Gene Therapy Approach, Tested on Liver Cells and Mice, Seen as Potential Treatment for Hemophilia B

Researchers, working with mice, have developed a new way of producing substantial numbers of gene-corrected liver cells with the possibility of repopulation in vivo. The strategy, which relies on the liver’s unusual regenerative skills, may hold promise for the treatment of diseases such as hemophilia B.

The study by scientists at Oregon Health & Science University, working in collaboration with Stanford Medical School and Baylor College of Medicine, is titled “A universal system to select gene-modified hepatocytes in vivo” and published in the journal Science Translational Medicine.

To date, some clinical success has been achieved using a gene therapy vector, called a recombinant adeno-associated viral (rAAV) vector, to treat hemophilia B (characterized by the lack of a liver-made protein — factor IX — that helps blood clot). However, the method suffers from limitations, such as transgene expression, immune responses, and concerns about mutagenesis and cancer.

The researchers used liver cells from mice as a model, due to their ability to regenerate. They delivered a gene therapy with an additional artificial RNA molecule used to silence target gene expression called hairpin RNA (shRNA). The introduced shRNA affected a key enzyme in a specified way, turning the cells more resistant to a toxic drug named Cehpoba.

Healthy newborn mice were given the new gene therapy, and a number were then treated with daily injections of Cehpoba for four weeks to guarantee that only the gene-corrected cells would survive and multiply in the liver, generating healthy genetic material that inhibits the development of liver disease.

Data found that the factor IX in the fully treated mice increased by 10- to 30-times that seen in mice given gene therapy but not Cehpoba. This is more than hemophilia B patients would need to fix their clotting problems. More importantly, the produced genetic material responsible for the higher levels of factor IX  could be controlled by the Cehpoba dosage. “You could dial in how many factors IX [or other protein] you wanted,” Dr. Markus Grompe at Oregon Health & Science University in Portland said in a news release.

Although Cehpoba is known to be toxic and is not an approved drug, the researchers think such a treatment approach might be possible in babies around 6 months old who are born with a liver-damaging condition mimicking Cehpoba. “We have the natural history of what happens to these patients as an argument to say you could do this,” Dr. Grompe said.

The method is promising for cell-based therapies for liver diseases and genetic conditions like hemophilia B, as well as for therapeutic expansion of gene-corrected cell populations. Further studies are needed, however, before it might be considered for human clinical trials.

“This is very much proof of concept. The authors [of the new study] would be first to admit it still has a way to go, but it’s a very exciting step in my view,” said Dr. Ian Alexander of the University of Sydney in Australia, who works on gene therapy for childhood liver diseases.

Hemophilia is caused by deficient clotting proteins (factor VIII in hemophilia A and factor IX in hemophilia B). The disease has no known cure, but can be controlled through regular blood transfusions.