GDNF & Parkinson's - hope on hold again

Big pharma won't fund new trial but a new approach shows promise

For some years, the letters GDNF spelled hope for people with Parkinson’s. GDNF (Glial cell line Derived Neurotrophic Factor) is what is known as a growth factor, a kind of fertiliser for the brain, and has been shown to have a powerful regenerative effect on dopamine cells - in a dish in the lab, that is.

What really excited the Parkinson’s community was a major trial staged between 2012 and 2017 at hospitals in Bristol which saw GDNF injected direct into the brains of participants. First, six people took part in testing to see if the method of getting the growth factor into the brain was safe, then 35 participated in a double blind placebo controlled trial, where a computer decided who got the drug and who received the placebo. After nine months, all participants were told what they had been getting and invited to continue for another nine months, this time with all of them receiving GDNF.

After this, both groups of trialists showed moderate to large improvements in their symptoms compared with how they were assessed at the very beginning of the study. This, not surprisingly, made the trial participants very enthusiastic about GDNF and that optimism spread to the wider Parkinson’s community.

But nevertheless, once the data from the double-blind trial had been examined it became clear that it had failed. Those given the drug had seen an improvement but only by 5% more than the trialists on the placebo, which was not deemed statistically significant - the hurdle for that is a 20% margin, so it was well short.

That seemed to be that, even though PET scans showed dramatic - and statistically significant - improvements in the movement of dopamine through the brains of those injected with GDNF in the double-blind trial. Professor Alan Whone, who had run the trial, did start a project to use technology to measure symptoms of Parkinson’s more accurately - surely a necessity if future drugs are to demonstrate more clearly that they are better than a placebo - but as far as I was aware, nobody was interested in trying again with GDNF.

Then I got an email from a listener to the Movers and Shakers podcast. Sara told me that the charity Parkinson’s UK had acquired the rights to the GDNF system and the technology used to deliver the drug to the brain from the Canadian biotech firm that ran the trial.

The charity had set about designing its own trial, one which would have involved a bigger dose than that given to the original participants over a longer period: “The intent,” wrote Sara, “was for this trial to be of sufficient scale to achieve market approval, if successful.” But to go ahead with a trial on this scale Parkinson’s UK would need to raise a large sum from partners and after three years and a lot of effort and expense it recently announced that its project had failed. GDNF is going nowhere, and Sara, who has Parkinson’s, is frustrated and appears to feel a little let down.

When I got in touch with Parkinson’s UK, they confirmed what Sara had told me. They needed £50 million to run the trial, a huge sum for a charity with an annual income of £53.5 million in 2022, so that meant going to the pharmaceutical industry. “Although we had lots of initially very promising conversations with companies and investors, ultimately none of them ended up biting,” said Claire Bale, associate director of research.

That seems like depressing news but Claire explained that part of the reason that funds were not forthcoming was that the GDNF story had moved on: “During the time since the trial results came out in 2019. there's actually been a lot of great work happening more broadly into GDNF and growth factors, particularly with things like gene therapy approaches.”

Whereas the Bristol trial had involved implanting a device in the brain and then pumping in the drug every month, the gene therapy approach involved a one-off operation and injection. The device used in the original trial to deliver the drug carried with it the risk of infection: “It's not ideal to have this bit of kit in your head long term.”

And Claire told me that many of the original participants from the Bristol trial had been involved in the Parkinson’s UK project and fully endorsed the idea that the gene therapy approach was the way forward.

So how is that going? Well, here is where many Parkies will get impatient. There has been a phase one trial which showed that this approach is safe but was too small to show whether it is effective. A phase two trial is expected to get underway at the end of this year - but the gene therapy research is being led by an American company, and while Parkinson’s UK hopes some UK patients can take part, there are no guarantees.

It is hard to see how a phase 2 and then a final phase 3 trial could be completed before 2030. So a journey that began in 2012 is likely to take 20 years and even then it may not reach the destination we all desire. But for people like my correspondent Sara, and many of the participants in the original trial, GDNF still spells hope and they aren’t going to give up on the dream of a treatment that can stop Parkinson’s in its tracks.