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More than a decade ago, researchers discovered that a rare congenital bone marrow failure syndrome, Diamond Blackfan anemia (DBA), is caused by mutations in a ribosomal protein RPS19. Subsequently, my mentor Dr. Benjamin Ebert identified RPS14 as the gene responsible for the profound macrocytic anemia in the 5q- syndrome, a subtype of myelodysplastic syndrome. This reinforced the connection between ribosomal abnormalities and defects in erythropoiesis. Moreover, mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes including Schwachman-Diamond syndrome, X-linked dyskeratosis congenita, Cartilage Hair Hypoplasia and Treacher Collins syndrome. Each of these disorders is associated with specific defects in ribosome biogenesis, which cause distinct clinical phenotypes, most often involving bone marrow failure, and have become collectively known as ribosomopathies. I have studied the molecular mechanisms by which ribosomal dysfunction leads to bone marrow failure by further characterizing the signaling pathways that are triggered and the subsequent effects on hematopoiesis. I published work on ribosomal haploinsufficiency causing selective activation of p53 in human erythroid progenitor cells and on the effects of a microRNA cooperating in the pathogenesis of the 5q- syndrome. I will continue to focus on understanding the effects of specific drugs on these disorders which may uncover further clues about pathophysiology and as importantly, will directly benefit patients. I have published work on the effects of dexamethasone and lenalidomide, the first line therapies for DBA and 5q- MDS respectively, on erythropoiesis and am an author on a manuscript examining the effects of leucine, a stimulator of the mTOR pathway, in these disorders. The goal of my lab is to make meaningful contributions to the elucidation of the pathophysiology of ribosomopathies, the development of novel therapies and the care of patients in the field.
Pilot Phase I/II Study of Amino Acid Leucine in Treatment of Patients With Transfusion-Dependent Diamond Blackfan Anemia
This study will determine the safety and possibility of giving the amino acid, leucine, in
patients with Diamond Blackfan anemia(DBA)who are on dependent on red blood cell
The leucine is expected to produce a response in patients with DBA to the point where red
blood cell production is increased. Red cell transfusions can then be less frequent or
The investigators will study the side effects, if any, of giving leucine to DBA patients.
Leucine levels of leucine will be obtained at baseline and during the study.
The drug leucine will be provided in capsule form and taken 3 times a day for a total of 9
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A Study of AG-348 in Adult Participants With Pyruvate Kinase (PK) Deficiency
Study AG348-C-003 is a multicenter study designed to evaluate the safety and efficacy of
different dose levels of AG-348 (mitapivat) in participants with PK deficiency.