Hydroxyurea has been demonstrated to reduce the incidence of painful crises and acute chest syndrome by 50% in adult sickle cell (Hb SS) patients; in addition, hydroxyurea reduces their transfusion requirements. It has become apparent that the rise in Hb F alone does not explain the benefits of hydroxy-urea fully, and it is felt that this drug must have other effects; for example, the reduction of sickle cell adhesion. Predictors of good results with hydroxyurea are high white cell count and the absence of the Bantu haplotype.

Bone marrow transplantation has been carried out in many patients with sickle cell anemia with reasonably good results, including the regeneration of the spleen in some cases. Mortality is between 5 and 20% depending on the protocol used. Selection of patients because of a history of central nervous system involvement in children initially produced strokes during convalescence, but adjustment of the protocol has reduced this risk. This procedure is generally restricted to severely ill patients because of the mortality of graft rejection, which occurs in up to 20%.

Preventive measures have been very successful in this disease, particularly in the reduction of infant mortality. These include prophylactic penicillin, pneumococcal vaccine and teaching patients about splenic sequestration.

The judicious use of exchange transfusion in acute chest syndrome, splenic sequestration, aplastic crises and liver crises has saved countless lives.

The treatment of painful crises remains a challenge. The best approach is a rapid assessment, preferably by quantitative instruments, of the intensity, quality and distribution of pain, the presence of comorbidities and the state of dehydration. Rapid, aggressive, individually tailored analgesia treatment, with the additional use of NSAIDs, has proved to be the best route. All of this is almost impossible in an emergency room; hence, a day hospital dedicated to sickle cell anemia is probably the best alternative service model.

Recent developments include therapy involving NO metabolism. As mentioned above, plasma arginine levels are low in sickle cell anemia and in the sickle transgenic mouse model (pS+S-Antilles). Hence, an arginine diet supplementation, with a four-fold increase in arginine maintained for several months, was explored. Surprisingly, mean corpuscular hemoglobin concentration (MCHC) decreased and the percentage of high-density red cells was significantly reduced. These outcomes were found to be the consequence of the inhibition of the Ca2+-activated K+ (Gardos) channel. Clinical trials of arginine supplementation in sickle cell anemia are in the offing. Potential uses of inhaled NO in acute painful crises, acute chest syndrome and pulmonary hypertension are being actively explored.

Allogeneic transplantation is available to some of these patients. The mortality of the procedure is around 10%; hence, with the survival of these patients increasing dramatically the selection of patients for this procedure is not easy. In addition, lack of appropriate marrow donors has been found to be a problem. Miniablation, after initial enthusiasm, has been unsuccessful after the cessation of immune suppression.

Finally, the prospect of gene therapy for hemoglobinopathies has improved considerably due to the realization that the HIV-related lentivirus vector is an efficient means of delivering an anti-sickling or anti-thalassemia construct to the patient's stem cells and then allogeneically transplanting such cells in a partially ablated recipient. This approach has been tested successfully in transgenic mice models of sickle cell anemia and severe P-thalassemia.

For sickle cell anemia, the lentivirus vector contained a PA globin gene that contains a change in amino acid (Gln^Thr) at position P87, which had previously been demonstrated to account for more than 90% of the Hb F anti-sickling potential. This lentivirus vector was optimized for transfer to hematopoeitic stem cells and also for high expression. Long-term expression was achieved, without preselection, with erythroid-specific accumulation of the anti-sickling protein in up to 52% of total hemoglobin and 99% of circulating red blood cells. In two mouse SCD models, BERK and SAD, inhibition of red blood cell dehydration and sickling was achieved by correction of hematological parameters, splenomegaly, and the prevention of the characteristic urine concentration defect.

Gene therapy of severe thalassemia in transgenic mice has also been achieved, with permanent, panerythroid correction by transplantation of syngeneic bone marrow transduced with an HIV-1-derived (P-globin gene/LCR) lentiviral vector. This was sustained for more than 7 months in both primary and secondary transplants, at which time approximately 95% of the red blood cells in all mice contained human P-globin, contributing to 32 ± 4% of all P-like globin chains. Hemoglobin levels, reticulocyte levels and red blood cell counts approached complete correction. Free P-globin chains were completely cleared from the thalassemic red cell membranes, splenomegaly was abated, and iron deposit was almost entirely eliminated from the liver.

These findings are encouraging for the future of gene therapy of hemoglobinopathies. Nevertheless, unknown challenges might lie ahead.

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