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Cambridge father completes mission to find black bone disease cure

From left are Ciarán Scott, head of projects & communications; Nick Sireau, CEO and chair of trustees, and Juliet Rowe, fundraising manager
From left are Ciarán Scott, head of projects & communications; Nick Sireau, CEO and chair of trustees, and Juliet Rowe, fundraising manager

When Dr Nick Sireau first’s son, Julien, was born in 2000, it was soon clear that something was not right.

The boy’s urine was red-black and it led to the devastating diagnosis of the ultra-rare genetic disease alkaptonuria (AKU), also known as black bone disease.

“We were extremely worried so we went online and came across all kinds of horrible stories of patients suffering from severe joint deterioration, agonising pain and disability, but the doctors told us there was nothing we could do,” Dr Sireau told the Cambridge Independent.

“I couldn’t accept this, so I joined forces with another patient and a doctor in Liverpool to set up the AKU Society in 2003 as the first-ever patient group for the disease.

“My second son, Daniel, was born the same year and was also diagnosed with black bone disease, which was really tough.”

AKU turns patients’ bones and cartilage black, causing severe disability as life progresses. Just one missing enzyme causes the body to accumulate homogentisic acid at 2,000 times the normal rate.

Based in Devonshire Road, Cambridge, the work of the AKU Society and Dr Sireau to push the cause of this rare disease and help find therapies has been relentless.

“We struggled in the early years because nobody was interested in such a rare disease. I was running half-marathons to raise funds for the autopsy of a patient, then to set up a research centre at the University of Liverpool,” says Dr Sireau.

“In 2010 I gave up my job as CEO of SolarAid to focus exclusively on finding a treatment for black bone disease.”

One was found in the form of nitisinone, made by pharmaceutical company Sobi.

“That then led to the past 10 years of travelling around all of Europe and the Middle East to identify patients for clinical trials, travelling repeatedly to Sweden to convince the company that owned the potential drug to get involved with us, raising £10m from the European Commission and other sources to fund clinical trials,” adds Dr Sireau.

The DevelopAKUre programme – a collaboration between patients, scientists, clinicians and industry – was established and ran a series of major international clinical trials between 2012 and 2019, run by a consortium of 12 European partners.

With £10m funding (half from the European Commission, half from consortium partners), the seven-year programme involved 138 patients from Europe and the Middle East.

The DevelopAKUre consortium partners, who saw the project through to a positive outcome, at its final meeting in Sienna, Italy, in January 2019.
The DevelopAKUre consortium partners, who saw the project through to a positive outcome, at its final meeting in Sienna, Italy, in January 2019.

It established that nitisinone reduces the production of homogentisic acid by an incredible 99.7 per cent.

“Nitisinone was originally a weedkiller, similar to a popular weedkiller you can now buy in most garden centres,” says Dr Sireau.

The European Medicines Agency gave a positive opinion in favour of nitisinone for AKU in September. This was then ratified by the European Commission in October when they granted marketing approval (a license) for the use of nitisinone in the EU (including the UK) - an incredible milestone for Dr Sireau, the AKU Society and all those involved.

“I went through lots of ups and downs on the way. I developed a close friendship with Prof Lakshminarayan Ranganath, who then led the European trials and who has been amazing. The clinical trials took eight years and were a resounding success,” says Dr Sireau.

Prof Ranganath, the AKU clinical expert at the Royal Liverpool University Hospital and leader of DevelopAKUre, explained: “AKU was identified as the first inherited metabolic disease in 1901 by Sir Archibald Garrod in London.

“Since then, hundreds of other inherited metabolic diseases have been identified, yet few have treatments. We believe the approval of nitisinone for AKU will bring hope to others who are seeking treatments for their diseases.”

World-leading collaboration was at the heart of the trials, said Prof Jim Gallagher, the AKU scientific expert from the University of Liverpool’s Institute of Life Course and Medical Science.

“Collaboration has been key to our success,” he said. “Never before have I participated in a group of people so focused on working closely together to bring a treatment from the laboratory to the clinic. It’s been hugely rewarding for everyone, especially the patients.”

Central to the consortium’s success was the close relationship with Sobi, which provided access to drug development expertise.

Ravi Rao, chief medical officer and head of R&D at Sobi, said: “We are extremely proud of the collaboration between Sobi and the DevelopAKUre partners over the past decade.

“Approval by the European Commission will help address a medical need that has been unmet for people with AKU since the discovery of the condition more than 120 years ago.”

Sir Archibald Garrod AKU black bone diseae (43216860)
Sir Archibald Garrod AKU black bone diseae (43216860)

Sir Archibald Garrodfirst identified AKU as an inherited disease in 1901 and then presented his theory of inborn errors of metabolism (based on his research into AKU and other diseases) in 1908 at the Croonian Lectures.

While investigating the mysteries of AKU, Sir Archibald became friends with William Bateson, a Cambridge scientist with an interest in the work of Gregor Mendel, a 19th-century scientist and Augustinian friar famous for early studies in the genetics of garden peas.

Bateson realised AKU and its inborn error of metabolism was actually a Mendelian recessive character, a compound that was inheritable along a predictable pattern and which caused disease.

Bateson’s work laid the foundations of modern genetics and the study of heredity.

Today, researchers believe that if nitisinone is administered early enough, it can prevent the build-up of homogentisic acid, allowing sufferers to lead a normal, pain-free life.

For Dr Sireau, it’s the culmination of a decade-long pursuit to help those with this dreadful condition – including his two sons.

“We’ve managed to show that nitisinone is a highly effective treatment for black bone disease,” he says. “Both my boys are now on the treatment, which will mean they won’t be condemned to a life of extreme joint deterioration, pain and disability.”

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