I came home late from London last night. We’d just had a brainstorm with a group of friends to think about how to build a strong rare disease movement in the UK. As you’ll see from my previous posts, I’m convinced that more can be done to create a mass social movement for rare diseases on the same scale as that for cancer or heart disease. Here’s why:

Rare diseases affect 3.5m people in the UK (see http://www.raredisease.org.uk/). If you include their family members (approximately four people per nuclear family), that means 14 million people have direct experience of a family member living with a rare disease. I’ll repeat that:

14 million people.

The total UK population is just under 60 million people. This means that 25% of the UK population has direct experience of a close family member living with a rare disease.

That’s one in four.

If you include grand parents, children, close cousins and close friends, the figure climbs higher, maybe even to half the UK population, or even more.

So why is there no mass movement? Where are the millions of mums, dads, brothers, sisters, sons and daughters, cousins, friends, colleagues, grand-mothers and grand-fathers of people with rare diseases? Why aren’t they on the streets, shouting about the injustices faced by their suffering family members and friends?

Maybe they’re too tired and exhausted from caring for them? Maybe they’re discouraged and don’t believe they can make a difference? Or maybe they think the disease is too rare, so why should anybody care?

I’ve often told people that my two boys have a rare disease (Alkaptonuria, or Black Bone Disease). Generally, people are sympathetic. I can see their sorry faces. ‘That’s a shame. I’m glad that’s not me,’ I can hear them think.

Others are more hostile. One family friend once said, ‘Who cares about your kids’ rare disease. There are more important things to worry about in the world.’

Unfortunately, I believe his reaction is common – it’s just that most people won’t say it out loud. The term ‘rare disease’ doesn’t work well as a way of raising awareness and generating support. When faced with the evil of cancer or the suddenness of heart disease, rare diseases seem more like a curiosity, something that isn’t widespread and that isn’t relevant to most people. There’s always an uphill struggle to explaining that rare diseases are common. But even then, most people don’t feel all that concerned.

So should we rebrand rare diseases? Should we find a term that challenges people? That makes them feel directly concerned? That makes them feel like they need to take action urgently?

This is a tough one. And I don’t pretend to have a solution. That’s why I’m writing this blog post – to generate some thinking. Last night, our brainstorm, which included a global branding expert, the head of a growing rare disease foundation, and the director of digital media in a major health foundation, looked at the options:

• Rare diseases: an accurate description, but makes people think that it doesn’t affect them. It reduces engagement.
• Orphan diseases: symbolic, but creates confusion in the public’s mind: could be diseases affecting orphans in Africa.
• Genetic diseases: could work, although few members of the public understand the term ‘genetics’. Sounds technical, scientific. Also, some genetic diseases are not rare diseases.
• Extreme diseases: captures the imagination and makes you wonder what it’s about. Many rare diseases do present themselves as extreme versions of common diseases (Alkaptonuria is an extreme form of osteoarthritis).  But this term can sound too sensationalist. And many common diseases are also extreme in their manifestations.
• Inherited diseases: easier to understand for the average member of the public. Everyone knows about inheritance. It engages them, makes them think ‘could I have an inherited disease?’. But some rare diseases aren’t inherited, and some common diseases have inheritance factors.

I’d love to hear what others think. In the end, maybe we should stick to the term rare diseases. Maybe we should accept that it’s not perfect, but that it’s the best we have at the moment. Or maybe there’s a better way out there? A way that will immediately grab the public’s attention, make them realise we need to take action, and kickstart a mass movement on a scale we’ve never seen before.

A scientific strategy to unite all rare diseases

by Oliver Timmis

By their nature, each rare disease only affects a few people. At the AKU Society, for example, we have identified 80 UK patients, and 650 patients worldwide. It’s not that many people. However, collectively, rare diseases do affect a significant number of people.

Rare Disease UK states that 1 in 17 people will be affected by a rare disease. That’s 3.5 million people in the UK, and nearly 400 million people worldwide. Collectively rare diseases are not rare; in fact they’re twice as common as diabetes [prevalence of all rare diseases=1 in 17; compared to prevalence of diabetes = 1in 35].

However, while it makes sense to unite all rare diseases as a whole – it gives us the power to have a bigger impact when applying for funding and raising awareness – does it make sense scientifically?

Medically, rare diseases can be very different; affecting many different bodily systems and with different causes. This could make it near impossible to study rare diseases as a whole. You may need to separate them into categories, so that some people would study the diseases affecting the heart; others, studying those affecting the brain; the lungs; the kidneys. The list would go on and on.

Maybe it is not that easy. Many rare diseases are not unique to a specific system. AKU mainly affects the cartilage, but can have significant effects on the kidneys, prostate, heart and heart vessels, eyes, ears, and pretty much every part of the body. Many of the syndromes without a name (SWAN) are due to a chromosome abnormality and so can have dramatic effects on the development of all body systems.

If you look at another well-developed campaign for health – the many projects in Cancer Research – we see that “cancer” is made up of many types. The US Centre for Disease Control lists the top 10 cancer sites for US men for 2007. The top 3 are cancers of the prostate, lung and colon; affecting many men in America. However, below the top 3, the prevalence for each type of cancer drops below 50 people in 100,000. This number is important, as 50 in 100,000 (equivalent to 1 in 2,000) is the European definition of a rare disease. That means that 7 out of the top 10 cancers affecting US men are, in themselves, a rare disease.

If you see “cancer” as a collective term for a collection of diseases – many of which are rare diseases – then it becomes a better idea to group rare diseases together. However there is still the problem of finding a unifying scientific strategy.

According to the European Organisation for Rare Disorders (EURORDIS), 80% of rare diseases have a genetic origin. Therefore, the ability to affect the genetics underlying a rare disease would be the most efficient way of treating them, scientifically, as a whole.

Methods of gene therapy do exist. The Genethon, a French biotech specialised for development of gene therapies for rare diseases, have recently announced the start of two clinical trials for rare diseases: one for Wiskott-Aldrich syndrome and another for Gamma-sarcoglycanopathy. At the AKU Society, we have just begun work on a gene therapy idea with a new partnership at Imperial College London.

The reality of using gene therapy as a cure-all treatment for rare diseases is still a long way off and there are certainly no guarantees that it will work. The tag line for Rare Disease Day USA says, “Alone we are rare. Together we are strong.” Gene therapies for rare diseases may be a long-time coming, but the more ideas that unite the rare disease movement, the stronger the claim that all rare diseases should be treated as one.

I went home last night and was lying in bed thinking about it, unable to sleep. The conversation had awakened in me a deep sense of injustice. How are we ever going to help the 8% of the population that has one of the 7,000 known rare diseases if most of the major funders still don’t see it as a priority?

It’s not the first time this has happened. Let me give you another example. A few months ago we applied to another major funder. Our application was so strong, our publications list so impressive, that we got selected out of 1,400 applications to go through two rounds of internal reviews, received glowing peer reviews, and got to the final assessment panel. Yet the questions of the panel showed that they had barely read the proposal and had no understanding of why studying rare diseases is so important.

I believe there are two key problems here:

1. Most funders – at least in the UK – are still stuck in the old numbers game. Cancer or heart disease, they say, are the biggest killers. Hence they invest in these areas.
2. The majority of funders have deeply flawed assessment processes. They don’t know how to select good applications. And I believe that’s a big reason why so much scientific research fails.

So what are the solutions? Here are my recommendations:

1. We need to build a mass movement for rare diseases. The other day I was walking through Cambridge and saw hundreds of women dressed in pink for Cancer Research UK’s Race for Life event. It’s the biggest women-only charity fundraising event in the UK, raising millions for Cancer Research UK and helping put cancer high on the public and political agenda.

We need a similar mass movement for rare diseases. It’s the only way of convincing the public, the politicians, the funders and the health system that the millions of people with rare diseases really count.

2. We need to show how studying rare diseases has wider implications. William Bateson, the famous Cambridge geneticist who died in 1926, once said ‘treasure your exceptions’. Bateson was a friend of Sir Archibald Garrod, who first identified Alkaptonuria as an inborn error of metabolism in 1901. Both Bateson and Garrod knew that the study of rare diseases – the ‘exceptions’ – was a golden gateway to understanding common diseases. More than 100 years later, our Alkaptonuria scientists in Liverpool are discovering that Alkaptonuria is an excellent model for understanding osteoarthritis – a very common disease – proving that Bateson was right.

3. We need to reform how traditional funders work. Traditional funding processes are often just form-filling exercises: if you tick the right boxes, lobby the right people and know how to fill in the form correctly, then you may get funded. Most traditional funders then provide grants for one to three years, forcing scientists to spend their time scrambling around for more funds rather than focusing on scientific research.

Traditional funders miss out the most important criterion in the success of any project: the strength and track record of the research team. And the only way to assess a team is by spending time with them – lots of time.

Fortunately, there is an answer to this. It’s called venture philanthropy. It’s based on how venture capitalists choose companies to invest it. They spend a lot of time on their due diligence: meeting the team, assessing their track record, discussing their strategy. And once they’ve found a team of A-players, they support it over a long period of time. Not a one or even a three year grant, but sometimes up to 10 years or more. Venture philanthropists know that persistence and commitment pays off.

That’s what we’ve done with the AKU Society. We’ve raised £1m from private sources, and we’ve invested all of it in an amazing research team in Liverpool, going from the most basic to the most clinical science. Over the past eight years, we’ve developed a symbiotic relationship with them, where we all work together for the same objective: finding a cure to Alkaptonuria.

If you want to find out more about venture philanthropy, check out the European Venture Philanthropy Association:http://evpa.eu.com.

4. We need independent funders dedicated to rare diseases. There’s an urgent need for a major foundation dedicated exclusively to funding research into rare diseases and supporting rare disease patient groups. We need something as ambitious as Cancer Research UK, which raises £0.5bn each year from the public for cancer. We need a Rare Disease Foundation that will support any rare disease – not just a small subset or those of its founders – over long time periods, using a venture philanthropy model, and with a focus on finding cures. It needs to be independent and free from political or corporate influence. It needs to exist for patients and only for them.

5. We need to support existing international initiatives on rare diseases and use these to lobby our national governments. Thanks to the work of groups such as Eurordis and NORD, the European Commission and the National Institutes of Health are leaders in supporting rare disease research. For instance, the EC’s FP7 health call that was announced this week has strong support for rare diseases. The International Rare Disease Research Consortium launched recently is another excellent initiative. However, compared to the scale of the need – the 7,000 rare diseases, most of which have no cure – it’s still a drop in the ocean. That’s why we need to build on these initiatives to get our national governments and funders to take action.

So that’s my five point plan. If you’re interested in discussing this further, do get in touch. My email is nick@akusociety.org.

(I wrote this post originally for Rare Disease Blogs: http://www.rarediseaseblogs.net/2011/07/22/the-system%E2%80%99s-broken-and-here%E2%80%99s-how-to-fix-it/.)

Topics for the Science Day will include:

• Building clinical trials for AKU using a disease severity score index
• Nitisinone, from weed killer to wonder drug
• Metabolomic investigation in AKU and OA
• Enzyme replacement therapy for AKU
• Gene therapy for AKU
• Novel biomarkers of cartilage and bone for AKU
• And more!

The Doctor-Patient Day will focus on topics such as:

• The new AKU Online Community, developed with the European Organisation for Rare Diseases (Eurordis).
• Stories from AKU patients about living with the disease.
• A demonstration of new physiotherapy techniques for AKU.
• Genetic counselling for AKU.
• Lay explanations of the latest progress in AKU research.

Speakers will include scientists (University of Liverpool, Imperial College, University of Siena), clinicians (Slovakia AKU Centre, Liverpool Hospital, National Institutes of Health), industry (Agilent, Protein Technologies Ltd, Nordic Biosciences) and patient groups (AKU Society, etc). At the previous International AKU Workshop in Cambridge, more than 70 people attended from 10 countries from North America, Europe and the Middle East.

To book, please contact booking@akusociety.org.

The most interesting sub-call for rare disease patient groups is the one on preclinical and/or clinical development of orphan drugs. This provides up to 6m euros in funding, including for phase 3 clinical trials. I’ve enclosed below text from the draft of the call for proposals that was circulated a few weeks ago.

We’ve already put together an excellent AKU consortium, which brings together industry, SMEs, academia, hospitals and patient groups from across Europe and the USA. We’ve developed a strong plan of action for the development of an orphan drug for AKU. But we know it’s going to be super competitive.

If you’re also going to apply to FP7, do get in touch so we can exchange ideas and advice.

Extract from FP7 draft call for health proposals: Preclinical and/or clinical development of substances as orphan drugs

In the meantime, here’s a very interesting article I found in the latest OrphaNews:

How forging relationships with scientists can help patient groups forward their research aims

An interesting new paper from a researcher at the Public Policy and Center for Society and Genetics at UCLA, published in the journal Social Studies and Science, explores how a rare genetic disease patient organisation can successfully draw research to its cause by the nature of the social relationship established with scientists working in related fields. Via a series of interviews with leaders of patient groups and the scientists involved with these groups, the author examines the ways in which patient groups are able to attract – and influence – scientific research via what the author labels ‘sociability,’ ie, a close relationship established between patient organisation members and researchers through which the patient group is able to influence the research agenda.

The article, entitled Generating Sociability to Drive Science: Patient Advocacy Organizations and Genetics Research, shows how “strategic manipulation” of sociability can allow a patient organisation “substantial influence” in the arena of research, although such social ties are not easily attained and “most forms of relationship-building offer [patient organisations] much less influence on research”.

In the first of a series of studies, Protein Technologies Ltd will be producing a range of recombinant mutants of homogentisate 1,2-dioxygenase (HGD  – the deficient enzyme in AKU) and test them in vitro and in vivo in mice models for their effects on homogentisic acid (the damaging substance in AKU). Using site-directed mutagenesis techniques and its proprietary unnatural protein technology, Protein Technologies Ltd will seek to prove that a recombinant HGD can be synthesized which is more active and more stable than the naturally occurring enzyme.

This work will be in close collaboration with our scientific team at the University of Liverpool. We’re extremely excited about this project. If successful, it will open up a new avenue of potential treatment not just for AKU, but for a wide range of other rare diseases caused by deficient enzymes.

For more about Protein Technologies Ltd, read this article entitled “Project ‘could be as revolutionary as silicon chip’”: http://menmedia.co.uk/manchestereveningnews/news/business/s/1408919_project_could_be_as_revolutionary_as_silicon_chip.

Here’s what the enzyme, homogentisate 1,2-dioxygenase (HGD), looks like:

HGD enzyme

This is very exciting work for us. More than 65 mutations in the homogentisate oxidase enzyme (HGO) gene have been identified in people with AKU. It is widely believed that these mutations result in disruption of the structure and function of the HGO enzyme, thereby increasing the levels of homogentisic acid, which is the molecule causing the damage in AKU.

HGO is expressed mainly in the liver and kidneys. A promising strategy for the treatment of AKU is therefore administration of a recombinant version of HGO that can restore HGA to normal levels. Such a recombinant HDO analogue must be active enough to break down HGA but not so active as to bring about tyrosinemia (i.e. high levels of tyrosine in the blood). Longevity of action is also important as is the route of administration which, in addition to injection or nano-needle array, could also potentially include include oral, topical and inhalation.

But fundraising plays a purpose for rare disease patient groups (and most other charities) that goes beyond raising funds. It’s about raising awareness, telling others about the issue you’re focusing on, using your supporters to spread the word.

This is something the AKU Society is increasingly trying to do. This Sunday, we have 10 runners taking part in the London 10k, a major sporting event with more than 25,000 runners participating and more than 40,000 spectators. It takes place in the middle of London and should be a fantastic event.

We got the idea from other rare disease patient groups. They encouraged us to register with the London 10k. One of these rare disease patient groups raises £25,000 a year thanks to the London 10k – that’s a substantial amount of funding that can be used as the charity wants in order to further its mission. I don’t think we’ll get anywhere near that amount this year, but it’s a good target to aim for in future years.

We do most of our fundraising for these events via our JustGiving page at www.justgiving.com/alkaptonuria. If you scroll down, you’ll see that there’s a whole bunch of supporters raising funds for us.

And if you’d like to sponsor me for the London 10k, you can donate on my justgiving fundraising page at: www.justgiving.com/Nicklondon10k. So dig deep!

Prof James Leonard chaired the meeting. He’s a world-class expert on metabolic diseases with a tremendous reputation, so we felt privileged that he led the meeting. He also has experience of treating AKU patients for much of his working life, hence his input was highly valuable.

Prof Jim Gallagher, head of the AKU Science Team at the University of Liverpool, presented the pathophysiology of AKU. He focused on the latest solid-state nuclear magnetic resonance (ssNMR) studies on AKU as well as the latest promising developments in our AKU animal model.

I then did a short presentation on the growth of the AKU patient movement. I emphasised the support the AKU Society provides to patients, particularly through online tools such as the AKU Online Community, but also our part in developing research and international collaboration.

Dr L Ranganath, our Medical Director, presented the results of a clinical study on AKU patients that led to the successful development of a disease severity score index. This is highly significant for our work as this severity score index means we now have a method for assessing, in a robust way, the evolution of the disease among AKU patients. This will allow us to assess the effectiveness of treatments in new clinical trials.

The meeting finished with a presentation by Dr Wendy Introne from the National Institutes of Health on the recent trial of Nitisinone, a drug that reduces by 95% homogentisic acid, which is the culprit molecule in all the damage caused by AKU. We then went on, after the meeting, to discuss plans for a new trial for Nitisinone in order to obtain marketing authorisation so that patients can access it as the first ever treatment for AKU.

For those of you who don’t know Ashoka, it’s a fantastic organisation that brings together social entrepreneurs from around the world, providing them with support, access to resources and advice for their work. I’ve been a fellow of Ashoka for 18 months now, and they’ve been excellent, providing introductions to key people and access to their networks.

The Changemakers week, under the patronage of the French president Nicolas Sarkozy, will bring together more than 1,000 participants at the campus of HEC, one of France’s leading business schools. Talks will cover everything from health to energy and housing and will include major networking sessions to meet new people and form new alliances.

Anyway, I’d better go. Got a train to catch!