Clinical trial NCT00721864: The Molecular Biology of Paroxysmal Nocturnal Hemoglobinuria (PNH)
Official title: The Molecular Biology of Paroxysmal Nocturnal Hemoglobinuria (PNH)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Hemoglobinuria, Paroxysmal
Keywords: Paroxysmal Nocturnal Hemoglobinuria
PIG-A Mutation
Prion Protein
Hematopoietic stem cells
Clonal disorder
Lead sponsor: University of Utah
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
First posted: 2008-07-25
Enrollment: 10
Sex: ALL
Minimum age (years): 7
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with paroxysmal nocturnal hemoglobinuria (PNH)

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Subjects suspected of or diagnosed with Paroxysmal Nocturnal Hemoglobinuria (PNH)
2. Age \> 7

Exclusion Criteria:

1. Those not meeting the inclusion criteria

Primary outcomes:
measure: Identify the mutation causing the predominant clones through analysis of extracted DNA/RNA from erythroid colonies
timeFrame: After sample is obtained
Secondary outcomes:
measure: Reconfirmation of PrP expression in human granulocytes, hematopoietic progenitors and stem cells
timeFrame: After sample is obtained
measure: Analysis of PrP function in human long term hematopoietic stem cells
timeFrame: After sample is obtained
Other outcomes:
Locations:
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: University of Utah
name: Josef T Prchal, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Durig J, Giese A, Schmucker U, Kretzschmar HA, Duhrsen U. Decreased prion protein expression in human peripheral blood leucocytes from patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2001 Mar;112(3):658-62. doi: 10.1046/j.1365-2141.2001.02602.x.
citation: Risitano AM, Holada K, Chen G, Simak J, Vostal JG, Young NS, Maciejewski JP. CD34+ cells from paroxysmal nocturnal hemoglobinuria (PNH) patients are deficient in surface expression of cellular prion protein (PrPc). Exp Hematol. 2003 Jan;31(1):65-72. doi: 10.1016/s0301-472x(02)01011-1.
citation: Zhang CC, Steele AD, Lindquist S, Lodish HF. Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal. Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2184-9. doi: 10.1073/pnas.0510577103. Epub 2006 Feb 7.