Scientists are seeking haemophilia's Holy Grail - a safe, cost effective treatment for this global problem. 20th and 21st Century Haemophilia treatment has evolved from Plasma replacement therapy to cryoprecipitate and purified plasma-derived [FVIII] concentrates. Unfortunately, this required large plasma pools, which encouraged the transmission of infection [HIV, Hepatitis B,C etc.], led to extensive litigation and kick-started the quest for safer products.
One of them, Recombinant Factor VIII, has a 15-year, infection-free history and a promising future. In 2010, SW Pipe of the University of Michigan wrote:-
"The production of recombinant coagulation factors has increased the worldwide capacity for replacement therapy and facilitated aggressive prophylactic therapy. Recombinant DNA technology remains a promising platform to develop novel haemophilia therapeutics with improved functional properties".
Another, gene therapy - a technique involving the insertion of a working gene into a patient to replace the disease causing gene - also looks promising. In 2008, Samuel L Murphy wrote,
"Safe, long-term expression of clotting factors has been successfully achieved in large animal models of haemophilia using multiple gene transfer strategies, but these findings have not yet been translated into success in patients".
Research at the University of London reported by Nature describes more positive results in humans.
Progress is necessarily slow, however. In 2009, The National Haemophilia Foundation warned,
"Any pathway which does not give due consideration to the catastrophic consequences which could result from an inappropriate attempt to short cut the regulatory approval process would be a disservice to patients"
The painstaking research required to ensure high standards in later manufacturing is often frustrating, as Professor William Velander, a Chemical and Biomolecular Engineer at University of Nebraska - Lincoln [UNL], knows only too well.
Professor Velander lists his research interests as, "Working on safer, abundant sources of plasma-derived medicines since 1987, when disease contamination of blood supply medicines by HIV, Hepatitis B and C reached a worldwide epidemic.".
His team has developed methods to produce large quantities of Factor using transgenic animals by inserting a gene for Factor IX [FIX] into pig embryos. Fully grown female pigs are then able to make large quantities of FIX through their mammary glands. 1 litre of milk has 1 million units of activity - far beyond the levels found today in recombinant preparations.
Some years ago, Velander hypothesised that,
"Once purified, the protein could be reconstituted for an intravenous infusion, similar to the approach used with today's recombinant factor. However, another possibility exists. It may be feasible to mix purified factor with pasteurized milk or any other drink and provide it as an oral treatment"
He also suggested that,
"Factor purified from milk of 10 to 20 animals could provide haemophilia B treatment for all of South America"
Oral intake has a number of advantages - it is easier and less painful than syringes/needles, babies prefer it and research suggests a reduced inhibitor risk. After positive findings in mice studies [Haemophilia B] and a $9.98 million grant from the National Institutes of Health, the research continued.
"We have done some very cursory work on oral delivery in dogs and got some Factor IX into their blood stream and will hope to do intravenous infusion pharmacokinetics studies this fall in haemophilic dogs"
He suggests that the stomach's destructive properties might make "buccal delivery" [absorption through the mouth lining] a better option. However, the current technology is inadequate for effective buccal delivery.
The large quantities of Factor obtained from transgenic animals and the resultant economic benefits will mitigate the costs dramatically. He believes this will be an incentive for healthcare agencies / governments in the US, Brazil and perhaps India to invest in his work, enabling them to pursue their own philanthropic aims with the savings. This model, he believes conquers the purely "for profit" approach. Looking to the future, Velander believes that pig Factor IX material will progress to human studies in 2-3 years if the results from animal studies are good, with Factor VIII arriving about three years later.
But he suspects that funding will remain a constant source of frustration. He says,
"You cannot publish very much, you cannot rely on traditional academic sources of funds, venture capital is not an option and this is why we are appealing to governments"
He ends with some encouraging words - in the future there should be some exciting data from his research. Velander's drive and determination in this area of research was captured in the Hollywood film Extraordinary Measures, starring Harrison Ford. For UNL's Indiana Jones, the Holy Grail has so far eluded him but he is serious about offering a cost effective haemophilia treatment, and never gives up. He says, "There's a glimmer of hope because we really can foresee clinical trials on this."
10. William H. Velander. Chemical & Biomolecular Engineering UNL