Gene therapy transforms lives for people with haemophilia A

Taking on the challenge

The technology was licensed by UCLB to BioMarin Pharmaceuticals Inc in 2013 using research from Professor Amit Nathwani and his team at UCL and St. Jude Children’s Research Hospital. They published a pivotal study in 2011 reporting the first clear evidence of successful gene therapy for haemophilia B. For Amit, tackling haemophilia A was the natural next step. But this posed some challenges, as he explains:

“Haemophilia A is caused by a deficiency of clotting factor VIII. The F8 gene is very complicated, it’s larger than the gene for haemophilia B, so we had to do quite a bit of engineering to get the viral vector to the right size. The factor VIII protein is also expressed at much lower levels, so there was a challenge of how to increase expression.”

Part of the answer turned out to be a process called ‘codon optimisation’ whereby the researchers changed some of the gene’s ‘code’ to replicate that of proteins which are synthesised at high levels in the liver. Once injected, the virus delivers the recombinant F8 gene to several tissues. Because the promoter is liver-specific, the factor VIII protein is only synthesised in liver cells, then released back into the bloodstream. The result was a tenfold increase in factor VIII expression – enough to almost eliminate the risk of bleeding in patients.

A model for industry-academic collaboration

It was also enough to interest BioMarin, who opened discussions about licensing the technology. Richard Fagan is UCLB’s Director of BioPharm, and led on the licensing deal.

“BioMarin didn’t have experience in gene therapy at the outset. But they’ve been great to work with and very collaborative. In ten years, they’ve taken this therapy all the way through clinical development to marketing authorisation. They’ve run the largest clinical trials for a gene therapy for the treatment of haemophilia A in the world. So it’s a great example of an industry-academic partnership which has delivered real patient benefit.”

Having experienced an alternative commercialisation model as founder of gene therapy spinout Freeline Therapeutics, Amit reflects that each has its benefits:

“Licensing is great for my mental health because I throw it over the wall, and someone else does the work while I watch from the sidelines. But it does mean you have less influence over the process.”

He is grateful to BioMarin, who he says have fostered an open and respectful long-term relationship:

“I’m very proud of the fact that we’ve maintained a good, collaborative relationship with BioMarin for almost 10 years. This is a company that really moved the [gene therapy] field forward in a substantial manner and continues to invest in it. We had a meeting a couple of weeks ago on other research areas, and it’s refreshing to see how much effort they’re putting into getting this right and getting it better.”