Screening and Development of Novel Therapeutics for Sickle Cell Disease and Thalassemia

Funding Type: 
Early Translational I
Grant Number: 
TR1-01255
Investigator: 
ICOC Funds Committed: 
$0
Public Abstract: 
The hereditary anemias ß-thalassemia major and sickle cell disease are caused respectively by deficiency or dysfunction of ß-globin. Currently there may be more than 1,000,000 individuals living with one of the two diseases. They are found in a belt stretching from the Mediterranean and West Africa to Southeast Asia and South China, and also in areas like the US that have received immigration from endemic areas. ß-thalassemia mutations impair production of ß-globin and cause severe anemia; attempts to compensatory red blood cell production leads to massive expansion of marrow spaces, with consequent severe bony disfigurement, and an enormous metabolic load that causes growth failure, wasting, and eventually death. The current standard transfusion/chelation therapy treatment must be continued for life, and requires a well developed blood banking system. Bone marrow transplantation can be curative, but it is available to only a few. Most children born with ß-thalassemia major do not have access to anything more than rudimentary health care, and die in childhood having received little or no therapy. Sickle Cell Disease(SCD) is a devastating disorder leading to chronic and cumulative damage to multiple organs. Its manifestations are highly variable; comprehensive management is required to identify and treat complications as they arise, but this treatment is expensive and difficult. Bone marrow transplantation can be curative, but does not reverse organ damage, and the variability of the clinical syndrome makes it difficult to predict which patients are most likely to benefit from transplantation until organ damage has occurred. More than 1 in 375 African-Americans is born with SCD, and there are ~6,000 affected individuals in California and ~80,000 in the US. In sub-Saharan Africa the incidence is much higher. These disorders can be substantially improved by increased production of γ-globin, the closely related ß-like globin expressed in fetal-stage human red blood cells. This strategy presents the best hope for a therapy that can be applied widely and cheaply, as it must be if it is to benefit the great majority of affected children. Any agent that will effectively reverse γ-globin silencing must work on blood stem cells and early differentiating erythroblasts, because it is at this stage that the program of globin expression is set up. We have invented a screen for such compounds, and tested it with promising results. The compounds we have identified appear to be unique and distinct from all known compounds and therapeutics utilized to date. We aim to improve and expand our screen, and to develop the lead compounds it produces. We will perfect our screen by deriving new and more powerful reagents for chemical screening, screen chemical libraries of known drugs, and supplement them with compounds selected by computational methods. Lead compounds will be tested for activity in models relevant to the ß-hemoglobinopathies.
Statement of Benefit to California: 
The hereditary anemias ß-thalassemia major and sickle cell disease affect more than a million individuals. They occur in a belt stretching from the Mediterranean and West Africa to Southeast Asia and South China, and also in areas like the US that have received immigration from endemic areas. More than 1 in 375 African-Americans is born with SCD, and there are ~6,000 affected individuals in California and ~80,000 in the US. In sub-Saharan Africa the incidence is much higher. The numbers of ß-thalassemia cases are lower, but are rising as the US (and particularly California) receives more immigration from areas, particularly India and South China, where the disorder is common. ß-thalassemia major is a severe anemia that when untreated leads to major bony disfigurement, and an enormous metabolic load that causes growth failure, wasting, and eventually death. The current standard transfusion/chelation therapy treatment must be continued for life, and requires a well developed blood banking system. Bone marrow transplantation can be curative, but it is very expensive and available to only a few. Most children born with ß-thalassemia major do not have access to anything more than rudimentary health care, and die in childhood having received little or no therapy. Sickle Cell Disease(SCD) is a devastating disorder leading to chronic and cumulative damage to multiple organs. Its manifestations are highly variable; comprehensive management is required to identify and treat complications as they arise, but this treatment is expensive and difficult. Bone marrow transplantation can be curative, but does not reverse organ damage, and the variability of the clinical syndrome makes it difficult to predict which patients are most likely to benefit from transplantation until organ damage has occurred. Both diseases can be substantially improved by increased production of γ-globin, the closely related ß-like globin expressed in fetal-stage human red blood cells. This strategy presents the best hope for a therapy that can be applied widely and cheaply, as it must be if it is to benefit the great majority of affected children. Any agent that will effectively reverse γ-globin silencing must work on blood stem cells because it is at this stage of red blood cell development that the program of globin expression is set up. We are proposing to use innovative stem-cell based methods to identify compounds that can be developed into oral agents for the treatment of ß-thalassemia and sickle cell disease. Successful development of such an agent would broadly benefit the many affected individuals in California, who would for the first time be able to live free from the onerous complications of these diseases, and it would reduce the cost of providing health care to these individuals. It would also contribute to the development of the biotechnology and pharmaceutical industries in California, since the agent would be very likely to have a very large market around the world.

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