Clinical trial NCT05883254: Pumilio1 (PUM1) Expression, Sickle Cell Anemia, β-thalassemia Intermedia
Official title: Detection of RNA Binding Protein Pumilio1 (PUM1) Expression in Patients With Sickle Cell Anemia and β-thalassemia Intermedia
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Sickle Cell Disease, Beta Thalassemia Intermedia
Lead sponsor: Assiut University
Sponsor class: OTHER
First posted: 2023-05-31
Enrollment: 80
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with sickle cell anemia and β-thalassemia intermedia

Brief summary: 1. To study the expression pattern of PUM1 gene in patients with sickle cell anemia and β-thalassemia intermedia.
2. To detect PUM1 protein levels in sickle cell anemia and β-thalassemia intermedia patients.
3. To correlate PUM1 gene expression pattern and protein levels with HbF levels in sickle cell anemia and β-thalassemia intermedia patients.

Detailed description: The disorders of β-hemoglobin, sickle cell disease (SCD) and β-thalassemia, are major causes of morbidity and mortality worldwide. These diseases are the most common genetic disorders in the world.

SCD is due to a single base-pair point mutation in the β-globin gene resulting in the substitution of valine for glutamic acid in the β-globin chain. The pathophysiology is directly related to polymerization of deoxygenated hemoglobin, leading to a cascade of pathologic events including erythrocyte sickling, vaso-occlusion, and hemolysis.

In β-thalassemia, insufficient production of the β-globin molecule results in an excess of free α-globin chains that can precipitate within erythroid precursors, impairing their maturation and leads to death of these precursors and ineffective production of erythroid cells. As a result, a significant anemia occurs and the consequent expansion of erythroid precursors can lead to secondary problems in bones and other organs.

The hemoglobin molecule is a tetramer composed of two subunits of α-like globin peptides and two subunits of the β-like globin peptides, along with heme moieties. β-globin switching from fetal γ-globin (HBG1 and HBG2) to adult β-globin is a developmental process that occurs in erythrocytes at around the time of birth. Fetal hemoglobin (HbF) induction in adult erythrocytes is an effective therapeutic strategy for SCD and β-thalassemia.

Pumilio1 (PUM1) is a novel target of the erythroid master transcription factor erythroid Krüppel-like factor (EKLF). PUM1 is a member of Pumilio-Fem3-binding factor (PUF) family of sequence specific RNA-binding proteins, acts as a posttranscriptional repressor by binding to the 3' untranslated region (3'-UTR) of messenger RNA (mRNA). It peaks during terminal erythroid differentiation and binds to fetal γ-globin (HBG1) mRNA and impairs its stability and translation. HBG1 has 2 core PUM1 consensus binding sites, but HBG2 and adult globins do not. Knockdown of PUM1 leads to a robust increase in HBF (∼22%) without affecting β-globin levels in human erythroid cells. Moreover, targeting PUM1 does not affect erythropoiesis, which provides a potentially safe and effective therapeutic strategy for SCD and β-thalassemia. Also it was found that elevated HbF levels in the absence of anemia in an individual with a novel heterozygous PUM1 mutation in the RNA-binding domain, which suggests that PUM1 is a critical player during human hemoglobin switching.

Eligibility criteria: Inclusion Criteria:

* Patients with sickle cell anemia and β-thalassemia intermedia.
* Patients are of both sexes (males and females) at any age.

Exclusion Criteria:

* Patients with any other type of haemolytic anaemias.
* Patients on Hydroxyurea therapy.

Primary outcomes:
measure: Expression pattern of PUM1 gene in patients with sickle cell anemia and β-thalassemia intermedia.
timeFrame: saple taken after diagnosis and before recieve treatment. If patients already on treatment , sample taken at least one month after stoppage of hydroxyurea or blood transfusion
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
References:
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