Hemoglobinuria, Paroxysmal Clinical Trial
Official title:
The Molecular Biology of Paroxysmal Nocturnal Hemoglobinuria (PNH)
This study is designed to better understand the molecular biology of paroxysmal nocturnal hemoglobinuria (PNH) and to determine if prion protein (PrP) functions in long term hematopoietic stem cell renewal.
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by hemolytic anemia, thrombosis,
and variable cytopenia. It can be associated with significant morbidity including acute
kidney failure, cerebral infarction, mesenteric infarction, Budd-Chiari syndrome, aplastic
anemia, and leukemic transformation. The average survival time from diagnosis is 15 years.
PNH is an acquired clonal disorder of the hematopoietic stem cell. Two distinct populations
of hematopoietic cells exist in each PNH patient: one non-clonal population of normal cells,
and one clonal population of PNH cells. The clonal population of PNH cells is identified by
a mutation in the PIG-A gene that results in absence of the glycophosphatidylinositol (GPI)
anchor of several surface proteins. Consequently, these surface proteins are unable to
perform their functions on the cell surface. Deficiency of two of these surface proteins,
CD55 (decay accelerating factor) and CD59 (membrane inhibitor of reactive lysis) that
prevent complement mediated destruction, have been shown to underlie the clinical
presentation of PNH. Identifying the mutation causing the predominant clones may help us
better understand the molecular biology of PNH. When this is accomplished, new therapies to
control and eventually cure the disease can be designed.
In addition, we propose to determine the function of PrP in human hematopoietic stem cells.
PrP is a glycoprotein attached to the cell membrane by a glycosylphosphatidylinositol (GPI)
anchor. In PNH, a disorder whose pathogenesis lies in the absence of GPI anchors, PrP
expression is reduced in monocytes and granulocytes from the PNH clone.
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Observational Model: Cohort, Time Perspective: Prospective
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