The most common genetic diseases worldwide affect the production of normal hemoglobins, the red blood proteins that carry oxygen to our organs. These disorders result in the diseases known as sickle cell disease (SCD) and thalassemia, common in patients of African, Mediterranean, Middle Eastern, and Asian origins. In California, due to the large African American and Asian American populations these diseases have resulted health problems that have significant social and economic ramifications.
Most patients with SCD require lifelong care that includes treatment of painful crises due to blockage of blood vessels, strokes at an early age, frequent infections throughout life, and kidney damage. Treatment involves management of the crises and infections as well as transfusions for strokes and severe anemia. Hydroxyurea can alleviate some symptoms and anemia in selected patients; however, the long-term effectiveness of this treatment has yet to be determined.
Thalassemia comes in two major forms; alpha thalassemia, where the affected fetus usually dies in the third trimester of pregnancy or soon after birth, and beta thalassemia (beta-thal), where children are born healthy, but develop severe anemia within weeks or months, due to the lack of adult type of hemoglobin. Patients require regular monthly blood transfusions that carry with them large, toxic amounts of iron that will cause organ damage over time and therefore need to take medications throughout life to remove iron from their bodies.
Both diseases impose heavy burdens on affected families and on healthcare costs. At present, the only effective cure is bone marrow or cord blood transplantation where there is a compatible donor. However, affected families usually have few children, and compatible donors are rare.
This development proposal offers an alternative to conventional bone marrow transplantation. Its aims are to institute a treatment approach that converts a patients cells into induced pluripotent (iPS) cells, corrects the disease causing beta-globin mutation, differentiates the corrected iPS cells into cells that reconstitute the hematopoietic system, and returns these cells to the patient for a cure.
While carrier screening or prenatal diagnosis and subsequent selective abortion of the affected fetus can control these diseases, this proposal offers cure through transplantation as an alternative to abortion. We have successfully reprogrammed cells from chorionic villus sampling (CVS) used for prenatal diagnosis between weeks 9-12 of pregnancy, into iPS cells. If SCD or beta-thal is detected by CVS or amniocentesis, cells cultured from these procedures will be converted into iPS cells, the mutation will be corrected, corrected cells will be differentiated into hematopoietic stem cells, and then transfused into the baby after birth. Since prenatal diagnosis is early in pregnancy, adequate time is available for corrective measures to be instituted.
Statement of Benefit to California:
Sickle cell disease (SCD) and thalassemia (thal) are among the most common genetic diseases in the world. Of the thalassemias, patients with alpha-thal generally die in the 3rd trimester or shortly after birth, while beta-thal patients are symptomless at birth, but develop severe anemia with weeks to months due to the lack of adult hemoglobin. In California, these diseases have become important and significant health problem because of the large African and Asian American populations. Of the approximately, 500,000 new births in California every year, the rate of SCD incidence is about 1 in 6,600 births every year, while beta-thal occurs less frequently at 1 in 55,000 births. Most patients with these diseases require lifelong care that involves expensive therapies to treat the many complications that result in organ damage and severe pain. At present, the only cure is by bone marrow or cord blood transplantation. However, these families usually have a small number of children and compatible donors are difficult to find. Aside from the human cost and suffering caused by SCD and beta-thal, the economic impact to California is substantial. Treatment of SCD is about between $12,000 - $45,000/yr/patient, while the cost of treatment for a beta-thal patient is about $100,000/yr/patient. Given that SCD patients have predicted life-span of 50 yr and beta-thal patients now live to 40 yr, the economic impact of treating this cohort of patients for their lifetime by conventional means would be significant. One approach to prevent the disease has been through early detection and prenatal diagnosis. At present, the usual outcome of prenatal diagnosis is selective abortion of the affected fetus. This development project offers an alternative possibility of curing both newborn and adult patients with their own cells that have been reprogrammed, corrected and converted to cells that will regenerate their hematopoietic system. The benefit to California would be to eliminate emotional and physical suffering in patients and mitigate the economic impact that the life-long treatment has on the medical system.