Gene Therapy for Hemophilia

Treatment for Hemophilia relies upon giving the proteins that patients lack in order to replace them. The proteins normalize the levels of factor 8 and factor 9 for a period of time before they are broken down by the body. The therapy is very effective to stop bleeding and is used effectively to manage the condition. However, it does not make the disorder go away and does not cure patients of Hemophilia.

One day, we hope to be able to use gene therapy to treat and cure patients with Hemophilia. Gene therapy promises to take the cells in a patient’s body such as a patient’s own liver cells, hepatocytes, and use them to produce the missing factor. This is done by placing a normal sequence of DNA that teaches the cell how to make the factor properly. Once the cell has been taught, it would be able to make the factor 8 or factor 9 for the rest of the patient’s life.

Scientists have long struggled to develop gene therapy treatments for the past few decades. One of the hurdles they have to overcome is finding an efficient delivery system. The best successes have been through hijacking viruses, which have naturally evolved to deliver genetic material to human cells. One such virus, adeno-associated virus (AAV), a non-pathogenic human virus, has had the greatest success in both animal and human studies to date for treating hemophilia. Much of the research in developing the AAV for gene therapy occurred at the University of Florida.

Even though Hemophilia A is more common, only recently were gene therapy trials for hemophilia A started due to challenges with fitting the larger sized factor VIII gene into their delivery vehicles. Stable expression of factor to > 5% has now been reported in both Hemophilia A and multiple Hemophilia B clinical studies and importantly, most of these patients have discontinued prophylactic clotting factor protein therapy and remained free of bleeds.

With these successes, gene therapy or gene replacement therapy is currently being evaluated in adult Hemophilia A and B patients. Some patients in the first trials in men have not reached therapeutic clotting factor expression or have maintained stable clotting factor levels. One issue is identifying the therapeutic dose of the gene therapy vector as a single administration of AAV triggers an immune response against AAV that prevents additional treatment. Secondly, since AAV naturally occurs in humans, many patients may have acquired immunity that will also recognize the gene therapy vector. Finally, it will take time to understand the risks and develop safe protocols to treat patients with historical or concurrent inhibitors, who are currently excluded from ongoing clinical trials.

Presently there are four registered and/or active clinical trials for Hemophilia A and six registered and/or active clinical trials for Hemophilia B (see table below). Some of these trials are being conducted at the University of Florida.

With each clinical study, investigators are learning and improving their treatment approaches. It is anticipated that the first gene therapy vector for Hemophilia B will receive FDA approval soon.

Hemophilia Gene Therapy trials available at University of Florida

Vector Sponsor Route Status Identifier Dose (vg/kg )
AAV6-(ZFN1, ZFN2, F9) Sangamo Biosciences IV Active, not recruiting NCT02695160 5×1012-5×1013
AAV6-F8 Sangamo Biosciences IV Recruiting NCT03061201 Not disclosed

Hemophilia A Gene Therapy Clinical Trials

Vector Sponsor Route Status Identifier Dose (vg/kg)
AAV5-F8 BioMarin IV Active, not recruiting NCT02576795 6×1012-6×1013
AAV?-F8 Spark Therapeutics IV Recruiting NCT03003533 Not disclosed
AAV8-F8 University College, London IV Not yet recruiting NCT03003533 6×1011-6×1012

Hemophilia B Gene Therapy Clinical Trials

Vector Sponsor Route Status Identifier Dose (vg/kg)
AAV2-CMV-F9 Avigen IM Terminated NCT00076557 2×1011 – 1.8×1012
AAV2-ApoE-hAAT-F9 Spark Therapeutics hepatic artery Completed NCT00515710 8×1010-2×1012
scAAV8-LSP-coF9 St. Jude Children’s Research Hospital IV Active not recruiting NCT00979238 2×1011-2×1012
scAAV8-coF9(R338L) Baxalta IV Active not recruiting NCT01687608 2×1011-3×1012
AAV5-F9 UniQure Biopharma B.V. IV Active not recruiting NCT02396342 5×1012-2×1013
AAV8-F9 Spark Therapeutics IV Terminated NCT01620801 Not disclosed
AAVrh10-F9 Dimension Therapeutics IV Terminated NCT02618915 1.6×1012-1×1013
SPK9001-coF9(R338L) Spark Therapeutics IV Completed NCT02484092 5×1011 – ?