Blood Disorders and Anemias
Blood disorders encompass a wide variety of diseases including anemias, cancer, hemophilias, and immunodeficiencies. Blood disorders include various cancers such as Leukemias, T cell lymphomas, B cell lymphomas, Burkitts Lymphoma, and Hodgkins Disease. Treatment of cancer with gene and cell therapy is more fully discussed under cancer. Hemophilias, which are clotting disorders, and immunodeficiency diseases (e.g., Chronic Granulomatous Disease, Severe combined immunodeficiency, Wiskott-Aldrich Syndrome) also have their own sections. This section describes anemias.
Anemias includes sickle cell anemia, beta and alpha thalassemias, and Fanconi anemia. Patients with anemia have low numbers of red blood cells or abnormal red blood cells. Inherited anemias are caused by a mutation in an essential gene involved in the development, function, or lifespan of the red blood cells or erythrocytes. The progress and challenges in development of gene and cell therapies for several types of anemia are summarized here.
Anemias susceptible to cell and gene therapy treatments includes sickle cell anemia, beta and alpha thalassemias, and Fanconi anemia. Anemias, like sickle cell anemia, beta, and alpha thalassemias, can arise from mutations that affect the structure or the amount of one of the two globin chains of adults (alpha and beta). The disorders are not rare. Hemoglobin in the red blood cells brings oxygen and removes carbon dioxide from all cells of the body. Sickle cell anemia arises from a mutation in codon 6 of beta globin and is called hemoglobin S. In the absence of oxygen, Hemoglobin S clumps and causes the crescent shape of sickle red blood cells. Beta thalassemia can be caused by any one of over 200 mutations in the sequences that control production of the beta globin chains of hemoglobin. Similarly, alpha thalassemias have mutations that alter production of the alpha globin chain. The existence of alpha and beta thalassemias indicates that the level of both alpha and beta chains of hemoglobin need to be produced in the correct ratio and amounts to yield normal red blood cells.
Fanconi anemia does not affect hemoglobin, but instead results from a mutation in one of 14 genes involved in the development of leukocytes, red blood cells and platelets. The proteins from these genes cluster together and help repair DNA after stress. Most patients with Fanconi anemia have a mutation in the FANCA gene (60-70%), the FANCC gene (9-15%) or the FANCG gene (8-9%).
Current therapy that treats the immediate symptoms or crisis includes blood transfusions. Current cell therapy transfers bone marrow or hematopoietic stem cells from normal, human lymphocyte antigen (HLA) matched individuals to the patients. This cell therapy is the preferred treatment for these three types of anemias because it provides normal hematopoietic stem cells. The hematopoietic stem cells give rise to normal red blood cells.
Gene and cell therapy is being developed for cases in which the patient does not have a HLA-matched sibling or donor. Basically, hematopoietic stem cells (HSC) are isolated from the patient. Gene therapy uses a vector to insert the correct gene into these hematopoietic stem cells from the patient. These corrected HSC are transferred into the patient so they can generate normal blood cells. Various methods that may increase the survival and function of the gene-corrected, transferred, hematopoietic stem cells in patients with anemia are being tested in the laboratory and animal models.
The development of gene therapy for treatment of sickle cell anemia and beta thalassemia has encountered several challenges:
First, individuals can vary in the severity of their disease. In the case of thalassemias, although individual patients may have one of many different mutations, generally the deficiency in globin production is severe and any significant level of added expression is likely to be therapeutic. Patients with Fanconi anemia may have the mutation in one of 14 different genes. Such patients, although diagnosed with the same disease, but having different mutations often require a gene therapy reagent specific for the gene in which their mutation is located. In clinical trials, investigators focus on testing the new treatment in patients with mutations in one specific gene because the gene therapy reagent was designed to correct it, but will not correct mutations in other genes.
Second, the development of vectors that express an adequate amount of beta globin has been challenging. For example, early vectors produced β globin for a short time only and stopped its production or were silenced. To overcome premature silencing of globin expression scientists have added insulators or sequences which block the effects of neighboring genes. Scientific challenges include the identification of the elements that permit silencing and those regions that are sensitive to silencing.
Third, scientists are developing new vectors such as Lentiviral vectors and adenoassociated virus type 8 (AAV-8) to improve long term expression of the introduced gene and to achieve targeting of the gene therapy to the right cell types. Recent clinical trials are testing the ability of new vectors to correct the defect in isolated human hematopoietic stem cells from anemia patients. These modified human cells are being transferred into special mice and monitored for their ability to make normal red blood cells. Other clinical trials are testing various approaches that can increase the survival of the gene-corrected cells transferred to the patients.
A fourth challenge is harvesting a sufficient number of stem cells from the patients. Several reagents increase stem cells numbers in healthy individuals. One recent trial is testing reagents that may increase the number of stem cells in the blood of anemia patients. After these approaches have been successful in producing normal human red blood cells in mice, then the protocol(s) can be developed further for phase I clinical trials.
Please consult your physician before making any medical decisions.