Merry Christmas for Patients with Hemophilia B

That was the headline of an editorial in the New England Journal of Medicine (NEJM) which discussed the very promising results of a small clinical trial of gene therapy to treat hemophilia B – also known as Christmas Disease*. Patients with haemophilia B suffer bleeding in the joints and muscles due to deficiency in a coagulation factor IX, which blocks the coagulation cascade that normally leads to blood clots forming and prevents bleeding. Hemophilia B can be successfully managed by intravenous infusion of factor IX several times a week, but this therapy is very expensive – it has to be isolated from donated human blood plasma – and causes allergic reactions at the injection site in some patients.

Studies in mice were key to developing gene therapy for hemophilia B

Clearly a more permanent solution to factor IX deficiency is highly desirable, and to develop one scientists at University College London and the St Jude Children’s Research Hospital in Memphis turned to a technology that we have discussed on several occasions on this blog in recent years – gene therapy. The results of their clinical trial, published in NEJM, were impressive, all the patients were able to stop regular factor IX injections to maintain adequate factor IX levels, or to greatly reduce the frequency of injections.

As the NEJM editorial points out, this therapy has the potential to not only improve the lives of people with hemophilia B, but also to save millions of dollars over their lifetime.

In an excellent post discussing the clinical trial science blogger ERV notes that:

This treatment is not perfect yet– but its a huge step in a right direction, and only possible because of viruses.”

A very good point, in medicine we usually think of viruses as the enemy, but when it comes to gene therapy they are an ally.

But they are not always the easiest of allies to campaign alongside, and that is where another scientific technique without which this advance would not have been possible comes in – animal research!

A key choice when developing any virus-based gene therapy is the vector used to deliver the replacement gene to the cells of the body.  The vector must deliver enough copies of the gene to the target tissue to be effective, enable the gene to express in sufficient quantity to ameliorate the condition, and do so safely. Adenoviruses are often chosen for this task, with the serotype AAV 2 being the most widely studied in animals and humans. But there is a serious problem with AAV2, roughly half the population have been exposed to AAV2 naturally, and mount an immune response that clears the vector from the bloodstream before it can deliver its gene cargo to the target tissue.

The researchers addressed this problem by turning to another adenovirus serotype AAV8, which was isolated from rhesus monkeys a decade ago.  They chose AAV8 for three reasons, firstly earlier studies in mice showed that AAV8 injected into a peripheral vein delivered genes to the liver – the natural site of factor IX production – much more efficiently than AAV2, secondly the mouse studies also showed that AAV8 uncoats and delivers its  gene payload to cells more swiftly that AAV2, helping to ensure that the gene is delivered before the body can mount an immune response, and thirdly prior immunity is far less common in the human population than immunity to AAV8.

The AAV8 vector wasn’t perfect though, it would still require a large number of virus particles to be injected – potentially enough to trigger liver damage or stimulate a larger and more rapid immune response – so they designed a modified AAV8 vector known as a self-complementary (SC) vector that delivers the gene to liver cells even more efficiently.  Injection of mice with an SC vector containing the factor IX gene was found to lead to a 20-fold increase in liver of factor IX expression compared to the same amount of standard AAV8 vector, with no increase in toxicity. Since the ability of vectors developed from different adenovirus serotypes to target gene expression to particular tissues can vary between mice and primates, they then evaluated this vector in rhesus monkeys, finding that the SC vector could drive safely therapeutic levels of factor IX production in the monkey liver, and that prior immunity to one adenovirus serotype did not diminish the efficiency of factor IX production by a vector based on another serotype.

These studies paved the way for the clinical trial that caused so much excitement in the scientific and popular press earlier this month. Hopefully further development and larger clinical trials in people with hemophilia B will confirm the potential of this exciting new therapy, a therapy that was developed thanks to viruses and to animal research!

* after a patient named Stephen Christmas from whom factor IX was first isolated.

Paul Browne