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May 11 and 12, 2017

at the Richard Doll Building, Old Road Campus

The 2nd Biennial Oxford Rare Diseases Initiative Conference further underlined the reputation of Oxford as a leading global centre in the investigation of rare medical conditions. The presentations and discussions involving a diverse range of speakers and over 150 delegates exemplify the benefit of a highly collaborative approach to understanding the biology underlying rare diseases as a foundation for finding effective treatments. Opening the conference, Professor Dame Kay Davies emphasised the ultimate goal of the scientific research to discover cures for devastating rare diseases. The work and insights presented during the two-day conference offer real promise in attaining this goal. Beyond the value of advancing care for the many patients with rare and often life-limiting conditions, the shared biological and metabolic pathways discovered are providing insights into more common ailments.

This article highlights points from some of the presentations which illustrate the enduring themes in rare disease discovery science and patient access to new treatments.



The complexity of rare diseases demands the collaboration of a broad range of interest groups in beating the path to development of new treatments. In his plenary lecture, Dr Wenhwa Lee (Oxford) described the Structural Genomics Consortium (SGC).

The SGC’s mission is to enable early stage drug discovery by working on completely novel targets and catalyse the translation of basic discoveries into clinical trials. Both academia and industry are risk averse: Dr Lee presented an example of kinase-targeted research showing a high concentration of publications and patenting on a limited number of drug targets. SGC’s Open Science model takes a different approach.

Formed in 2004, the SGC is a partnership of public academic institutions and private companies operating in Oxford and five other global centres. The outputs of research on novel proteins conducted within the SGC partnership – including all the reagents and novel specific inhibitors – is freely available and provides identification and validation of potential drug targets: SGC scientists do not file patents. In one example of the speed of progress enabled by the SGC, working in partnership with leading pharmaceutical companies and global academia, the group has pioneered and validated a completely novel family of targets from scratch, leading to the first patient enrolled into a clinical trial within three years.

Patient organisations can also partner with the SGC. Open access has high appeal to patient groups who represent their members’ impatience for new and effective treatments. The SGC’s innovative 'I’MPATIENT’ programme was described by Dr Lee as a patent-free collaboration in which outputs and results are shared with research communities across the globe to crowd source and accelerate fundamental discoveries for drug discovery.

The SGC and its I’MPATIENT programme is helping to create a completely new ecosystem in Oxford, UK and beyond to enable many rare diseases foundations  access to state-of-the-art equipment, scientific platforms and a forward-thinking network of pioneering experts to quickly explore new routes to therapy.

With so many investigational programmes taking place within public and private institutions, one practical need is for an efficient way for clinicians to tap the relevant expertise when they are managing a patient with a rare disease.


The comparison of genotype and phenotype and need for large data sets was discussed. This theme was picked up in her presentation of the DECIPHER platform by Dr Helen Firth (Wellcome Trust Sanger Institute, Cambridge). Advances in genetics, and in particular, the pooling of data from patients, is transforming the understanding of rare diseases. The DECIPHER study ( ) is a multicentre project aimed at integrating and interpreting genotypic and phenotypic data. Dr Firth presented the background to DECIPHER that now displays data from over 250 genetics services worldwide and shows how clinicians can use it to benefit their patients and research. By way of background, the 100K genome project has identified 4 – 5m variants in each genome; phenotypic variation in rare diseases is also common. DECIPHER has the potential to display sequence and copy number variation across the nuclear and mitochondrial genomes encompassing all genes and complemented by over 10,000 phenotype terms derived from the Human Phenotype Ontology (HPO) covering the diverse phenotypes seen in rare diseases.

DECIPHER’s goal is to find patients with variants in the same gene and compare their phenotypes. Such correlation helps us to understand functional consequences of genes for rare diseases. DECIPHER offers a free on-line resource to share and compare phenotypic and genotypic data; currently over 23,000 patients have consented for their data to be openly shared. Dr Firth presented an example of variants in EP300, implicated in epigenetic tagging. The on-line resource contains details on EP300 gene variants and their pathogenicity and shared phenotypes. Sharing records openly in a database such as DECIPHER may increase the opportunity for patients with very rare conditions to participate in research or trials of new therapies.

Patient centricity

Patient-centred care

Rare diseases, of which more than 7,000 are included in OMIM (Online Mendelian Inheritance in Man) are mainly genetic, affect children and are associated with multiple morbidities. These factors demand a highly patient-centred approach to management. Traditionally children affected by rare diseases have been seen by multiple specialists at separate visits. Prof Tim Barrett (Birmingham) provided an overview and update on the pioneering Centre for Rare Diseases (CfRD), attached to Birmingham Children’s Hospital and due to open in November 2017. The CfRD offers children and their parents the opportunity to receive the full range of required consultations in the same hospital visit. As well as being convenient for families, this focus is an efficient way for the hospital to offer healthcare. Birmingham is a particularly suitable location for this new centre; the city has a skewed health profile for rare diseases with consanguinuity contributing to one of the highest infant mortality rate (7.2/1000 live births) in the UK.


Accurate diagnosis of rare conditions can be a lengthy process with the consequences that a patient’s underlying condition can worsen or they may receive inappropriate treatment, including surgery. Dr Alex Bullock (Oxford) presenting on Fibrodysplasia Ossificans Progressiva (FOP) (also see Drug repurposing, below) provided a dramatic example of the outcome of misdiagnosis, a female patient who was misdiagnosed with a tumour leading to the catastrophic amputation of her right arm.

Professor Perry Elliott (London) is a practicing cardiologist with a long-standing interest in patients with rare conditions. He addressed the question why cardiologists, in general, are not effectively translating science into accurate diagnosis at the front line of patient care.

The traditional focus in cardiology has been on technology for diagnosis of major diseases (arrhythmias, heart failure, vascular disease). There has been a common misconcpetion, still prevalent, that rare diseases largely affect children and are fatal. Prof Elliott presented evidence that challenges the myth. For example, a Finnish study revealed that 101 genes were associated with cardiomyopathies in 145 unrelated patients. In patients with uncharacterised left ventricular failure, the rare genetic condition Fabry disease is found in up to 4% of cases of LVH. A take home message for practicing cardiologists is that an appreciable number of their patients will have a rare underlying disorder and that accurate diagnosis is possible in most cases using existing technologies. In order to raise the index of suspicion phenotyping is necessary. Prospects for improvement in diagnosis are good based on hybrid training as part of an education drive on rare disorders.  

Patient access to new treatments

The first plenary presentation, by Dr Francesco Muntoni (London), on Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA) stimulated discussion of patient access to new treatments. With the increasing number of rare disease treatments being authorised by regulators, the pressure on public healthcare funding is growing. 

SMA is life-limiting and the most common motor neuron disorder in childhood; it is caused by depletion of SMN protein. IONIS-Biogen has developed an intrathechal treatment with an antisense oligonucleotide, nusinersen. This treatment has been shown to improve survival and total motor milestone score, and reduce the risk of ventilation. Nuninserin received marketing authorisation in the EU on 1 June 2017 for the treatment of 5q SMA, the most common form of the disease. (Marketing authorisation was granted in the US in December 2017.)

The practicalities of this treatment are burdensome: to treat the entire UK SMA Type 1 population would require more than 700 lumbar punctures in the first year of therapy. Biogen has initiated an Extended Access Programme (EAP) in the EU (and US). Although in many EU states all target patients have been recruited to the EAP, in the UK the figure is less than 10%. The obstacle is that NHS England does not allocate resources for the admission of patients and the drug administration until NICE has evaluated the drug. This review process can take years.  Dr Muntoni noted that, despite the national programmes designed to aid research and development in rare disease in the UK, there is a gap in translating this support into the availability of new treatments.

One radical idea debated during the panel discussion, was that the UK NHS invest in development of treatments on basis that product is eventually accessed at preferential prices.



The historical convention for naming new medical conditions has been to adopt the name of the clinician(s) responsible for characterising the first cases. In the age of molecular biology and genetic analysis this personalised approach can hinder research, especially in the context of developing treatments for patients based on disease pathways. A preference was voiced for the use of names more descriptive of disease to make the link with other diseases sharing similar disease pathways easier.


Clinical end points and animal models

The selection of end points for clinical studies and the utility of animal models for pre-clinical investigation were discussed throughout the conference. It was recognised that end points selected for studies have not necessarily reflected patients’ concerns nor found favour with regulatory authorities. Given the variability in morbidity between patients with the same diagnosis and the chronic nature of so many conditions, surrogates end points have been a feature of many studies in rare diseases. Translating such intermediate measures into clinically meaningful benefits can be contentious.

The use of animal models featured in much of the research presented. The major concern raised during discussion is that frequently these models do not predict human outcomes and frequently insufficient animals are tested to identify a true effect. Commercial companies may have resources which can usefully supplement the work of academic institutions. As an example of collaboration in action, Dr Christell Perros-Huguet (Alexion Pharmaceuticals) explained that she can run test compounds through animal systems at her laboratory, giving the reassurance that all data remains in control of the provider of the compound. She can also provide tool compounds developed at Alexion for investigators to test in their model systems and thus help advance understanding of pathway modulation.


Innovative research methods

A feature of modern medical research is the identification of disease pathways common to disparate disorders. Dr Cheng (Sanofi) presented an example of the repurposing of drugs developed for a rare Lysosomal Storage Disease, Gaucher (caused by mutation in the glucocerebrosidase gene; GBA1) as a gateway for more common disorders, synucleinopathies (notably Parkinson disease), based on shared biology.

Mutations in glucocerebrosidase (GBA1) gene present an increased risk factor for developing Parkinsonism and related disorders and the association between Parkinson and Gaucher disease may extend to other LSDs.

For Gaucher disease, established treatment options are enzyme replacement therapy and substrate reduction but there remains an unmet need to treat CNS manifestations. Emerging evidence suggests that increasing glucocerebrosidase activity and/or reducing glycosphingolipid levels in the CNS may represent potential therapeutic concepts.

The role of endogenous chaperones in ensuring correct protein folding is now being translated into drug development. Dr Richard Roberts (Minoryx) noted in his presentation that approximately 60% of the 7000 rare diseases listed in OMIM are amenable to the chaperone solution, effectively ‘rescuing’ the enzyme. A high proportion of inherited metabolic disorders are suitable targets for the chaperone therapy approach. Minoryx focuses on non-competitive chaperones, that is, small molecules that do not compete with enzyme’s binding site. The company has developed a technology to overcome a barrier to drug discovery in this area, with its Site Directed Enzyme Enhancement Technology able to screen high number of suitable compounds to identify potential chaperone leads. An initial disease target is Morquio B caused by misfolded beta galactosidase (GLB1) enzyme. Studies with transfected COS-7 cells showed enhancement of GLB1 enzyme activity. The promise is for small molecule chaperones with a broad therapeutic window, high specificity and  drug-like properties applicable to range of protein targets.

Novel genetic and mechanistic insights into rare cerebellar disorders were presented by Dr Esther Becker (Oxford). Cerebellar ataxia is genetically complex with over 40 genes implicated to date.  Currently patients have no effective medication available; convergent disease mechanisms might suggest drug targets. Using exome sequencing, Dr Becker’s team has identified the first functionally pathogenic mutation in the human TRPC3 gene (R672H) accounting for spinocerebellar ataxia- 41 (SCA41).  They have shown that mutations in TRPC3 also lead to cerebellar ataxia in a mouse model, the Moonwalker (Mwk) mouse. The Mwk model has great utility: Dr Becker’s group has shown that TRPC3 is an important gene for Purkinje cell development, function and survival. Dr Becker explained that TRPC3 is a key gene affected in cerebellar ataxia. Also mutations in other genes in the TRPC3 signalling pathway cause a spectrum of cerebellar disorders, including both late-onset cerebellar neurodegeneration and childhood-onset ataxia with intellectual disability. The team is now developing human iPSC-derived cellular models of cerebellar ataxia.



Innovation in financing and drug development

Drug repurposing

The essence of drug repurposing is to take a generic drug licensed for a more common disorder and investigate its utility for another, rare condition. The advantage of this approach is to reduce the cost of early development and demonstrate clinical safety. Several examples of drug repurposing were presented during the conference.

The first example was presented by Dr Duncan McHale (UCB Pharma). The target disorder is a subset of primary immune deficiency (PID) caused by mutations in the PIK3R1 gene and resulting in overactive PI3Kδ heterodimer.  UCB Pharma is repurposing a pipeline compound, UCB5857, intended for immune-inflammatory disease, for the treatment of activated PI3Kδ syndrome (APDS) on the basis it is a selective PI3Kδ antagonist.  The agent has received (ultra) orphan designation for APDS.

Drug repurposing - Enzyme Replacement Therapy and AKU

Many rare diseases result from a dysfunction of a single protein in a pathway resulting from a defective gene. In such 'monogenic' diseases, the most appropriate therapeutic option is replacement of the dsyfunctional protein or enzyme. In some cases, the function of proteins can be rescued using drugs which are able to stabilise the structures of the proteins. In this approach, known drug libraries can be utilised to screen against mutant proteins to yield drug candidates which can used as 'repurposed' drugs for the disease.

Recently, the generic drug nitisinone was repurposed for alkapturia (AKU, ‘black bone disease’). AKU is a genetic disorder of phenylalanine and tyrosine metabolism. The metabolic pathway leads to homogentisic acid (HGA). HGA accumulates due to lack of the enzyme homogentisate 1,2-dioxygenase (HGD) that normally degrades it. Nitisinone offers a treatment for AKU but it does not treat the cause of the disease and is associated with severe side effects. The drug acts on a previous enzyme in the metabolic pathway and leads to abnormal accumulation of tyrosine; this results in eye lesions in some patients.


A direct therapy is required to recover the enzyme function which is missing in the disease pathway. Dr. Farid Khan (Protein Technologies) and his colleagues at The University of Liverpool have taken this approach: direct enzyme replacement therapy. Dr Khan succeeded in recombinant synthesis of the missing HGD enzyme and tested the formulation in pre-clinical studies using an AKU mouse model (funded by the  Wellcome Trust and the AKU Society). Remarkably the enzyme is very active in vitro; even though it is a large hexameric protein it can be formulated for long-term stability. The enzyme has shown high efficacy, restoring HGA plasma to normal levels over a four-hour period in mice studies. Furthermore, the enzyme assay itself has allowed a screening approach against known drugs; one candidate showed promising repairing or 'pharmaco-chaperone' properties for HGD. This is a unique example of development and discovery of a biologic and a small molecule (repurposed) drug, an approach which can be used for many 'orphan' rare diseases. 


Drug repurposing - FOP

Another promising example of drug repurposing, for the devastating condition Fibrodysplasia Ossificans Progressiva (FOP), was presented by Dr Alex Bullock (Oxford). In FOP, muscle and connective tissue are gradually ossified. A significant advance in understanding FOP was the identification of the ACVR1 gene locus (ALK2 protein) at the Botnar Research Centre, Oxford.

Screening of compounds binding to ACVR1 was conducted through the Structural Genomic Consortium. This led to the identification of the compound, saracatinib (Astra Zeneca). Pre-clinical testing in the mouse FOP model showed promising effects, which now need to be clinically tested (study in design).

Conducting clinical trials in rare diseases is subject to particular hurdles. These were discussed by Dr Tauhid Ali (Takeda) during his presentation of the TAK-celerator, a group within Takeda dedicated to external R&D initiatives. One disorder under investigation is Mevalonate Kinase Deficiency (MKD), a rare genetic inflammatory disorder. Working with MKD highlights the difficulties facing companies investing in rare diseases:

  • Diagnosis can take up to 6 years and this contributes to low patient numbers hindering trial recruitment
  • Genetic testing is difficult to do and expensive; only a very limited number of laboratories in the world offer the tests
  • Lack of natural history data
  • Lack of regulatory precedent for a treatment for MKD
  • Availability of suitable animal model
  • Trial design presents difficulties


Funding drug development

Orphan drug legislation spawned a biotech industry consisting of small companies, backed by venture capital, to develop treatments for rare disorders. Generally, these treatments were out-licensed or sold to traditional pharmaceutical companies. This model still holds, although the development of orphan drugs by pharma is now commonplace.

An alternative route to funding development of a treatment for a rare disorder in the UK is social finance. An example of this approach, to aid drug repurposing, was presented by Dr Rick Thompson, Findacure. The financial tool involved is a Social Impact Bond (SIB). The funds from investors are used for the drug repurposing project. If trials are successful, the NHS will have evidence to prescribe, off-label, a low-cost generic drug to otherwise untreatable patients. This will save money through the improved health of the treated patients. A proportion of the savings made accrue to the SIB, which can be used to repay investors and/or fund further clinical trials. Budget impact models are used to estimate the cost burden of the specific disease and therefore the financial savings expected from a repurposed drug. Three diseases have been targeted by a proof of concept study: congenital hyperinsulinism, Wolfram syndrome, and Friedreich’s ataxia and a business plan for the social impact project is in development.

During discussion some of the commercial difficulties of generic drug repurposing were discussed:

  • securing Intellectual Property on generics
  • prevention of off-label prescription of alternative generics

The SIB has addressed both of these concerns. The model relies on there being no IP and the availability of multiple generic alternatives to be prescribed to minimise the chance of price increases.

One delegate voiced a concern that the availability of a low cost treatment might raise the bar for developing an improved therapy, so deterring a company from investing in a full drug development programme. Speaking after the meeting, Rick Thompson commented: ‘although this is a theoretical concern, in the majority of rare diseases the pharmaceutical industry is not developing treatments; drug repurposing can help fill an urgent void in the options available to many patients currently without hope’.



David Bennett

Rare and Orphan Diseases Consultancy

    The programme for the Oxford Rare Disease Conference 2017 is still available online