A New Gene Therapy Strategy for Sickle Cell Disease and Beta-Thalassemia

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Sickle-shaped red blood cells (sickle cell disease) © Inserm/Anne-Marie Chevance
Sickle-shaped red blood cells (sickle cell disease) © Inserm/Anne-Marie Chevance de Boisfleury
Both sickle cell disease and beta-thalassemia are genetic disorders that affect hemoglobin, and as such are categorized as beta-hemoglobinopathies. A team of scientists from Inserm, Université Paris Cité and the Paris Public Hospitals Group AP-HP at the Imagine Institute has shown the efficacy of a gene therapy approach to treat these two disorders. The principle is to reactivate in patients the production of fetal hemoglobin, a protein whose expression usually ceases after birth. In a study published in Nature Communications , the research team describes a promising approach for future therapeutic applications.

Sickle cell disease and beta-thalassemia are genetic disorders known as beta-hemoglobinopathies. They are caused by mutations on chromosome 11 of the gene responsible for the production of beta globin, a constituent protein of hemoglobin which is the main component of red blood cells.

In sickle cell disease, the structure of beta globin is altered, affecting the integrity of red blood cells and leading to anemia, very painful local obstructions of the blood circulation (vaso-occlusive crisis), and gradual organ damage. In beta-thalassemia, beta globin production is drastically reduced, causing hemoglobin deficiency and leading to severe anemia.

In the 1970s, researchers observed that rare individuals with mutations specific to each of these conditions did not develop the disease. What was it they had in common? They were all carriers of compensatory mutations on another chromosome 11 gene, which stimulated the production of fetal hemoglobin (gamma globin). This protein that usually ceases to be produced at the end of fetal life is able to advantageously replace the defective adult beta globin to form healthy hemoglobin, thereby ensuring the production of perfectly functional red blood cells in sufficient quantities.

A research team led by Annarita Miccio, Inserm researcher at the Imagine Institute (Inserm/Université Paris Cité/Paris Public Hospitals Group AP-HP) conducted a series of in vitro experiments to determine the most effective strategy for stimulating fetal hemoglobin production, using gene therapy to reproduce these beneficial mutations for treatment purposes. The most effective approach was to insert a genetic mutation that generates, in red blood cells, a molecular mechanism with the dual advantage of stimulating fetal hemoglobin production and blocking the mechanism that naturally inhibits that production.

Furthermore, the researchers have shown in animals that this strategy is effective over the long term, which is a very important finding in the context of therapeutic application.

"There is still a long way to go before this new gene therapy approach can be used in a clinical setting,” explains Panagiotis Antoniou, first author of the study, for example, we need to optimize the protocol in order to genetically modify more red blood cells, as only 60% are done so with the current protocol. Nevertheless, our research is paving the way for the clinical development of a safe and innovative treatment for patients with beta-hemoglobinopathies, with the objective of improving their quality of life,” concludes the researcher.

Sickle cell disease, which affects 5 million people worldwide, is the leading genetic disorder worldwide and the most common in France. Every year, about 100,000 children worldwide are born with a severe form of beta-thalassemia. In order to continue to support the advances of research in fighting rare diseases, the 2022 edition of the Telethon (only available in French) will be broadcast over a 30-hour period on December 2-3, on France Télévisions.

Link : https://presse.inserm.fr/en­/a-new-gen­e-therapy-­strategy-f­or-sickle-­cell-disea­se-and-bet­a-thalasse­mia/46042/