Beta-thalassemia is a genetic, red blood cell disorder affecting the
beta-globin chain of the adult
hemoglobin gene. This results in excess accumulation of unpaired alpha-chain gene products leading to reduced red blood cell life span and the development of severe
anemia. Current treatment of this disease involves regular
blood transfusion and adjunct
chelation therapy to lower
blood transfusion-induced
iron overload.
Fetal hemoglobin switching agents have been proposed to treat genetic blood disorders, such as
sickle cell anemia and
beta-thalassemia, in an effort to compensate for the dysfunctional form of the
beta-globin chain in adult
hemoglobin. The rationale behind this approach is to pair the excess normal
alpha-globin chain with the alternative fetal gamma-chain to promote red blood cell survival and ameliorate the
anemia. Reprogramming of differentiation in intact, mature, adult white blood cells in response to inclusion of
monoclonal antibody CR3/43 has been described. This form of retrograde development has been termed "retrodifferentiation", with the ability to re-express a variety of stem cell markers in a heterogeneous population of white blood cells. This form of reprogramming, or reontogeny, to a more pluripotent stem cell state ought to recapitulate early hematopoiesis and facilitate expression of a fetal and/or adult program of
hemoglobin synthesis or regeneration on infusion and subsequent redifferentiation. Herein, the outcome of infusion of autologous retrodifferentiated stem cells (RSC) into 21 patients with
beta-thalassemia is described. Over 6 months, Infusion of 3-h autologous RSC subjected to hematopoietic-conducive conditions into patients with
beta-thalassemia reduced mean
blood transfusion requirement, increased mean
fetal hemoglobin synthesis, and significantly lowered mean serum
ferritin. This was always accompanied by an increase in mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) in such patients. No adverse side effects in response to the infusion of autologous RSC were noted. This novel clinical procedure may profoundly modify the devastating course of many
genetic disorders in an autologous setting, thus paving the way to harnessing pluripotency from differentiated cells to regenerate transiently an otherwise genetically degenerate tissue such as thalassemic blood.