Reimaging beta-thalassemia and its treatment

Reimaging beta-thalassemia and its treatment


Beta-thalassemia is one of the most common
blood disorders in the world, particularly in Southeast Asia and North Africa. Research
that published in Science Translational Medicine details a new promising approach for this
blood disorder. Beta-thalassemia is a hemoglobin disorder. Hemoglobin is the protein in red
blood cells that carries oxygen from lungs to all tissues in the body. Hemoglobin is formed by four different globin
subunits, two alpha globin subunits and two beta globin subunits. Beta-thalassemia patients
inherit point mutations that decrease beta-globin synthesis. The biochemical hallmark of this
reduced beta-globin synthesis is accumulation of toxic free alpha-globin proteins. Free alpha-globin forms toxic precipitates
and shortens the half-life of red blood cells, but also destroys progenitors, in a process
termed ineffective erythropoiesis. Beta-thalassemia causes morbidity and early mortality of hundreds
of thousands of people worldwide. So far, the only treatment for beta-thalassemia are
blood transfusions and medication to limit the iron accumulation from those transfusions. But many of these patients do not get access
to this treatment. We have identified an enzyme named ULK1. And, this protein acts to increase
the clearance of free alpha-globin in these red blood cells through autophagy. Autophagy
is a process from the cells to clear toxic proteins. The loss of ULK1 in those mice with beta-thalassemia
increase accumulation of alpha-globin subunits and worsens the phenotype. Previous studies indicated that ULK1 could
be inactivated by another protein named mTOR. Therefore, we hypothesized to use an mTOR
inhibitor named rapamycin to improve ULK activity and increase clearance of free alpha-globin
in those beta-thalassemic mice. The electron micrograph shows the particular
site of mice treated with rapamycin. As you can see, these drugs reduce significantly
free alpha-globin precipitate in those mice. More importantly, this effect of the drugs
occur only when the ULK1 gene is present. Rapamycin also reduced free alpha-globin accumulation
in our erythroblast in culture from patients with beta-thalassemia. These patients are
still under care in Milan, Italy. This project was a long-standing collaboration
between two research labs at St. Jude Children’s Research Hospital—Dr. Weiss and Dr. Kundu’s
labs—but also we got help from two expert clinicians from Italy—Dr. Cappellini and
Dr. Motta. In conclusion, we showed that the loss of
ULK1 gene in thalassemic mice reduce the clearance of free alpha-globin and worsens the phenotype.
Rapamycin treatment improved ineffective erythropoiesis and red blood cells survival via an ULK1-dependent
pathway. Rapamycin is FDA approved, inexpensive, and
we can manage the toxicity of this drug. Our next challenge will be to test the proof-of-principle
clinical trial to see if this drug could be effective and safe for patients with beta-thalassemia.

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