Gene Therapy Vehicle for Sickle-Cell Disease Shifts Forward - Healing Genes

Gene Therapy Vehicle for Sickle-Cell Disease Shifts Forward

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A radically redesigned viral vector may improve the delivery of therapeutic genes to patients with sickle-cell disease. According to tests in animal models, the new vector is up to ten times more efficient at incorporating corrective genes into bone marrow stem cells than conventional vectors, and it has a carrying capacity that is up to six times higher.

The conventional vectors that have been used to deliver gene therapies for sickle-cell disease have a reverse structural orientation. This orientation, which obliges the viral vector-making machinery to read the therapeutic genes in reverse, results in viral titers and transduction efficiencies lower than those that could be achieved with a forward orientation. For decades, the drawbacks of the reverse orientation were accepted because it was a convenient way to prevent a persistent problem attributed to RNA splicing.

Basically, treating sickle-cell disease with gene therapy requires that the delivery vector’s various components include intron 2. It is required for high-level expression of another key component, the β-globin gene. Intron 2, however, gets “clipped out” during the normal vector preparation process if it is left in the natural, forward direction.

To move the delivery of the β-globin gene forward—in both senses, researchers based at the National Institutes of Health (NIH) have been working on a unique workaround. John Tisdale, MD, chief of the Cellular and Molecular Therapeutic Branch at the National Heart, Lung, and Blood Institute (NHLBI), has led an effort to create a viral vector that leaves intron 2 intact but also incorporates a new forward-oriented β-globin vector.

In contrast to the old vector, the gene sequence, or “message,” of the new β-globin vector is read forward, making the gene translation approach less complicated.

“Our new vector is an important breakthrough in the field of gene therapy for sickle cell disease,” said Tisdale. “It’s the new kid on the block and represents a substantial improvement in our ability to produce high-capacity, high-efficiency vectors for treating this devastating disorder.”

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