About 100,000 people in America have sickle cell disease. Of those, an estimated 27 people have undergone experimental gene therapy using conventional vectors—virus-based vehicles for delivering “therapeutic genes.” Now National Institutes of Health researchers have taken the vector idea and revved it up, bringing the possibility of curing sickle cell disease a bit closer.
With gene therapy, doctors add a normal copy of the β-globin gene to the patient’s hematopoietic stem cells, then reinfuse the modified stem cells into the patient to produce normal disc-shaped red blood cells. In animal studies, the new vector was up to 10 times more efficient at incorporating corrective genes into bone marrow stem cells with a carrying capacity of up to 6 times greater viral load than current vectors. The new vectors also can be produced in much higher amounts, saving time and lowering costs.
The researchers call it a “forward-oriented” vector because it changes the usual direction of how gene sequences in globin-containing vectors are read: from right to left. That backward orientation—globin-containing vectors are the only therapeutic vectors in clinical development that use it—the researchers say, “has remained unchallenged for decades despite its negative impacts on efficiency.”
The right-to-left orientation was dictated by the need to prevent the loss of a key molecular component, intron 2, by RNA splicing during the vector preparation. The redesigned forward-reading method crucially leaves intron 2 intact and makes the gene-translation approach less complicated, says John Tisdale, MD, chief of the Cellular and Molecular Therapeutic Branch at the National Heart, Lung, and Blood Institute, who, with Naoya Uchida, MD, PhD, came up with the idea.
In testing, the new vectors also proved longer lasting, remaining in place 4 years after transplantation.
National Institutes of Health is working to accelerate research and development through the Cure Sickle Cell Initiative, launched by NHLBI in 2018 to identify and support the most promising genetic therapies for the more than 20 million people worldwide who have sickle cell disease. NIH holds the patent for the new vector, which still will need clinical testing in humans. Clinical trials are actively enrolling.