2014 Crick Symposium on Rare Diseases

The Francis Crick Institute is a new multi-disciplinary medical research institute, and is due to open in 2015. It is a consortium of six UK organisations – the Medical Research Council, Cancer Research UK, the Wellcome Trust, University College London (UCL), Imperial College London, and King’s College London. The consortium members have committed to invest £650 million to establish the institute, which is expected to become a hub of medical research expertise and innovation. Rare diseases are high on the research agenda at the Crick Institute, and they recently hosted a symposium on rare diseases in London, with roughly 450 researchers in attendance.

Genetic research was a popular topic at the meeting, which is not surprising as 80% of rare diseases are thought to have a genetic cause. Currently, whole exome sequencing (WES) is performed more commonly than whole genome sequencing (WGS), as it is faster, cheaper and the results are more straight-forward to interpret. However, Professor Veronica van Heyningen, University of Edinburgh, presented data showing that non-coding mutations in the downstream regulatory region of Pax6 ablate its expression in the eye and cause the developmental eye disorder aniridia (Bhatia et al., 2013). As the cost of sequencing falls and analysis pipelines are improved, research projects will increasingly perform WGS and will likely find many more examples of pathogenic mutations affecting how genes are regulated.

It is estimated that 75% of rare diseases affect children, more than a third of whom will not live to see their 5th birthday. The Dechiphering Developmental Disorders Project, which aims to determine the genetic basis of childhood developmental disorders, was introduced by Dr Matt Hurles, Wellcome Trust Sanger Institute. As of February 2014, 8,000 families have been enrolled in the study which performs WES, array Comparative Genomic Hybridisation, and SNP genotyping on trios (the affected child and both parents) to find de novo coding mutations, copy number variants and uniparental disomies in affected children. Thus far, the project has reported ~1200 causative genes corresponding to 27% of the trios analysed and all results have been deposited in the DECIPHER database, which is a freely available international resource for researchers and clinicians.

New therapies were also discussed by several speakers. Firstly, Professor Tim Aitman, Imperial College London, presented examples of personalised medicines, where treatment is chosen depending on the specific genetic lesions that have caused the disease. This will be discussed in more depth in an upcoming blog post. Professor Fran Platt, University of Oxford, spoke about her work in successfully repurposing the drug Miglustat, which was developed as an HIV treatment, for the lysosomal storage disorders Type I Gaucher’s Disease and Neimann Pick Type C. (Bennet and Mohan, 2013, Lyseng-Williamson, 2014)

Duchenne Muscular Dystrophy (DMD) is caused by mutations that disrupt the reading frame of the Dystrophin gene, causing the RNA transcript to be degraded. Professor Francesco Mutoni, University College London, presented his work on RNA therapy – where anti-sense RNA is injected directly into muscle and causes target exons to be skipped and excluded from the final mRNA transcript. Exon skipping restores the reading frame and allows a truncated form of the protein to be synthesised (Cirak et al., 2013, Kinali et al., 2009). While not a complete cure, RNA therapy halts the progression of DMD, and patients who have received RNA therapy have remained stable for two and half years so far.

The Crick Symposium was an interesting and varied meeting, and showed there is significant interest in rare disease research. Indeed, rare disease research is increasingly viable due to better technology, political pressure and increased patient interest. The Crick Institute aims to become a leader in rare disease research, and is well-placed to do so: there are estimated to be around 500,000 people in London with a rare disease, and 40 out of 70 commissioned rare disease services are in London. Furthermore, at UCL there are already 250 research groups that work on rare diseases, covering roughly 400 diseases, meaning there is already an active research programme in place.


  • Bennett LL, & Mohan D (2013). Gaucher disease and its treatment options. The Annals of pharmacotherapy, 47 (9), 1182-93 PMID: 24259734
  • Bhatia S, Bengani H, Fish M, Brown A, Divizia MT, de Marco R, Damante G, Grainger R, van Heyningen V, & Kleinjan DA (2013). Disruption of autoregulatory feedback by a mutation in a remote, ultraconserved PAX6 enhancer causes aniridia. American journal of human genetics, 93 (6), 1126-34 PMID: 24290376
  • Cirak S, Feng L, Anthony K, Arechavala-Gomeza V, Torelli S, Sewry C, Morgan JE, & Muntoni F (2012). Restoration of the dystrophin-associated glycoprotein complex after exon skipping therapy in Duchenne muscular dystrophy. Molecular therapy : the journal of the American Society of Gene Therapy, 20 (2), 462-7 PMID: 22086232
  • Kinali M, Arechavala-Gomeza V, Feng L, Cirak S, Hunt D, Adkin C, Guglieri M, Ashton E, Abbs S, Nihoyannopoulos P, Garralda ME, Rutherford M, McCulley C, Popplewell L, Graham IR, Dickson G, Wood MJ, Wells DJ, Wilton SD, Kole R, Straub V, Bushby K, Sewry C, Morgan JE, & Muntoni F (2009). Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. Lancet neurology, 8 (10), 918-28 PMID: 19713152
  • Lyseng-Williamson KA (2014). Miglustat: a review of its use in Niemann-Pick disease type C. Drugs, 74 (1), 61-74 PMID: 24338084


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