Rare diseases are fundamental to understanding common diseases

Research has historically concentrated on more common diseases, seeking to benefit the many rather than the few, and as a result rare diseases have often been overlooked. However, a growing body of evidence shows that rare disease research can yield important insight into more common conditions. Additionally, rare diseases are often more extreme and have a more straightforward aetiology than their common counterparts, and therefore provide models of disease that are easier to study.

Findacure, a new charity promoting the research and development of treatments for rare diseases, thinks that terminology – “rare”, “orphan”, “neglected” – also explains why this group of diseases has been overlooked for so long. Thus, they are seeking to re-frame rare diseases as “fundamental diseases”, because they are fundamental to understanding more common diseases. Specifically, Findacure’s definition of a fundamental disease is one that has a genetic cause, is rare and largely neglected, and is likely to be amenable to a therapy. To raise awareness of this concept in the scientific community, Findacure recently held their First Scientific Workshop on Fundamental Diseases at Sidney Sussex College in Cambridge.

Professor Eamonn Maher, from the University of Cambridge, presented his work on the rare genetic kidney cancer predisposition syndrome Von Hippel-Lindau (VHL), and how this has benefited patients with more common kidney cancers. VHL is the most commonly mutated gene in sporadic kidney cancers, accounting for around 74% of clear cell RCCs (Banks et al., 2006). Research on VHL showed that under normoxia, the VHL protein marks HIF1a and 2a for proteolysis, thus preventing angiogenesis, and correlates with the observation that VHL-null kidney tumours are highly vascular (Maxwell et al., 1999). These findings suggested that these cancers might respond well to anti-angiogenic drugs, specifically Tyrosine Kinase inhibitors, which are now a commonly used therapy for kidney cancer.

Professor Timothy Cox, from the University of Cambridge, spoke about the historical link between rare and common diseases. One interesting example he used was that of Familial Hypercholesterolemia (FH), which is caused by mutations in the LDL Receptor gene. Biallelic mutations cause the most severe form of disease, and heart attacks have been reported in children as young as 2 years old (Carlson, 2010). Statins were developed as a cure for FH, and are now the most commonly prescribed drug in the UK for high cholesterol, with Pfizer reporting Lipitor sales revenues of $12.4 billion in 2008.

Professor James Gallagher, from the University of Liverpool, explained how his work on the rare disease Alkaptonuria (AKU) has yielded insight into normal ageing and osteoarthritis, which affects 1 in 3 people over the age of 45. AKU is caused by recessive mutations in the HGD gene, which causes an early onset and severe form of arthritis. Through his work with AKU patients and mouse models, Professor Gallagher has shown that collagen fibres become more vulnerable with age due to general wear and tear (Chow et al., 2011), and that this ageing process starts early, well before any macroscopic signs of ageing are visible. Additionally, he has shown that joint degeneration begins in calcified cartilage, and that trabecular excrescences and sub-chondrial protrusions are characteristic of both damaged AKU joints and arthritic joints (Taylor et al., 2011, Taylor et al., 2012).

Dr Anil Mehta spoke about how research on a specific Cystic Fibrosis mutation has revealed information about the selection forces humans have been subject to during evolution. Cystic Fibrosis is a life-threatening and disabling rare disease caused by biallelic mutations in the CTFR gene. 70% of Cystic Fibrosis cases are caused by biallelic inheritance of the ΔF508 mutation (Riordan, 2005). ΔF508 is a founder mutation that arose in Europe around 50,000 years ago and now is now common in the UK population, with 1 in 60 people estimated to be carriers (Morral et al., 1994). Research from Professor Mehta’s lab has found that the peptide sequence surrounding this mutation is found in the IgG binding domain in many pox viruses (Treharne et al., 2009). Thus, having a single copy of ΔF508 ablates CFTR’s binding site and confers resistance to pox, which may explain the prevalence of this allele in European populations.

Thus research on fundamental diseases can yield important insight into the pathogenesis of more common diseases, lead to the development of block-buster drugs, and can even explain how certain genetic mutations have become so common in today’s population. By working with patient groups, academia and the Pharmaceutical industry, Findacure aims to build a movement for fundamental diseases that drives research, drug development and health policy reform.

  • Banks RE, Tirukonda P, Taylor C, Hornigold N, Astuti D, Cohen D, Maher ER, Stanley AJ, Harnden P, Joyce A, Knowles M, & Selby PJ (2006). Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer. Cancer research, 66 (4), 2000-11 PMID: 16488999
  • Carlson R (2010). Familial hypercholesterolemia captures gene test controversies. Biotechnology healthcare, 7 (1), 8-9 PMID: 22478804
  • Chow WY, Taylor AM, Reid DG, Gallagher JA, & Duer MJ (2011). Collagen atomic scale molecular disorder in ochronotic cartilage from an alkaptonuria patient, observed by solid state NMR. Journal of inherited metabolic disease, 34 (6), 1137-40 PMID: 21735270
  • Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, & Ratcliffe PJ (1999). The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature, 399 (6733), 271-5 PMID: 10353251
  • Morral N, Bertranpetit J, Estivill X, Nunes V, Casals T, Giménez J, Reis A, Varon-Mateeva R, Macek M Jr, & Kalaydjieva L (1994). The origin of the major cystic fibrosis mutation (delta F508) in European populations. Nature genetics, 7 (2), 169-75 PMID: 7920636
  • Riordan JR (2005). Assembly of functional CFTR chloride channels. Annual review of physiology, 67, 701-18 PMID: 15709975
  • Taylor AM, Boyde A, Wilson PJ, Jarvis JC, Davidson JS, Hunt JA, Ranganath LR, & Gallagher JA (2011). The role of calcified cartilage and subchondral bone in the initiation and progression of ochronotic arthropathy in alkaptonuria. Arthritis and rheumatism, 63 (12), 3887-96 PMID: 22127706
  • Taylor AM, Boyde A, Davidson JS, Jarvis JC, Ranganath LR, & Gallagher JA (2012). Identification of trabecular excrescences, novel microanatomical structures, present in bone in osteoarthropathies. European cells & materials, 23 PMID: 22522284
  • Treharne KJ, Cassidy D, Goddard C, Colledge WH, Cassidy A, & Mehta A (2009). Epithelial IgG and its relationship to the loss of F508 in the common mutant form of the cystic fibrosis transmembrane conductance regulator. FEBS letters, 583 (15), 2493-9 PMID: 19596328

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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