Like BHD, LAM is a cystic lung disease caused by an over-proliferation of smooth muscle tissue in the the lungs, mainly affecting women of child-bearing age and individuals with tuberous sclerosis complex (TSC). Professor Krymskaya’s group found that deletion of TSC2 led to the smooth muscle over-proliferation seen in LAM by dysregulation of mTOR signalling. This study also showed that in cell culture the mTOR inhibitor, rapamycin, reduced mTOR signalling and slowed down the growth of TSC2-null cells. This study was the first that suggested that rapamycin could be an effective treatment for LAM, and formed the scientific basis of the MILES trial, which showed rapamycin is an effective treatment for pulmonary LAM (Goncharova et al., 2002; McCormack et al., 2011). This study used cells taken directly from LAM patients’ lungs and grown in culture; Professor Krymskaya’s lab remains the only group in the world to successfully perform this procedure using cells from LAM patients.

While rapamycin halts the growth of lung cysts it does not reverse the lung damage seen in LAM, and has to be taken continuously to stop the disease progressing (McCormack et al., 2011). However, long-term use of rapamycin has been shown to have some severe side-effects, such as hypercholesterolemia and mucositis (McCormack et al., 2011). More recently, Professor Krymskaya’s team have shown that combined therapy of rapamycin and simvastatin in a mouse model of LAM not only stopped the progression of the disease, but that simvastatin seemed to partially reverse the lung damage seen in these animals (Goncharova et al., 2012). Simvastatin is widely used to reduce cholesterol and is not known to have any common adverse side-effects with long-term use. Therefore, if simvastatin proved effective in the treatment of LAM in clinical trials, it could be made available to all LAM patients very quickly.

Hoping to reproduce her success in LAM, Professor Krymskaya’s work on BHD aims to elucidate how FLCN mutations cause cyst formation in the lungs, with the expectation that finding this mechanistic link will suggest potential therapies. Indeed, Professor Krymskaya’s team co-authored a recent study reporting that FLCN interacts with PKP4 to regulate RhoA signalling (Medvetz et al., 2012; Nahorski et al., 2012), suggesting that progress in this area is already being made.

To find out more about Professor Krymskaya and her work at the University of Pennsylvania, please watch our video interview (with its accompanying transcript and audio-only files). Video interviews are also available with Professor Frank McCormack, who also works on LAM and was instrumental in the set up of the MILES trial; and Dr Doug Medvetz and Professor Elizabeth Henske who led the FLCN and RhoA signalling study.

• Goncharova EA, Goncharov DA, Eszterhas A, Hunter DS, Glassberg MK, Yeung RS, Walker CL, Noonan D, Kwiatkowski DJ, Chou MM, Panettieri RA Jr, & Krymskaya VP (2002). Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). The Journal of biological chemistry, 277 (34), 30958-67 PMID: 12045200
• Goncharova EA, Goncharov DA, Fehrenbach M, Khavin I, Ducka B, Hino O, Colby TV, Merrilees MJ, Haczku A, Albelda SM, & Krymskaya VP (2012). Prevention of alveolar destruction and airspace enlargement in a mouse model of pulmonary lymphangioleiomyomatosis (LAM). Science translational medicine, 4 (154) PMID: 23035046
• McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC; National Institutes of Health Rare Lung Diseases Consortium & MILES Trial Group (2011). Efficacy and safety of sirolimus in lymphangioleiomyomatosis. The New England journal of medicine, 364 (17), 1595-505 PMID: 21410393
• Medvetz DA, Khabibullin D, Hariharan V, Ongusaha PP, Goncharova EA, Schlechter T, Darling TN, Hofmann I, Krymskaya VP, Liao JK, Huang H & Henske EP (2012). Folliculin, the Product of the Birt-Hogg-Dube Tumor Suppressor Gene, Interacts with the Adherens Junction Protein p0071 to Regulate Cell-Cell Adhesion. PloS one, 7 (11) PMID: 23139756
• Nahorski MS, Seabra L, Straatman-Iwanowska A, Wingenfeld A, Reiman A, Lu X, Klomp JA, Teh BT, Hatzfeld M, Gissen P, & Maher ER (2012). Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis. Human molecular genetics, 21 (24), 5268-79 PMID: 22965878

A clinical trial aims to answer a medical question and requires patient participation to do so. The question being asked is usually whether a new treatment – most often a drug – is better than the current gold standard of treatment, although other types of trials, such as observational trials and patient preference trials do take place. If you would like more information about how clinical trials are conducted and specific information about trials currently open to BHD patients, please visit our new Clinical Trials page for patients.

It has been estimated to cost $1 billion to get a drug to market (DiMasi et al., 2003). Although this figure has been called into question by Sir Andrew Witty of GSK, the vast majority of clinical trials are still run by large pharmaceutical companies. Rivalry within the industry has caused a culture of secrecy to prevail and data from clinical trials – particularly negative results – are often not published. This makes it extremely difficult for doctors to make fully informed decisions about which drugs to prescribe their patients. Additionally, the amount of regulatory process and paperwork required to initiate new trials is often a major stumbling block for researchers who are new to the process.

In recent years, calls to make clinical trial data available – such as the Alltrials petition spearheaded by Dr Ben Goldacre, author of Bad Pharma – have been heard by pharmaceutical companies, and a number of companies, including GSK and Roche, have drawn up policies on how they will improve the transparency of clinical data. Furthermore, the Health Research Authority (HRA) – a UK-wide steering committee founded in 2011 – aims to streamline the regulatory process involved with starting a new trial, while maintaining rigour and safety. The HRA has also recently announced plans to collaborate with pharmaceutical companies to improve the transparency of clinical trial data. The increase of freely available data, coupled with reducing the barriers to launching new trials, will hopefully lead to more life-saving treatments becoming available to patients more quickly.

Access to clinical trials is often difficult for patients due to strict eligibility criteria. Additionally, many patient advocate groups feel that they have not been included in the design of clinical trials, both of which may contribute to the fact that nearly a third of clinical trials close early because they cannot enrol enough patients to make the data statistically significant (data presented by Jaime Richardson of Cedars-Sinai Hospital at the Kidney Cancer Association conference, May 2013). If this happens in Phase III, the result is that an effective drug is not approved for general use purely because the trial was badly designed. This was described by Ms Richardson, as “heart-breaking and wasteful.”

In the UK, the Health and Social Care Act of 2012, aims to make access to clinical trials an integral part of patient care pathways within the NHS, which will hopefully increase patient participation in trials. Patient education is also an invaluable part of this process and the need for patient advocate organisations to provide information about clinical trials to their patients is paramount. A number of information resources for both patients and researchers are now available online, and several of these can be found towards the bottom of our new Clinical Trials page.

Recognising the importance of educating patients about clinical trials has led to the development of a number of initiatives to support patients wanting to learn more. For example, Cedars-Sinai Hospital in Los Angeles recently created the role of Clinical Trials Recruitment Navigator, which is currently held by Jaime Richardson. Jaime provides patients with information about appropriate trials, and acts as a point of contact and support for those participating in trials. Meanwhile, in the UK the National Institute for Health Research (NIHR) has launched the “Ok to ask” campaign, which promotes the message that it’s ok for patients to ask their doctor about clinical trials.

However, the above plans and initiatives will be in vain if the public perception of clinical trials is not improved. Currently, many patients are understandably wary of participating in a clinical trial as they are worried about receiving a placebo treatment, or that they will be treated as a guinea-pig. Additionally, clinical trials are seen by many as a last resort; only to be considered once all other lines of treatment have failed. In reality, clinical trials are sometimes the only way to access the best drugs and because patients are monitored so closely during the trial, they often receive a better standard of care. Placebo treatments in clinical trials are increasingly rare, and are never used in cancer clinical trials, due to the ethical implications of giving someone who is ill a fake treatment. Contrary to the opinion that clinical trials are a last resort, instead they should be considered as another treatment option upon diagnosis: prior treatment can often make a patient ineligible for a clinical trial, whereas if the clinical trial drug proves ineffective, it is always possible to leave the trial and start traditional treatments before the disease has progressed.

The only trials open to BHD patients at present are observational (details can be found at the bottom of our Clinical Trials page). As BHD is a rare disease, there is currently relatively little data to accurately determine the chances of an individual with a FLCN mutation developing skin lesions, pulmonary cysts, or kidney cancer. As previously discussed, determining this epidemiological data accurately would be a great help in being able to advise newly diagnosed patients of their likely disease progression. There are also several other symptoms, such as parotid lesions and colon cancer, which may be associated with BHD but cannot be conclusively proven at this stage. Observational trials may allow clinicians to conclusively determine whether these symptoms are a risk in BHD syndrome.

Looking to the future, as the profile of rare diseases is raised within the research and pharmaceutical communities, more clinical trials testing potential cures for rare diseases are likely to be launched. The role of patient advocate groups will prove fundamental to this process, as in the case of the Multicenter International LAM Efficacy of Sirolimus (MILES) trial (McCormack et al., 2011) for which The LAM Foundation’s involvement was pivotal in recruiting patients.

Of course, participation in a trial must always be the patient’s decision, but the choice to not participate must be due to “informed refusal” rather than to a lack of access or information. The reasons for participation – or not – are complicated, visceral and utterly personal, and rightly so. But it is always worth bearing in mind that today’s drugs were yesterday’s clinical trials; were it not for James Lind’s efforts in 1747, we wouldn’t know that citrus fruits are a cheap and effective cure for scurvy.

• DiMasi JA, Hansen RW, & Grabowski HG (2003). The price of innovation: new estimates of drug development costs. Journal of health economics, 22 (2), 151-85 PMID: 12606142
• McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC, National Institutes of Health Rare Lung Diseases Consortium, & MILES Trial Group (2011). Efficacy and safety of sirolimus in lymphangioleiomyomatosis. The New England journal of medicine, 364 (17), 1595-606 PMID: 21410393

• FNIP2 causes MNU-induced apoptosis (Sano et al., 2013)
• FLCN inhibits MMP9 (Pimenta et al., 2012)
• FLCN inhibits HIF-1a, mTORC1 and mTORC2 (Nishii et al., 2013)
• FLCN and PTEN compound heterozygosity causes oncogenesis (Pradella et al., 2013)
• FLCN and SSH2 are synthetically lethal (Lu et al., 2013)
• FLCN inhibits Cyclin D1 (Kawai et al., 2013)
• FLCN inhibits HIF1a (Gharbi et al., 2013)

• FNIP2 causes MNU-induced apoptosis (Sano et al., 2013)
• FLCN inhibits MMP9 (Pimenta et al., 2012)
• FLCN inhibits HIF-1a, mTORC1 and mTORC2 (Nishii et al., 2013)
• FLCN and PTEN compound heterozygosity causes oncogenesis (Pradella et al., 2013)
• FLCN and SSH2 are synthetically lethal (Lu et al., 2013)
• FLCN inhibits Cyclin D1 (Kawai et al., 2013)
• FLCN inhibits HIF1a (Gharbi et al., 2013)

Since the Myrovlytis Trust was founded in 2007, there has been growing momentum in the field of BHD research, which is nicely demonstrated in how the signalling diagram has evolved in that time.

The first version of the signalling diagram was posted in March 2011, to coincide with the launch of BHDSyndrome.org. This diagram showed how FLCN slots neatly in to a signalling pathway that includes other genes known to be mutated in kidney cancer, but at this stage there was relatively little known about the functions of FLCN itself.

Version 1 – March 2011

The second version of the signalling diagram was posted a year later in April 2012, adding six new studies to the pathway. In that year, more had been discovered about FLCN’s role in mTOR signalling, and a role for FLCN and its interacting partner FNIP2 in programmed cell death was added to the diagram. The biggest change between versions 1 and 2 of the diagram however, was the increase in information regarding the post-translational modifications of FLCN and its interacting partners. And thus, the first pop-up box was added to display these post-transciptional modifications seperately.

Version 2 – April 2012

The third version of the signalling diagram was published just nine months later in January 2013, incorporating data from a further 15 studies. In those months, a number of hitherto unknown roles for FLCN were reported and the structure of the C-terminus of FLCN was published in August 2012. Additionally, the discovery of several new interacting partners of FLCN necessitated the addition of a second pop-up box to show the structure of FLCN and its interactome. The number of additional proteins and pathways on the diagram made it very busy, and thus all proteins not directly interacting with FLCN were faded out. This allowed the focus of the diagram to be on FLCN and its function, while still retaining the contextual information of FLCN’s position within the “kidney cancer pathway” that formed the core of the original signalling diagram.

Version 3 – January 2013

This month’s update, version 4, incorporates data from the seven new studies listed above. When the diagram was first published in March 2011 it referenced 14 studies, whilst the current version references 42 and soon it will not be possible to fit new information into the diagram in its current form, meaning that a redesign of the diagram will be required. It is greatly encouraging that the amount of BHD research is clearly increasing in pace and volume to make this re-design necessary; increased knowledge about FLCN’s function will provide insights into how FLCN mutations cause BHD Syndrome, and this will hopefully lead to the development of a cure.

Version 4 – May 2013

• Sano S, Sakagami R, Sekiguchi M, & Hidaka M (2013). Stabilization of MAPO1 by specific binding with folliculin and AMP-activated protein kinase in O⁶-methylguanine-induced apoptosis. Biochemical and biophysical research communications, 430 (2), 810-5 PMID: 23201403
• Pimenta SP, Baldi BG, Nascimento EC, Mauad T, Kairalla RA, & Carvalho CR (2012). Birt-Hogg-Dubé syndrome: metalloproteinase activity and response to doxycycline. Clinics (Sao Paulo, Brazil), 67 (12), 1501-4 PMID: 23295609
• Nishii T, Tanabe M, Tanaka R, Matsuzawa T, Okudela K, Nozawa A, Nakatani Y, & Furuya M (2013). Unique mutation, accelerated mTOR signaling and angiogenesis in the pulmonary cysts of Birt-Hogg-Dubé syndrome. Pathology international, 63 (1), 45-55 PMID: 23356225
• Pradella LM, Lang M, Kurelac I, Mariani E, Guerra F, Zuntini R, Tallini G, Mackay A, Reis-Filho JS, Seri M, Turchetti D, & Gasparre G (2013). Where Birt-Hogg-Dubé meets Cowden Syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours. European journal of human genetics : EJHG PMID: 23386036
• Lu X, Boora U, Seabra L, Rabai EM, Fenton J, Reiman A, Nagy Z, & Maher ER (2013). Knockdown of Slingshot 2 (SSH2) serine phosphatase induces Caspase3 activation in human carcinoma cell lines with the loss of the Birt-Hogg-Dubé tumour suppressor gene (FLCN). Oncogene PMID: 23416984
• Kawai A, Kobayashi T, & Hino O (2013). Folliculin regulates cyclin D1 expression through cis-acting elements in the 3′ untranslated region of cyclin D1 mRNA. International journal of oncology, 42 (5), 1597-604 PMID: 23525507
• Gharbi H, Fabretti F, Bharill P, Rinschen M, Brinkkötter S, Frommolt P, Burst V, Schermer B, Benzing T, & Müller RU (2013). Loss of the Birt-Hogg-Dubé gene product Folliculin induces longevity in a hypoxia-inducible factor dependent manner. Aging cell PMID: 23566034

A new treatment can take the form of a new drug, surgical technique or medical device, either alone or in combination with an existing treatment. Clinical trials testing new treatments aim to determine whether the new treatment is better than those currently available to patients. Clinical trials can also be observational, and aim to collect information about the symptoms and medical problems people with a particular disease have. This sort of trial is particularly useful for rare diseases, where the disease has not been fully characterized in many cases.

Between developing a new treatment in the lab and it being approved for use in the clinic, it has to be tested in people during a clinical trial. This testing is done in phases:

• Phase I: tests the safety and the best way to administer the new treatment in a small number of patients.
• Phase II: tests the effectiveness and side effects of the treatment in a larger number of patients.
• Phase III: tests the effectiveness and safety of the treatment compared to placebo or another treatment in a large group of patients. If a treatment passes Phase III, it is deemed to be clinically beneficial and can be approved for general use.
• Phase IV: occurs in a “real-world” setting once the treatment is freely available. This phase typically determines the long term risks and benefits of the treatment when it is used more widely in the population.

The best way to accurately determine how well a new treatment works is to split the patients into two groups at random and to give patients in one group the new treatment and patients in the other a “control” treatment. How the two groups respond to their respective treatments can then be compared. This is known as a randomised controlled trial and usually happens in Phase III.

In a placebo controlled trial, the control group is given a dummy treatment. Alternatively, patients in the control group can be given the best currently available treatment. Given the ethical implications of giving patients a fake treatment, placebo controlled trials are increasingly rare, meaning that in the majority of clinical trials, all participating patients will receive an effective treatment.

Many trials are performed “blinded”, which means that during the trial, the patient does not know which treatment they are getting. Some trials are “double-blinded” which means that neither the doctor nor the patient know which treatment the patient is getting. This is to ensure that the results obtained from the trial are as objective as possible.

In order to participate in a trial, you must give informed consent. This means that the individual participating in a trial can only take part once a healthcare professional has explained the aims, procedures, benefits and risks of the study and the patient has demonstrated that they have fully understood this information and give their consent to participate. In some cases it may be possible for someone else to give informed consent on a patient’s behalf, for example when a parent consents to their child’s inclusion in a clinical trial.

Recruitment and access to clinical trials will vary greatly depending on the type of study, the phase of the trial, where the trial is located and where you are located. However, the most common way of entering a clinical trial is to be referred by your clinician. Therefore, if you find a trial you are interested in joining, you should talk this through with your doctor. Additionally, you could also contact the trial coordinator to discuss your eligibility to participate. Please do bear in mind that eligibility for clinical trials is generally quite strict, so even if you would like to participate in a trial, it may not always be possible.

Clinical trials are not without a degree of risk. You should always consult your doctor about participating in a clinical trial.

If you are interested in taking part in a clinical trial, more information about trials currently in progress can be found at the following sites:

• http://www.clinicaltrials.gov/ – a searchable database of clinical trials conducted around the world.
• http://www.controlled-trials.com/ – a searchable database of randomized controlled clinical trials, which also allows users to register and share information.
• http://www.ukctg.nihr.ac.uk/ – a searchable database of clinical trials currently recruiting patients in the UK
• http://www.cancer.gov/clinicaltrials/ – a searchable database of oncology clinical trials currently recruiting patients in the United States. This site also provides further patient information about clinical trials.
• http://cedars-sinai.edu/Patients/Clinical-Trials/Clinical-Trials—Frequently-Asked-Questions.aspx – a list of questions patients frequently ask about clinical trials

There are currently two clinical trials that individuals with BHD syndrome are eligible for:

• Genetic Analysis of Birt-Hogg-Dube Syndrome and Characterization of Predisposition to Kidney Cancer

This trial aims to fully characterise the types of kidney cancer caused by BHD Syndrome and to calculate the risk BHD patients have of developing kidney cancer. Patients on this trial will undergo a number of non-invasive scans and tests on an outpatient basis. This study is open to all BHD patients worldwide.

• Clinical Manifestations and Molecular Bases of Heritable Urologic Malignant Disorders

This is an observational study aiming to investigate the clinical symptoms of familial kidney cancers. This study is open to all those with a family history of kidney cancer, including those with Birt-Hogg-Dubé. Enrolled patients will undergo periodic clinical assessment at the Warren G. Magnuson Clinical Center in Bethesda, MD.

There is currently one completed clinical trial for individuals with BHD syndrome:

• Topical Rapamycin to Treat Fibrofolliculomas (funded by the Myrovlytis Trust).

This trial tested whether a topical Rapamycin treatment was effective in reducing the size and/or number of fibrofolliculomas. This trial is now closed and results will be posted in due course.

IRDiRC aims to develop 200 new therapies and the means to diagnose most rare diseases by 2020, and has committed to spend €500 million in order to achieve this goal. Indeed, since IRDiRC was founded in 2010, 64 new rare diseases therapies have been developed through IRDiRC projects, meaning that excellent progress is already being made. However, given that there are estimated to be between 6000-8000 rare diseases, even at this rate, it would take hundreds of years to develop therapies for all of these diseases.

To address this problem, the NIH has set up a National Centre for Advancing Translational Sciences (NCATS), which was introduced to the consortium by Dr Christopher Austin. Because the field of rare diseases is so large and varied, a “one size fits all” approach will not be effective in developing therapies for every disease. Rather than focussing on a particular disease, NCATS researches new methods of developing therapies. One such project they are working on in collaboration with the Office for Rare Disease Research (ORDR) is the development of a tissue chip, containing human tissues and “wired up” to mimic organ function. Once developed, this chip will be used for preliminary toxicity tests for new drugs, meaning that the most dangerous drugs will not reach clinical trials and be tested in people.

Another encouraging development reported at the conference was data showing that gene therapies are providing clinical benefit in patients. Dr Katherine High spoke about the use of adeno-associated virus vectors, which can be used to correct gene function in patients with genetic disorders. The first treatment of this type, Glybera, was licensed in Europe in November 2012 for individuals with Lipoprotein Lipase Deficiency (Kastelein et al., 2013). There are currently more than 1000 phase III gene therapy trials listed on clinicaltrials.gov, suggesting that this is likely to prove a viable cure for a number of rare diseases.

A major theme of the conference was the need for collaboration at all levels to effectively tackle such a complicated and far-reaching problem as rare diseases. Firstly, researchers and clinicians must collaborate to share resources and knowledge. To this end, both IRDiRC and NCATS actively seek to facilitate and fund large-scale collaborative projects. Secondly, patient registries need to be set up in order to ensure patients are getting the correct care and treatment, and to identify patients that might be eligible to participate in research or clinical trials. Additionally, patient registries are essential for natural history and epidemiology studies, which have thus far not been possible for the majority of rare diseases. Setting up a useful patient registry will require multicentre collaboration and infrastructure requiring input from patients, clinicians and researchers to ensure it serves the needs of all parties. Thirdly, patients need to collaborate with one another. Lesley Murphy of RARE Voices, Australia, spoke of the need to unify the activities of all rare disease organisations into a single entity, providing a single, clear message and greatly increasing the success of lobbying and advocacy activities.

The take-home message of the conference was one of great hope, as the founders and members of IRDiRC are committed and passionate about effecting change in the care and treatment of patients with rare diseases. It is expected that this will be achieved through increased funding of rare diseases projects and by developing a culture of collaboration. With 64 rare disease therapies having been developed since 2010, it seems that IRDiRC is already changing the lives of patients with rare diseases.

• Kastelein JJ, Ross CJ, & Hayden MR (2013). From Mutation Identification to Therapy: Discovery and Origins of the First Approved Gene Therapy in the Western World. Human gene therapy PMID: 23578007

In particular, their Therapeutics for Rare and Neglected Diseases (TRND) Program funds drug discovery and development research collaborations between academic, non-profit organisations and industry. Although this program is not currently accepting applications, there will be a funding call later this year and they are particularly interested in applications for projects on rare diseases.

If you would be interested in applying to NCATS for funding, you can subscribe to the NCATS funding announcement service here.

I have been looking for prices for private treatment, but as its such a rare thing, there are no ‘model’ quotes, and I don’t really want to be bombarded by companies offering their services if I get a tailored quote, then find I can’t afford it.

Has anyone in the UK had any private treatment for their fibrofolliculomas? Can you tell me how many you had treated, and what it cost?

Sorry if its a rude question, But I’m beginning to feel quite desperate about my appearnce.

Many thanks in advance.

The Seventh Framework Programme for Research and Technological Development (FP7) is an EU initiative that has funded around 100 collaborative rare disease research projects since 2007. One such project is EUROPLAN, involving clinicians, researchers, health authorities, and patient organisations from 34 countries, to develop care plans for rare diseases. Based on the recommendations made by EUROPLAN, the EU has now called for all member states to draw up and implement national care plans for rare diseases by the end of 2013, ensuring that access to health care and treatment for rare diseases will be standardised throughout all EU member states.

Founded in 2010, the International Rare Disease Research Consortium (IRDiRC) is a network of rare disease researchers and funders. IRDiRC aims to develop 200 new therapies and the means to diagnose most rare diseases by 2020 and has committed to spend €500 million on rare disease research. The consortium had its inaugural conference in Dublin last week, and will be the subject of next week’s blog.

Historically, pharmaceutical companies have been reticent to develop drugs for rare diseases, so-called orphan drugs, as they are unlikely to recoup the cost of developing the drug. The Orphan Drug Act of 1983 – and similar initiatives in Europe and Japan – set out financial and operational incentives to encourage companies to develop orphan drugs (O’Conner, 2013). Currently the research published on orphan drugs is scattered throughout the literature and can be difficult to find. A new journal, Expert Opinion on Orphan Drugs, collates research on orphan drugs into a single place and will provide reviews and editorials from experts in the field. Additionally, two further journals focussed on rare disease research the Journal of Rare Disorders and Rare Diseases, have also been launched this year. Together, these three journals nearly double the number of journals dedicated to rare disease and orphan drug research.

The lack of interest in rare diseases from pharmaceutical companies could be, in part, due to the term “rare”, which could be interpreted to mean “not of broad clinical significance” or “unprofitable”. A recent article by Dr Anil Mehta, says that rare diseases should be considered as extreme versions of common diseases, and should instead be called “sentinel diseases”. Dr Mehta illustrates his point using the example of BHD Syndrome and suggests that by determining how FLCN mutations cause kidney cancer in BHD syndrome, we will inevitably learn how other forms of kidney cancer develop.

This sentiment was echoed several times at the IRDiRC conference and is embodied by the ethos of Findacure, a funder of rare disease research. Findacure believe that fundamental disease mechanisms underlie both common and rare diseases, and will be best elucidated – and ultimately cured – by studying the most extreme form of these diseases, which are usually the rarer forms. Thus, Findacure refer to these diseases as “fundamental diseases” rather than “rare”.

It is also becoming increasingly clear that drugs developed for common ailments can be re-purposed to treat rare diseases (McCormack et al., 2011), meaning that the reverse is likely to be true. Thus, rare disease research will also lead to insights into the causes of and new interventions for common diseases, making it an increasingly attractive area for pharmaceutical research and investment and hopefully speeding up the development of much needed therapies for common and rare diseases alike.

• McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC, National Institutes of Health Rare Lung Diseases Consortium, & MILES Trial Group (2011). Efficacy and safety of sirolimus in lymphangioleiomyomatosis. The New England journal of medicine, 364 (17), 1595-606 PMID: 21410393
• O’Connor, D. (2013). Orphan drug designation – Europe, the USA and Japan Expert Opinion on Orphan Drugs, 1 (4), 255-259 DOI: 10.1517/21678707.2013.769876

Your chance to have a say on the draft Wellcome Trust and Medical Research Council framework on health-related findings in research

During a study involving human participants, researchers may make a finding that is relevant to an individual’s health. For example, an MRI scan may reveal an abnormality that looks like a tumour or genetic analysis may reveal that the participant is at high risk of developing breast cancer. There is an intense ethical debate on whether and how these findings should be fed back to the participant.

In the absence of general UK-wide guidelines for researchers and clear ethical consensus on how these health-related findings should be handled, the Wellcome Trust and Medical Research Council have drafted a framework to support researchers’ decisions about individual feedback.

We would now like your help to ensure that the framework reflects the perspective of patients and the public. We are interested to receive your comments on the draft framework (attached) from the patient and public perspective.

Feedback should be sent to Beth Thompson at b.thompson@wellcome.ac.uk by 26 April.

Any patient and public perspectives are welcome, but the following questions may guide your comments:

1)   Do you agree with the proposed requirements for researchers outlined in section B.8?

2)  Does the framework sufficiently reflect the research participant’s perspective? If not, how could this be improved?

3)  Is the framework clear? Do any elements need to be strengthened or removed?

Please get in touch if you have any questions and thank you for considering this.