Multi-tasking Vector to the Rescue of Red Blood Disorders

Researchers in the Rivella Laboratory have developed a superpowered vector — to treat, and potentially cure, red blood disorders.

By Nancy McCann

Researchers at Children’s Hospital of Philadelphia have created a new gene therapy technology — a superpowered vector — to treat, and potentially cure, hemoglobinopathies such as sickle cell disease (SCD) and beta-thalassemia. The vector’s multi-tasking abilities provide a proof-of-concept treatment that can concurrently reactivate production of fetal hemoglobin and elevate adult hemoglobin, while suppressing mutant adult hemoglobin. A superpower, indeed.

“Until now, researchers have been exploring one of two approaches to treating blood disorders like sickle cell disease or beta-thalassemia: adding a functional copy of the adult hemoglobin gene, or increasing production of fetal hemoglobin,” said senior author Stefano Rivella, PhD, scientific director of the CuRED Frontier Program. “In this study, we have done both simultaneously, which provides an opportunity to produce more hemoglobin per vector in these patients.”

Hemoglobin 101

Hemoglobin is a protein in red bloods cells that delivers life-sustaining oxygen to cells throughout our bodies. In utero, the gamma-globin gene produces fetal hemoglobin, but after birth, this gene is switched off, and the beta-globin gene, which produces adult hemoglobin, is switched on. Patients with blood disorders such as SDC and beta-thalassemia have mutated beta-globin genes. These mutations cause deficient or altered hemoglobin production and consequently lead to serious health complications ranging from delayed growth, jaundice, and anemia to episodes of severe chronic pain, stroke, and premature death.

Current studies have focused primarily on treating these blood disorders by either reactivating fetal hemoglobin — which is not mutated in these conditions — or using a technique called gene addition, which adds a functional copy of adult hemoglobin via a viral vector, an engineered vehicle for delivering the new genetic material needed to correct the abnormality. While these approaches seem promising, they are limited on a single strategy. This novel vector combines the best of both methods.

How the Multi-tasking Vector Works — a Hemoglobin Trifecta

In order to increase hemoglobin levels in just one therapy, the research team led by co-first authors Danuta Jarocha, PhD, and Silvia Pires Lourenço, PhD, both of the Rivella Lab, combined the two methods mentioned above into a single gene therapy vector. They focused on the gene BCL11A which regulates the expression of adult hemoglobin versus fetal hemoglobin. It operates like a light switch, turning off the production of fetal hemoglobin and turning on the production of adult hemoglobin after birth.

The researchers hypothesized they could induce greater hemoglobin production by using an engineered vector to suppress BCL11A in order to keep fetal hemoglobin production turned on and at the same time switch off the production of mutant adult hemoglobin, while also adding a functional copy of the beta-globin gene.

Working in vitro with cell lines of patients with SCD and beta-thalassemia, the scientists tested their vector, which included a gene coding for adult hemoglobin and a microRNA sequence that would target BCL11A. They discovered that the vector was able to reactivate fetal hemoglobin and elevate adult hemoglobin simultaneously. Although BCL11A was not completely knocked down, the suppression was enough to reduce production of the mutated adult hemoglobin. By elevating both fetal and functional adult hemoglobin, the vector was able to induce more functional hemoglobin production than that of a vector expressing beta-globin alone.

Future studies will examine and refine this technology by using an even stronger vector developed in the Rivella Lab, which will allow for a higher level of curative hemoglobin. Molecular Therapy recently published the findings from the Lab’s preclinical study of this particular vector, and Cornerstone covered the story.

“By combining these two technologies, we hope to make an even more powerful vector that can provide curative levels of hemoglobin to these patients,” Dr. Rivella said.