucositis is treated with pain medications plus intravenous infusions to prevent dehydration and malnutrition.

Infection

Bone marrow transplantation usually requires that the recipient's own bone marrow is destroyed ("myeloablation"). Prior to "engraftment" patients may go for several weeks without appreciable numbers of white blood cells to help fight infection. This puts a patient at risk of infections, sepsis and septic shock despite prophylactic antibiotics. The immunosuppressive agents employed in allogeneic transplants for the prevention or treatment of GVHD further increase the risk of opportunistic infection for at least a year post-transplant.

Gene therapy

Gene therapy is the insertion of genes into an individual's cells and tissues to treat a disease, and hereditary diseases in particular. Gene therapy typically aims to supplement a defective mutant allele with a functional one. Although the technology is still in its infancy, it has been used with some success. Antisense therapy is not strictly a form of gene therapy, but is often lumped together with them.

Types of gene therapy

In theory it is possible to transform either somatic cells (most cells of the body) or cells of the germ line (such as sperm cells, ova, and their stem cell precursors). All gene therapy so far in people has been directed at somatic cells, whereas germline engineering in humans remains only a highly controversial prospect. For the introduced gene to be transmitted normally to offspring, it needs not only to be inserted into the cell, but also to be incorporated into the chromosomes by genetic recombination. Somatic gene therapy can be broadly split in to two categories: ex vivo (where cells are modified outside the body and then transplanted back in again) and in vivo (where genes are changed in cells still in the body.) Recombination-based approaches in vivo are especially uncommon, because for most DNA constructs recombination has a very low probability.

Problems and ethics

For the safety of gene therapy, the Weismann barrier is fundamental in the current thinking. Soma-to-germline feedback should therefore be impossible. However, there are indications that the Weissman barrier can be breached. One way it might possibly be breached is if the treatment were somehow misapplied and spread to the testes and therefore would infect the germ line against the intentions of the therapy.

Some of the problems of Gene Therapy include:

Short-lived nature of gene therapy - Before gene therapy can become a permanent cure for any condition, the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be long-lived and stable. Problems with integrating therapeutic DNA into the genome and the rapidly dividing nature of many cells prevent gene therapy from achieving any long-term benefits. Patients will have to undergo multiple rounds of gene therapy.
Immune response - Anytime a foreign object is introduced into human tissues, the immune system is designed to attack the invader. The risk of stimulating the immune system in a way that reduces gene therapy effectiveness is always a potential risk. Furthermore, the immune system's enhanced response to invaders it has seen before makes it difficult for gene therapy to be repeated in patients.
Problems with viral vectors - Viruses, while the carrier of choice in most gene therapy studies, present a variety of potential problems to the patient --toxicity, immune and inflammatory responses, and gene control and targeting issues. In addition, there is always the fear that the viral vector, once inside the patient, may recover its ability to cause disease.
Multigene disorders - Conditions or disorders that arise from mutations in a single gene are the best candidates for gene therapy. Unfortunately, the combined effects of variations in many genes cause some of the most commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer's disease, arthritis, and diabetes. Multigene or multifactor disorders such as these would be especially difficult to treat effectively using gene therapy

	More Articles
1. Depression Diagnosis Depression Diagnosis Before depression can be treated, it must be accurately diagnosed. Your health care provider will: Ask about your symptoms. Ask about [...]
2. Teen Depression Help Teen Depression Help Being a young person in today's world is no easy task. Young people, as well as adults, have to deal with [...]
3. Suffering with Clinical Depression Suffering with Clinical Depression Is there someone who you're close to who you're concerned may suffer from clinical depression? If so [...]
4. Childhood Disorder: Disruptive Behavior Disorders Disruptive Behavior Disorders: Childhood Disorder Though many children with Oppositional Defiant Disorder or Conduct Disorder are found to have neurologically related symptoms over time, [...]