Podcast Extra: The quest for a rare disease treatment

Host: Benjamin Thompson

Hi listeners, Benjamin here. In this week’s Nature, we have a feature article investigating a quest to find a treatment for a rare genetic disease. In this podcast extra, Geoff Marsh speaks to some of the people involved.

Interviewer: Geoff Marsh

Having your first child can be a nerve-wracking time in anyone’s life but for Nick Sireau, things took an early turn for the worse.

Interviewee: Nick Sireau

So, it was in the year 2000. It was a Sunday and we’d brought our baby son Julian back from the clinic where he was born, and we were changing his nappies and we noticed that they were red black. We were very alarmed and we called the doctor and the doctor came in and tested for blood and didn’t find any. And then he kind of scratched his head and said well what have you been eating today, and it so happened that we’d had some red cabbage, and so he said it’s the red cabbage going into the breastmilk, into the child and into the urine. Now he just went off and we…

Interviewer: Geoff Marsh

Nick and his wife were very sceptical, and sought out a second opinion. A few months later, after tests were run at Great Ormond Street Hospital in the UK, the results came back. Their son had a rare genetic disease called alkaptonuria or AKU for short.

Interviewee: Nick Sireau

And we were just completely shocked, you know, we’d never heard about it and we’d never really heard about rare diseases to be perfectly honest, you know, it was really a step into a whole new world.

Interviewer: Geoff Marsh

At the time, this new world looked very bleak to Nick. His inevitable internet searches –which he’d been warned against – threw up plenty of scare stories about what lay ahead for his newborn son, but almost nothing about how to help. At around the same time, another AKU patient, Robert Gregory or Bob, had started the ball rolling on a mission that would come to dominate Nick’s life to this day. The mission – finding a treatment for AKU. Bob had sought the help of a doctor, who at the time was almost as unfamiliar with the disease as he was. When Robert Gregory first approached you, was AKU, alkaptonuria, kind of, was that something you’d thought about a lot before that?

Interviewee: Lakshminarayan Ranganath

No, I had seen just two cases in my entire life before that, so very esoteric, very rare, very unusual for people to see a case in their life.

Interviewer: Geoff Marsh

That’s Dr Lakshminarayan Ranganath from the Royal Liverpool University Hospital.

Interviewee: Lakshminarayan RanganathPeople call me Ranga for short. It’s a condition where one of the genes for an enzyme called homogentisic acid dioxygenase (HGD) is missing. Proteins are made up of building blocks. One of the building blocks is tyrosine, and the way the body normally degrades tyrosine is by going through this chemical called homogentisic acid. So, in AKU, the homogentisic acid accumulates in the body, comes out in the urine, causing black urine. It stains the tissues in the body, causing black joints, black pigment in the white of the eye and it also turns the ears blue black. All tissue become brittle and breaks down easily, so if this happens in the cartilage and the joints, you’re going to get very early arthritis. By the time they’re 20-30, they start to get severe pain in the joints of the body and in the back, and then just when life should be getting really good for them, it starts to deteriorate. They need painkillers forever.

Interviewer: Geoff Marsh

Nick wasn’t content to accept this prognosis for his son, but there was room for optimism. Across the Atlantic in the United States, Dr William Gahl at the National Institutes of Health was doing a clinical study for AKU on a drug which had been used to treat a much more severe disease called type-1 tyrosinaemia. Originally developed as a weedkiller, this drug had proven to be somewhat of a miracle cure. Patients with type-1 tyrosinaemia, who would normally die before the age of two, were thriving on this drug. Theoretically, this drug nitisinone should work for AKU as well, as it works on a different part of the same metabolic pathway. But theory, of course, isn’t enough to get a drug approved. So, this NIH trial ran for three years, looked at just 40 patients, and used as its end point a single measure of hip rotation. Unfortunately for everyone involved, it failed.

Interviewee: Nick Sireau

People were absolutely devastated. Patients were devastated, the researchers were devastated and the company that owned the drug were just like look, we can’t do this anymore. It’s just not going to work. This is a drug that biochemically works, it just works, because it’s an enzyme inhibitor and it stops the accumulation of the homogentisic acid, and that is the damage. We knew all that, so in theory we knew it was meant to work really well, so to have patients not be able to have access to it just seemed radically unfair.

Interviewer: Geoff Marsh

At this point, Nick and Ranga knew that they were going to have to go about things differently. First, Nick ran a sponsored marathon to raise enough money to transport an AKU patient’s body to Liverpool for an autopsy, to help Ranga start to build a better understanding of the disease. Then they decided they would need an animal model of the disease. For this, Nick managed to raise £500,000 from Britain’s Big Lottery Fund to fund another University of Liverpool scientist, James Gallagher, in developing a mouse model of the disease.

Interviewee: Nick Sireau

So, we went on a two-prong strategy. The first strategy was to apply to NHS England, and in the UK, we have a very particular situation called highly specialised services within the NHS, and this is a part of the NHS that realises that for ultra-rare diseases, you need a different model because they realise that otherwise they just fall through the cracks. So, we applied to highly specialised services to set up a national AKU centre based in Liverpool. And one of the things we did to try and kind of convince NHS England that this was important, we did a health economics study, and without treatment, he showed that the average AKU patient was costing £100,000 a year to the NHS. Now what we asked for was roughly £1 million to treat 80 patients. So as you can see, you know, otherwise they’d be costing £8 million so it’s actually saving the NHS money to have this treatment centre and have people on the drug, and that is the case for many rare diseases. And so, all patients in England and Scotland can come once a year to Liverpool where they’ll have a week of tests, X-rays and blood tests and MRIs, physiotherapy and all that kind of stuff, and then they’re given access to nitisinone, and then Ranga and Jim and their team then evaluate the evolution of the disease over time to see whether it’s helping.

Interviewer: Geoff Marsh

This has meant that last year, Nick’s oldest son got his first dose of nitisinone off license. But this centre is only there for patients in England and Scotland. With lots of positive data now from this observational study at the AKU centre, Nick and his colleagues wanted to change the lives of more people, so they turned their gaze to Europe.

Interviewee: Nick Sireau

We decided to answer a call for proposals from the European Commission for rare diseases. So, what this funding from the EC allowed us to do was a dose finding study. Then we did a four-year, what’s called phase 3 study – this is the ultimate phase where you prove effectiveness before you get a license – and we did that on 138 patients and that ends in a month’s time at the end of January. And that – we’re hopeful because the data from the national centre is positive, from the mouse model is positive and all that kind of stuff – so we’re hopeful that the data from the randomised control trial will be positive, but as in any scientific experiments, you never know until you get the data.

Interviewer: Geoff Marsh

Nick’s children, both of whom have AKU, will have access to this drug in the UK, and if these upcoming European trial results are positive, which they’re expected to be, nitisinone will hopefully be accessible to patients outside of the UK. I wondered if now, after all this progress, Nick was ready to hang up his gloves, but it seems like he’s found a home in the fight to treat rare diseases.

Interviewee: Nick Sireau

There’s 7,000 rare diseases and they’re all very different, but the fundamental issues that you face as a rare disease patient or family are all the same – it’s isolation, it’s misunderstanding from the medical profession, it’s lack of access to finance to do clinical studies, it’s all the same things, and what we did when we set up the AKU society was that we went to see other rare disease patient groups and asked them how did you do it, and we learnt from them. So that’s why we then set up another charity called Findacure which is there to build the patient movement and to help new patient groups that are emerging and teaching them all the skills to really accelerate their growth.

Interviewer: Geoff Marsh

Is it normal that this field of medicine has been pushed forward so much primarily that the driving force has been sort of non-scientists, members of the public essentially?

Interviewee: Lakshminarayan RanganathI think this is a partnership. It shows the power of the patient societies when they come on-board and engage in a perfect way with the medical profession. So, the medical profession also needs to learn to work in a collaborative way and facilitate working with patient groups. The second thing to not forget is the importance of basic scientists as well because our basic scientists have been crucial to us because we understood the natural history and the effect of medicine on natural history in the mouse model. Professor Jim Gallagher from the University of Liverpool has been key to that. So, what our programme has demonstrated is if you can get clinicians, basic scientists and patient societies and potentially funders as well, coming together and working collaboratively, I think you can make rapid strides as we have shown in such a small space of time because we only really started doing the research in 2006-2007, so in ten years we have gone from having nothing to really having a working treatment for a condition which has not had one for more than 100 years.