Hemophilia B: Lentiviral Vector Safe, Effective in Dogs

Ricki Lewis, PhD

March 05, 2015

Lentiviral vectors effectively deliver the gene that encodes coagulation factor IX (FIX) to the liver in dogs with naturally occurring hemophilia B (factor IX deficiency), researchers report in an article published in the March 4 issue of Science Translational Medicine. In addition, the vectors did not insert in or near oncogenes in mouse models.

Hemophilia B is an attractive candidate for gene therapy because a small improvement in clotting factor activity can lead to less frequent or no reliance on exogenous FIX. A single gene transfer could confer sufficient endogenous production of the clotting factor to last a lifetime.

Gene transfer to deliver the FIX gene to hepatocytes in patients with hemophilia B is in clinical trials, using adeno-associated virus (AAV). In the current study, Alessio Cantore, PhD, a postdoctoral researcher at the San Raffaele-Telethon Institute for Gene Therapy in Milan, Italy, and coworkers evaluated lentivirus (LV) as an alternative vector.

LV could be advantageous as it would not have the problem of preexisting antibodies seen with AAV because HIV infection is relatively rare. LV also accommodates a larger gene insert and might be the preferred vector in children who have high hepatocyte turnover because, unlike AAV, LV inserts into the genome.

To test the concept, the researchers treated three dogs: Hemil received the wild-type FIX transgene, Valentine got the wild-type codon-optimized gene (which increases transcription efficiency), and Enzo received a codon-optimized hyperfunctional gene that bears a mutation that causes thrombophilia in humans.

All the dogs did well. Hemil was followed for 5 years and achieved 0.08% to 0.05% of normal clotting, with seven bleeds over that time compared with 27 bleeds predicted based on pretreatment experience. Valentine, followed for 2.5 years, experienced 0.3% to 1.7% FIX levels and two bleeds. Enzo, followed for 1.75 years, had 0.6% to 1.9% restoration of FIX levels and no bleeds.

Anti-inflammatory and antihistamine pretreatment was necessary. The vector stayed in the liver and ameliorated the phenotype.

The researchers also investigated the sites of viral integration in mouse models, because insertional mutagenesis into oncogenes ("genotoxicity") was an adverse effect seen in previous gene transfer clinical trials that used gamma retroviral vectors. Mice prone to liver tumors were used because wild-type mice do not live long enough to develop a cancer phenotype. LV did not preferentially insert into oncogenic regions of the mouse genome.

"Our findings suggest that lentiviral vectors may be an attractive candidate for gene therapy targeted to the liver and may be potentially useful for the treatment of hemophilia," the researchers conclude. They call for further preclinical studies and consider lentiviral vectors as complementing the use of other vectors.

They note several study limitations, including the small number of dogs followed, the different treatment of each, and the low doses of vector given.

Dr Naldini is an inventor on pending and issued patents on lentiviral vector technology. The other authors have disclosed no relevant financial relationships.

Sci Transl Med. 2015;7:277ra28. Abstract

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