Researcher studying hemophilia

New Hemophilia Therapies

Researchers share their hemophilia breakthroughs
Author: Katarina Grande

Hear from the consumer panelists who attended the workshop.

Scientists specializing in bleeding and clotting disorders research convened at the National Hemophilia Foundation’s 10th Workshop on Novel Technologies and Gene Transfer for Hemophilia at the University of North Carolina at Chapel Hill, February 5–6, 2010. The workshop, co-chaired by Glenn Pierce, PhD, MD, of Biogen Idec Hemophilia in Waltham, Massachusetts, and Thierry VandenDriessche, PhD, of the University of Leuven in Belgium, supplied a forum for 43 of the world’s hemophilia experts to share and discuss breakthroughs in research and technology. Presenters provided insights on improved clotting factors, immune responses to new treatments and gene therapy safety.

A collaborative and optimistic attitude permeated the sessions. “We want to achieve a cure, or we want to achieve long-term correction with the advanced bioengineered products,” VandenDriessche said. “With the progress that has been reported over the past few days, I’m more confident than ever that we will get there.”

New Technologies

While a cohort of biochemists and microbiologists study biochemical details about immune responses to factor VIII (FVIII), others are contributing new technologies. Researchers in the lab of Friedrich Scheiflinger, PhD, of Baxter BioScience, Biomedical Research Center in Vienna, Austria, are examining the potential of fucoidan, a compound extracted from seaweed, as a component of an oral therapy for bleeding disorders. Fucoidan hampers the body’s inherent anticlotting actions. Piggybacking on the research of Srinivasa Prasad, PhD, of Avigen, Inc., in Alameda, California, the goal is to bypass the usual clotting pathway and instead enhance biochemical cues other than factor VIII to promote clotting. Because fucoidans can be a natural part of a person’s diet, there is less concern about adverse immune system reactions. “They eat a large amount of fucoidans in Asia; they’re part of the normal diet,” Scheiflinger said. “The appealing part with the fucoidans is that they seem to be harmless. And if the thrombin generation in vitro, per se, is predictive of how it is in vivo, then fucoidans at the right dose would probably be an interesting therapy.”

Inhibitor Treatment

Another researcher working in the area of oral therapy for hemophilia is Roland Herzog, PhD, of the University of Florida in Gainesville. His team is focusing on the increasing number of people with hemophilia who develop inhibitors, antibodies to therapeutic factor. People with hemophilia B who develop inhibitors are at risk of severe allergic reactions to factor IX (FIX) product, which makes treatment especially difficult. Herzog’s team is developing an orally delivered FIX modified to grow in plant leaves. It has been shown in animal models to promote tolerance to FIX therapy while substantially lowering the risk of allergic reaction.

Clinical Trials

Other technologies are making the move from the lab into the clinic. Protein engineering figured prominently in the presentations. This involves making small changes to the amino acid sequence of factors VIII, IX and VIIa to either enhance their circulation time in the bloodstream or increase their activity at the site of a clot or both. “This is a very active area of research,” Pierce said. “Some new clotting factors have entered the clinic, and more are advancing through preclinical studies.” Clinicians reported positive results from clinical trials testing both longer-lasting and faster-acting recombinant factor VIIa (FVIIa) products, which will benefit people with inhibitors to factors VIII and IX. Three products are in advanced stages of testing.

The topic of clinical trials inspired discussion of the increasingly challenging patient recruitment process researchers face. With each new study requesting participation from the bleeding disorders community, the time it takes for qualified, willing individuals to join increases. This makes sense, say researchers, because people are satisfied with current treatment options and many are wary of the risks of clinical trials.

“The community will vote with its feet. Where there aren’t convincing data behind a clinical program in preclinical or in vitro data, then it’s very important that people judge for themselves what to participate in and what not to participate in,” said Stephanie Seremetis, MD, of Novo Nordisk A/S in Soborg, Denmark. “But the motivation is strong for most of the people to continue.”

“There needs to be a candid presentation of the advantages and potential limitations of the novel therapies that are approaching clinical assessment,” said workshop organizer David Lillicrap, MD, of Queen’s University in Ontario, Canada.

These sentiments were echoed in a 2009 survey of 2,500 people with hemophilia conducted by Lillicrap’s team. Almost half the respondents said they would need to see evidence that a therapy is effective in human patients before considering participating in clinical trials for gene therapy. At the same time, the voices of the bleeding and clotting disorders community indicate that science must push toward new therapies and solutions. Survey respondents expected therapeutic gene therapy to become a viable and realistic treatment option within five to 15 years. Similarly, representatives on the workshop’s patient panel commented on the value of clinical trial participation. They expressed optimism regarding the new and emerging therapies presented at the conference.

Gene Therapy

While improved recombinant clotting factor products remain an important area of research, the quest for effective and safe gene therapy treatment for hemophilia continues concurrently. Researchers are aiming to repair the single gene mutation responsible for hemophilia by delivering a correct copy of the factor-encoding gene. Although the perfect combination of genetic packaging and delivery method has yet to be determined, many options look promising.

One of the problems with gene therapy has been the immune system’s attack on either the gene’s packaging—often a safe version of a virus—or the factor produced by the introduced gene. Since FVIIa is familiar to the immune system of people both with and without inhibitors, the chance of rejection is decreased. Paris Margaritis, PhD, of The Children’s Hospital of Philadelphia, is zeroing in on the potential of the FVIIa gene transported via an adeno-associated virus (AAV), a type of virus that doesn’t cause disease. People with and without inhibitors could potentially benefit from FVIIa gene therapy, as this factor prompts clot formation differently than FVIII or FIX. Margaritis and his team tested the gene transfer in mice and dogs with positive results; levels of factor remained for months without any adverse reactions. The team is now researching ways to lower the dose of vector needed to achieve similar positive results.

Vector Squad

Teams of researchers from the University of North Carolina at Chapel Hill Gene Therapy Center are tinkering with the AAV vector to allow it to do a better job of carrying genes, entering cells and properly delivering the genetic material. R. Jude Samulski, PhD, the center’s director, is tracking closely how these modified viruses enter and travel throughout a cell by looking at fluorescent-dyed viruses through a super-high-powered microscope. While AAV is a compelling vector option because it doesn’t cause disease, it presents several problems. It has trouble entering the central part of the cell where it needs to deliver the therapeutic gene. Samulski’s team examined where the holdup was and what could be done to coax the virus into getting to its correct final destination. They found that empty vectors, a byproduct of their lab origin, compete with gene-containing vectors to enter the cell center. To help the gene-containing vectors enter the cell, the team added a proteasome inhibitor, a drug that prevents proteins from breaking down. “The drug is essentially acting as an adjuvant,” Samulski said.

The lab of Paul Monahan, MD, at the University of North Carolina at Chapel Hill Gene Therapy Center, is also working to improve AAV vector efficiency. Researchers have been testing the effects of a proteasome inhibitor called bortezomib, previously used to treat multiple myeloma and a type of lymphoma in humans, on gene delivery in mice and dogs with hemophilia A. Delivering the large FVIII gene inside an AAV vector only partially corrected the dogs’ FVIII deficiency. However, when bortezomib was added, the AAV vector successfully caused more FVIII to be produced, meaning, for a sustained period, the dogs had far fewer bleeds than would be expected. “Giving doses of AAV that would otherwise have been ineffective, the proteosome inhibitor bortezomib enabled phenotypic correction in two species for years,” said Monahan. “Proteosome inhibitor combination therapy seemed to provide a paradigm for the expansion of the use of therapeutic drugs in gene therapy.”

Safety First

The challenges of delivering a functional factor-encoding gene to the body without triggering the immune system remain. Yet, innovative approaches arise from apparent roadblocks. VandenDriessche’s research team is investigating an emerging technology involving transposons, groupings of mobile DNA, to combat hemophilia B. The team is working to plug the FIX gene into a super-efficient transposon that could safely deliver the gene to cells that could make FIX. Because this approach doesn’t use a modified virus as a gene delivery vehicle, the expectation is that the immune system will be less likely to reject the gene containing the FIX blueprint.

As new research discoveries emerge, one fundamental theme remains: patient safety. “It’s necessary that people understand that although there are very safe and efficacious therapies out there, innovation should continue,” said Scheiflinger. “However, safety should not be compromised in favor of patient convenience.”

In addition to Pierce, VandenDriessche and Lillicrap, other members of the organizing committee were Katherine A. High, MD, The Children’s Hospital of Pennsylvania; Nigel Key, MD, University of North Carolina, Chapel Hill; and Steven Pipe, MD, University of Michigan. The workshop has been organized every one to two years since 1996 to identify the state-of–the-art research in bleeding disorders and stimulate cross-fertilization among scientists and clinicians working in the field.