Güncel Haberler Hematoloji Uzmanlık Derneği

Mutant protein brings gene therapy for hemophilia a step closer - 16-03-2015

 Published in the journal Blood, the study reveals how the protein - named FIX-Padua - successfully relieved symptoms of hemophilia in three dogs with severe forms of the disease.

It is estimated that around 20,000 people in the US are living with hemophilia, and around 400 babies are born with the condition every year. The disorder primarily affects males.

Hemophilia is an inherited condition caused by a mutation in a gene responsible for producing proteins in the blood needed for normal blood clotting, called clotting factors. As a result, people with hemophilia are prone to internal bleeding - particularly in the joints - and prolonged bleeding following an injury.

The two main types of hemophilia are A and B. Hemophilia A is where a person is missing or has low levels of the clotting factor VIII, whereas hemophilia B is where an individual is missing or has low levels of clotting factor IX. The lower the levels of a certain clotting factor, the more severe the disorder is.

The search for new hemophilia treatments

The most common form of treatment for hemophilia is replacement therapy, whereby a patient undergoes intravenous infusion of clotting factors in order to help replace the ones that are low or missing.

However, this treatment has significant downfalls; patients with more severe hemophilia may need frequent sessions, which is expensive and time consuming. In addition, some patients can develop antibodies that attack and destroy the clotting factors before they have a chance to work.

For many years, researchers have been investigating the use of gene therapy as an alternative treatment option for patients with hemophilia. One gene therapy strategy that has shown some promise involves injecting patients with vectors - nondisease carrying viruses - to carry DNA sequences that hold a genetic code that enables clotting factor production.

However, early trials of this technique have raised concern. Vectors appear to trigger a strong immune response, and the higher the vector dose, the stronger the immune response is.

As such, the researchers of this latest study - led by Dr. Valder R. Arruda, a hematology researcher at The Children's Hospital of Philadelphia (CHOP) - set out to find a technique that delivers lower vector doses to reduce immune response, while effectively producing clotting factors.

FIX-Padua alleviated hemophilia symptoms without activating an immune response

In 2009, Dr. Arruda and colleagues came across an Italian man with thrombosis - a condition characterized by excessive clotting in the blood vessels. The researchers found that this man's condition was triggered by a mutation in a factor IX (FIX) gene.

Fast facts about hemophilia

  • The average age of hemophilia diagnosis in the US is 36 months for mild forms, 8 months for moderate forms and 1 month for severe forms
  • Hemophilia A is around four times more common than hemophilia B
  • People with hemophilia who receive care in specialist treatment centers are at around 40% lower risk of hospitalization and mortality than those who do not receive this care.

Learn more about hemophilia

The researchers explain that all previously identified FIX mutations had been found to cause hemophilia, but this one - which they named FIX-Padua after the Italian man's home city - was the opposite. Its ability to clot blood is 8-12 times stronger than normal FIX genes, making it a potential candidate for gene therapy in patients with hemophilia.

The team set out to see whether the increased blood clotting ability of FIX-Padua would allow lower vector doses to be delivered, achieving an effective treatment without triggering a strong immune response.

FIX-Padua was administered via injection to three dogs who had severe forms of hemophilia B similar to those found in humans. One dog already possessed inhibitory antibodies prior to treatment having been exposed to clotting factors before, while two of the dogs had never been exposed to clotting factors and had no inhibitory antibodies.

The two dogs that had no prior inhibitory antibodies showed significant improvement in their hemophilia within 1 week, easing from severe to mild. In addition, the dogs had no bleeding episodes for up to 2 years. They had no immune response to FIX-Padua and there was also no sign of thrombosis.

The third dog that had pre-existing inhibitory antibodies also showed significant improvement following treatment with FIX-Padua. The animal's hemophilia also eased from severe to mild, and this persisted for up to 3 years. What is more, the inhibitory antibodies that the dog already possessed were eradicated by the injection - something the researchers say has never been seen in an animal model before.

The team also tested FIX-Padua in mouse models of hemophilia and found it produced similar results.

Commenting on their results, Dr. Arruda says:

"Our findings may provide a new approach to gene therapy for hemophilia and perhaps other genetic diseases that have similar complications from inhibiting antibodies."

A clinical trial is already underway for FIX-Padua. Researchers at the University of North Carolina at Chapel Hill are testing the safety and efficacy of the gene therapy in adult patients with hemophilia B.

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