The Molecular Biology of Paroxysmal Nocturnal Hemoglobinuria (PNH)

Hemoglobinuria, Paroxysmal Clinical Trial

Official title:

The Molecular Biology of Paroxysmal Nocturnal Hemoglobinuria (PNH)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00721864
• Other study ID #: 17790
• Secondary ID: R01HL5077-12
• Status: Completed
• Phase: N/A
• First received: July 23, 2008
• Last updated: August 5, 2011
• Start date: May 2006
• Est. completion date: December 2010

Study information

• Verified date: August 2011
• Source: University of Utah
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: December 2010
• Est. primary completion date: December 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 7 Years and older

Eligibility

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

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• Hemoglobinuria
• Hemoglobinuria, Paroxysmal

Locations

Country	Name	City	State
United States	University of Utah	Salt Lake City	Utah

Sponsors (2)

Lead Sponsor	Collaborator
University of Utah	National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

References & Publications (3)

Dürig J, Giese A, Schmücker U, Kretzschmar HA, Dührsen 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. — View 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. — View 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. Epub 2006 Feb 7. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Identify the mutation causing the predominant clones through analysis of extracted DNA/RNA from erythroid colonies		After sample is obtained	No
Secondary	Reconfirmation of PrP expression in human granulocytes, hematopoietic progenitors and stem cells		After sample is obtained	No
Secondary	Analysis of PrP function in human long term hematopoietic stem cells		After sample is obtained	No