New experimental gene therapy may aid sickle cell disease

June 3, 2021
New experimental gene therapy may aid sickle cell disease

Researchers in the US have designed a new gene therapy strategy for sickle cell disease (SCD), a complex and sometimes deadly heritable blood disorder that dramatically affects the structure and function of oxygen-transporting red blood cells (RBCs). The new and improved form of gene therapy has been shown to boost levels of foetal haemoglobin, which is normally produced only during foetal development and is more efficient at transporting oxygen than its adult counterpart. Boosting levels of foetal haemoglobin not only increases oxygen transport but dramatically lowers the frequency of disease complications.

About 7% of the world’s population are carriers of a gene that can lead to a haemoglobin (blood) disorder; most of these people have genetic roots in Africa, the Mediterranean and Asia. In SCD, the patient’s RBCs take on the characteristic crescent moon or sickle shape. The crescent shape can cause severe logjams of misshapen RBCs that have difficulty gliding though the vasculature, as do disc-shaped healthy RBCs. Another one of the heritable haemoglobin diseases is beta thalassaemia, where RBCs do not sickle but are substantially smaller than normal, and likewise are impaired as transporters of oxygen.

Gene therapy technologies for haemoglobin diseases is aimed at producing healthy disc-shaped RBCs that efficiently transport oxygen throughout the body. In the case of blood disorders like SCD, the treatment corrects a constellation of medical problems—haemolytic anaemia, pain, and organ damage.

At the National Heart, Lung, and Blood Institute in Bethesda, Maryland, Dr. Naoya Uchida and colleagues have boosted levels of foetal haemoglobin by increasing gamma-globin concentrations in a single gene therapy, thereby aiding sickle cell and potentially other haemoglobin diseases. Gamma-globin is a component of the haemoglobin molecule, the iron-containing oxygen-transport metalloprotein in RBCs.

According to Dr. Uchida’s reimagined gene therapy, the patient’s blood-producing stem cells are first modified in the laboratory by adding a normal copy of the beta-globin gene via a high-efficiency lentiviral vector, to transfer corrective transfer genes into chromosomes. They additionally engineered the vector to deliver a microRNA that suppresses the haemoglobin-regulating gene BCL11A. By knocking down expression of BCL11A, the production of foetal haemoglobin is turned on. Increasing foetal haemoglobin produces a form of the protein that doesn’t sickle and therefore directly reduces crescent-shaped haemoglobin. Doctors then reinfuse the modified stem cells into the patient to produce normal, disc-shaped RBCs.

“The sustained foetal haemoglobin induction may represent a viable gene therapy strategy for haemoglobin disorders,” Dr. Uchida and colleagues said. They also noted in their research that one of the shortcomings in current gene therapy techniques is the lack of a robust therapeutic effect for some patients. Tweaking the technique, they say, may ultimately improve outcomes and make gene therapy a feasible option for more patients.

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