New Viral Vector Improves Sickle Cell Gene Therapy

A unique, improved viral vector for use in treating sickle cell disease with gene therapy has recently been created by researchers from the National Institutes of Health (NIH). When tested in animal models, this vector was able to incorporate correct genes into bone marrow stem cells up to 10 times more efficiently than current vectors. This new viral vector also has a carrying capacity up to six times higher than the conventional vector, as per the researchers. The use of this new technique could potentially make gene therapy more effective and prevalent in treating sickle cell disease, which affects roughly 100,000 people in the US and millions globally. The NIH team’s findings were published on October 2 in the journal Nature Communications.

“Our new vector is an important breakthrough in the field of gene therapy for sickle cell disease,” said senior author John Tisdale, MD, chief of the Cellular and Molecular Therapeutic Branch at the National Heart, Lung, and Blood Institute (NHLBI). “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.”

In gene therapy, the viral vector serves as a delivery vehicle that leverages the virus’s innate ability to infiltrate host cells and administer genetic material. The vector is modified to carry a beneficial gene that will induce therapeutic effects in the patient, often by counteracting a genetic mutation.

Patients with sickle cell disease have an inherited mutation in the beta-globin gene, resulting in a faulty hemoglobin structure that yields sickle-shaped red blood cells. This shape causes the blood cells to stick to blood vessel walls, causing pain, anemia, blockage, organ damage, and premature death. Gene therapy for sickle cell involves the modification of bone marrow hematopoietic stem cells. These blood-producing cells are altered to possess a normal copy of the beta-globin gene in a lab and are then reinfused into the patient, ultimately inducing the production of healthy red blood cells.

Though this approach has been effective, Tisdale notes that there is always room for improvement in such treatments. He compares this new viral vector to a new model of a car that is easier and more scalable to produce.

Researchers have been developing these beta-globin vectors in a reverse structural orientation for over 30 years. This approach entails that the genes incorporated into the virus are translated from right to left by the enzymes, analogous to a sentence being read backward. This is done due to the sensitive expression of intron 2, a key molecular component of the vector that is required for high beta-globin expression. This intron gets excluded during the normal vector preparation process if it is not oriented in this reverse manner.

Gene therapy studies that incorporate these reverse-oriented vectors for sickle cell disease and beta-thalassemia, a similar inherited blood disease, have been encouraging thus far. The researchers note that this complicated gene translation process has made both the preparation of the vector and the gene-transfer efficiency more challenging, however.

Roughly 10 years ago, Tisdale worked with Naoya Uchida, MD, PhD, a staff scientist in his lab, to find an improved beta-globin delivery vehicle. They found a unique way to leave the intron 2 intact by creating a new forward-oriented beta-globin vector. Unlike the previously used, reverse-oriented vector, this novel vehicle is read left to right in typical fashion. Tisdale notes that this simplifies the translation of this genetic information into a tangible protein compound, like beta-globin.

These unique vectors were used in mouse and monkey models, with the results being compared to reverse-oriented vectors. The NIH team found that their vector delivered a viral load of up to six times more therapeutic beta-globin genes than the traditional vector and had four to ten times higher transduction efficiency (ability to incorporate therapeutic genes into repopulating bone marrow cells).

In addition, these new vectors remained in place four years after transplantation, supporting the longevity of this approach. This forward-oriented vector can also be produced in greater quantities than the traditional vector, cutting time and costs that come with industrial production.

“Our lab has been working on improving beta-globin vectors for almost a decade…and finally decided to try something radically different–and it worked,” Tisdale concluded. “These findings bring us closer to a curative gene therapy approach for hemoglobin disorders.”