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Hemoglobinopathies: a gene therapy modifies 100% of targeted cells

The researchers at the François Jacob Institute's Department of Innovative Therapies  are pursuing the development of their gene therapy for hereditary blood diseases. They are looking to increase the performance of their strategy so that it can bring benefits to the greatest number of patients possible.

Published on 21 December 2017

​As early as 2010, research teams, particularly those at the François Jacob Institute of Biology's Department of Innovative Therapies (STI), had begun showing that it was possible to use gene therapies to treat severe forms of beta thalassemia and sickle-cell anemia, two hereditary blood disorders involving a fault in the HBB gene, which codes the beta-globin protein. Although encouraging, those early successes  concerned only those individuals in whom a sufficient number of target cells were corrected by the therapeutic vector (which contained a functional HBB gene). 

It is important to keep in mind that this therapeutic approach targets the blood's stem cells, called hematopoietic stem cells (HSCs), located in the bone marrow. However, the STI team, headed by Emmanuel Payen, showed that not all HSCs responded to the correction afforded by the vector. This variation in response limited the efficacy of their strategy. It was also possible that the vectors deliver too many copies of the corrected gene to any one HSC, increasing the frequency of multiple, inappropriately-located insertions and in turn the risk of genotoxicity. 

Payen's team thus focused on improving their therapeutic vector so that it would deliver the right number of copies to the HSCs and give a selective advantage to those corrected cells via the addition of a gene conferring resistance to an antibiotic . In in vitro testing, they verified that it was possible to obtain a 100% rate of HSCs genetically modified by only one or two vector-delivered HBB gene copies. Thereafter, the team confirmed the selective advantage of the corrected HSCs through in vivo testing in murine models. 

More generally and in addition to these new properties, this second-generation vector benefits from efficient production  and maintains the qualities of the initial vector ( efficacious gene transfer, protocol duration, level of expression of the therapeutic gene, etc.). Since the products used to confer selection already have their market authorizations, all conditions are united for a rapid deployment in the clinical setting. Nonetheless, toxicology studies will be necessary before testing begins in patients with severe forms of beta thalassemia or sickle-cell anemia. 

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