Disease Targets

Sickle Cell Disease (SCD), also referred to as sickle cell anemia, affects approximately 72,000 individuals in the United States; there are approximately 8,000 new cases each year. The disease is associated with approximately 25-30 year decrease in life expectancy, and total annual disease costs in the US are estimated at $1.8 billion dollars. SCD is caused by a single point mutation at amino acid 6 in the beta –globin gene, which results in the production of a structurally abnormal and dysfunctional hemoglobin. Hydroxyurea is currently the only FDA-approved agent for the treatment of SCD. Allogeneic hematopoietic stem cell transplantation is curative for this disease, although such treatments require an HLA-matched donor and they are associated with significant morbidity as well as high costs. Genetic modification of stem cells is emerging as a viable therapeutic modality, and recent studies suggest that this technique can be applied for the treatment of hemoglobin disorders.

Beta-thalassemia is one of a family of inherited anemias resulting from mutations of either the alpha or beta hemoglobin chains. Beta-thalassemia results from chromosome 11 mutations usually inherited in an autosomal recessive fashion. In this form, beta chains are deficient and although alpha chains are formed, they tend to bind to erythrocyte membranes (rather than forming oxygen-carrying tetramers), or form toxic aggregates. This causes decreased oxygen carrying capacity, membrane fragility, and microcytic anemia. The severity of the disease depends upon whether one (thalessemia minor) or both (thalessemia major or Cooley’s anemia) of the beta gobulin alleles is affected with the mutation. The latter condition is life threatening, usually causing death in young adulthood. There is also an intermediate condition that requires occasional treatment throughout a patient’s lifetime. Beta-thalassemia affects thousands of infants each year. It occurs most frequently in Mediterranean countries, e.g., North Africa, the Middle East, India, Central Asia, and Southeast Asia.

Acquired immunodeficiency syndrome (AIDS), first reported in the USA in 1981 results from infection of CD4 T cells of the immune system by the Human Immunodeficiency Virus (HIV). This results in a progressive failure to fight infections or cancers, increasing debilities and death. HIV infection does not progress to AIDS in a predictable manner and, due to current combination therapies, many infected people have been able to live normal lives for several years on chronic therapy. Despite intense efforts and some progress, the incidence of HIV/AIDS and the associated toll on society remains huge. The molecular events involved in the process of HIV infection and AIDS generation have been studied intensely. One well documented event is the binding of the HIV virus to the CCR5 molecule on the surface of T cells, a requisite step for viral entry into the target cells. Interestingly, a naturally occurring mutation in the CCR5 gene in a small percentage of people causes them to be resistant to HIV entry into T cells, and thus resistant to HIV induced AIDS.

Chronic Granulomatous Disease (CGD) is an inherited disorder in which immune phagocytes cannot function properly. Phagocyte cells with this defect cannot generate reactive oxygen species which are used to kill certain pathogens. This leads to chronic infections of bone, skin and joints, persistent diarrhea, pneumonia, etc. CGD often leads to enlarged liver, spleen and swelling of multiple lymph nodes. Treatment includes aggressive use of antibiotics and antifungals for acute infections and chronic daily prophylactic antibiotic therapy to decrease frequency of infection. Abscesses are common and hospitalization is frequent. The only cure for CGD currently is a bone marrow transplant, which carries significant risk and morbidity. CGD affects about 1 in 200,000 people in the US, with about 20 new cases diagnosed each year.

Gaucher's Disease is an inherited genetic disorder that causes too much of a substance called glucocerebroside to build up in the spleen, liver, lungs, bones and in some patients, the brain. The buildup causes enlargement and prevents these organs from working properly.

There are three types of Gaucher's Disease:

  • » Type 1 is the most common form, and causes liver and spleen enlargement, bone pain, broken bones, and occasionally lung and kidney problems. It does not involve the brain and can occur at any age.
  • » Type 2 affects infants and causes severe brain damage. Most children who have Type 2 Gaucher’s disease die by age 2.
  • » Type 3 typically includes liver and spleen enlargement with gradual brain involvement.

Gaucher's disease has no cure. Treatment options for types 1 and 3 include enzyme replacement therapy, which is usually very effective, but chronic and costly. There is no good treatment for the brain damage as enzyme replacement therapy does not cross the blood brain barrier.

Hurler syndrome results from a dysfunctional metabolizing enzyme, iduronidase, resulting in accumulation of mucopolysaccharides in lysosomes. This autosomal recessive disease is also known as mucopolysaccharidosis type I. Symptoms appear during early childhood and early death can occur due to multiple organ damage. Typical features include liver and spleen enlargement, dwarfism and gargoyle-like features. There is progressive mental retardation. Enzyme replacement therapy is commonly used, but reduces only non-neurological symptoms. Bone marrow transplants are possible in a few cases, with an appropriately matched donor. There is no cure for Hurler syndrome.