UF researchers receive $4.7 million to study improved therapies for hemophilia

University of Florida researchers have received four grants totaling almost $4.7 million to develop therapies for improving the health and quality of life of people with hemophilia.

New treatments are urgently needed because those in current use are often rejected by the patient’s immune system and are very expensive, in some cases costing up to $1 million for a round of therapy.

Two of the grants are from the National Institutes of Health and the others are from Bayer HealthCare.

“The portfolio of grants allows UF to build and sustain a robust hemophilia research program covering both forms of the disease, hemophilia A and B, and fulfill an unmet need in Florida and the region,” said Roland Herzog, Ph.D., an associate professor in the UF College of Medicine’s department of pediatrics, who is principal investigator on both NIH grants and co-investigator on both Bayer awards.

The other principal investigators, also faculty members in the pediatrics division of cellular and molecular therapy, are division chief, Arun Srivastava, Ph.D., the George H. Kitzman professor of genetics and a professor of molecular genetics and microbiology, and associate professor Sergei Zolotukhin, Ph.D., also of the department of molecular genetics and microbiology. All are members of the UF Genetics Institute.

A four-year, $2.6 million grant from the NIH National Heart, Lung and Blood Institute will fund all three researchers in their efforts to develop and test better gene therapy methods for the form of the disease known as hemophilia B.

A five-year, $1.7 million grant to Herzog, also from the National Heart, Lung and Blood Institute, supports work to prevent the immune system from rejecting gene or protein therapies. That work is in collaboration with the Wistar Institute, the Children’s Hospital of Philadelphia, and Harvard Medical School.

In addition, a two-year, $200,000 Bayer Hemophilia Award to Srivastava will fund development of better gene therapy delivery vehicles for hemophilia A, and a second two-year $200,000 Bayer award funds Herzog as co-investigator with University of Central Florida professor Henry Daniell, Ph.D., to develop ways to induce tolerance to protein therapy for hemophilia A by orally introducing the protein before therapy is needed.

Hemophilia is characterized by defects in the gene that produces a protein required for blood to clot. People with the disease can suffer from spontaneous internal bleeding or severe bleeding from minor injuries. Males get the disease, which is linked to the X chromosome, while female “carriers” rarely show symptoms.

Many people around the world have hemophilia — 1 in 5,000 boys are born with hemophilia A, the more common form. Standard treatment is intravenous infusion of the missing protein. But in 25 percent of patients with the severe form of hemophilia, the immune system rejects that clotting protein and makes inhibitors that prevent it from working.

To help patients tolerate therapy, doctors try to exhaust the immune system by administering the therapeutic protein intravenously at frequent intervals and for long periods until the body no longer produces inhibitors in response.

That brute force approach works for hemophilia A, but often doesn’t for hemophilia B, in which patients risk death from severe systemic allergic reactions if exposed to the protein used in therapy. In addition, treatment is very expensive. A single round of therapy can cost up to $1 million, including hospitalization charges.

“There have to be better ways to do this,” Herzog said.

One study will investigate how minor chemical changes to viruses that are used as gene therapy vehicles to deliver working copies of malfunctioning genes to the liver, and reduce the chance that the protein produced will be rejected.

“The hope is that you can now treat the disease using less of this virus, so you can deliver more, in a more stealthy manner and make it less likely that the immune system will target cells infected by this virus,” Herzog said.

To find new ways to make the immune system more tolerant of protein therapy, the researchers will focus attention on enlisting the help of certain cells that normally suppress the body’s immune system as a way to prevent autoimmune diseases.

Other key studies include developing ways to administer the clotting factor protein orally in an effort to build immune tolerance before patients are in need of therapy.

“New and safer ways to deliver therapy would be far more welcome than what we’re doing now,” said Vishwas Sakhalkar, M.D., director of benign hematology in the division of pediatric hematology/oncology, who treats patients with hemophilia and other blood disorders. “Patients, their families, caregivers and doctors will embrace those advances, after seeing all that patients have to go through now for treatment.”