A recently published study by researchers at the Baylor College of Medicine demonstrates the successful use of a vector to deliver gene therapy to treat hemophilia B. The lead author of the study was Nicola Brunetti-Pierri, MD, Assistant Professor in the Department of Molecular and Human Genetics at the Baylor College of Medicine in Houston, TX.
Hemophilia B is a prime candidate for successful gene therapy because achieving even a modest rise in factor IX (FIX) levels--1%-5% of the blood clotting protein--could be enough to prevent bleeding, according to Brunetti-Pierri and co-authors. Genetically modified viruses are being studied as vectors because they are adept at infiltrating host cells.
The goal is to use the virus as a vehicle without triggering an immune response or the disease itself. Many scientists favor using adenoviruses because they infect cells without causing disease. However, efficiency can be an issue. Often trillions of vector particles need to be administered for the corrective gene to penetrate the nucleus of a cell and carry out its therapeutic function. In addition, these vectors often need to be delivered in a high volume, which may prompt an unfavorable immune response in the host.
Brunetti-Pierri and his colleagues employed a technique with the potential to deliver a genetically based therapy with lower vector doses. They combined two bioengineered FIX molecules (R338A-FIX and FIXVIIEGF1), previously shown to be effective in studies using dog models, with a helper-dependent adenoviral vector (HDAd). HDAds have demonstrated an ability to both replicate and elicit high levels of effective transgene expression.
In a study of mice with hemophilia B, each was injected with one of the following using HDAd: R338A-FIX alone, FIXVIIEGF1 alone, the R338A-FIX/FIXVIIEGF1 combination or an unmodified, so-called “wild-type” FIX molecule. Investigators monitored the FIX activity of the mice for up to 44 weeks. Results showed that the mice injected with R338A-FIX alone demonstrated increases of FIX activity during the study period--from 2.2 fold to 3.6 fold--when compared to the wild-type. The FIXVIIEGF1 also showed an increase in comparison to wild-type FIX, by 2.0 to 4.8 fold. The most dramatic increases, though, occurred in the mice that received the novel R338A-FIX/FIXVIIEGF1 combination. The FIX activity increased by 8.9 fold to 16.7 fold, compared to the wild-type FIX.
“The increase in catalytic activity was confirmed with a lower dose, thus confirming that the double modification allows the use of a lower vector dose to achieve an improved therapeutic function,” concluded Brunetti-Pierri and co-authors. Lower vector doses are crucial since higher doses can produce toxicity in subjects.
The study, “Bioengineered Factor IX Molecules with Increased Catalytic Activity Improve the Therapeutic Index of Gene Therapy Vectors for Hemophilia,” was published online in February 2009 in the journal Human Gene Therapy.