Better understanding of the science behind rare genetic diseases could lead to new treatments in blockbuster disease areas

In many common diseases it can be difficult to decipher the pathways involved, however with rare genetic diseases investigations can provide clearer insights. The falling cost of sequencing, and the development of new tools for managing and interpreting the data, are making a ‘multi-omics’ approach more accessible for the identification of potential drug targets.

Pulmonary arterial hypertension (PAH) is a rare form of heart and lung disease caused by the blood vessels leading to the lungs narrowing. This makes it harder for the heart to pump blood through to the lungs, leading to breathlessness and heart failure. Current treatments only target the symptoms so the prognosis remains poor for the 6,500 people in the UK affected, mostly women in their 30s. For many, the only long-term treatment is a heart and lung transplant. Given the relatively young age of diagnosis and the high mortality rate, the impact of PAH on both sufferers and their families is devastating.

However, recent research has revealed the cause of the disease to be a mutation in a gene for a protein called bone morphogenetic protein receptor type II or BMPR-II, offering an exciting new target for treatment of the condition. The research, by Professor Nick Morrell, director of the British Heart Foundation’s Centre for Research Excellence, and colleagues at Cambridge University’s Department of Medicine, also discovered that patients who have other, non-genetic causes of PAH, such as lung disease and heart failure, the same pathway that controls BMPR-II is not working correctly.

These types of investigations provide new strategies for developing therapies that can address the underlying causes of the disease. Additionally, stratifying patients by their genotype will ensure a higher chance of success in clinical trials, an especially important factor when estimates suggest that 90 percent of compounds entering clinical trials fail because the biological target is not well understood.

Deciphering Developmental Disorders

According to scientists at the Wellcome Trust Sanger Institute, most rare genetic disease is caused by a mutation in one gene. However, not all mutations result in disease because the protein-coding region makes up only 1-2 percent of the total DNA and mutations in the ‘non-coding’ parts have not generally been shown to have same level of impact.

The Deciphering Developmental Disorders study – a UK-wide collaboration to facilitate the translation of genomic sequencing technologies into the National Health Service (NHS) – has provided whole-genome analysis of around 14,000 children with a previously undiagnosed genetic disease, as well as their parents, offering diagnoses to over a quarter of the 1,133 previously investigated yet undiagnosed children.

Their study also revealed that the use of exomes – sections of the genome that code for proteins – supports a much higher rate of diagnosis, narrowing the area in which to look for disease-causing mutations.

At Congenica, we have further developed the tools created during this research to make it easier for clinicians to identify gene–disease associations. Our Sapientia platform has recently been selected by Genomics England and is also attracting the attention of pharma companies looking to unpick the mechanisms behind novel rare diseases to better understand fundamental biological processes.

“We need to be able to analyse and interpret next-generation sequencing data in the correct biological context and in a manner that allows us to make informed decisions on what might, or might not be, a relevant target or mechanism to pursue,” commented Martin Armstrong, senior director of molecular genetics at UCB.

Genomics revolution

One area of interest is genotyping ‘anti-disease’ phenotypes or traits that are therapeutic in common disease settings. For example, studies into rare human bone disorders have led to the identification of important signalling pathways that regulate bone formation.

It has been found that the cause of sclerosteosis – a rare debilitating disease where the bones thicken and harden that affects only 100 people worldwide – is a mutation in the SOST gene, which provides instructions for making sclerostin, a protein that inhibits bone formation.

Knowledge of this pathway may provide a new therapy for the small number of people afflicted with this disease, for which the current treatment is potentially risky surgery. However, knowledge gained from a study of sclerosteosis has led to the development of a treatment for osteoporosis, where, in trials, a single injection of a monoclonal antibody that inhibits sclerostin markedly increased bone-formation markers in post-menopausal women. The new therapy has an estimated market of 150 million people and a value of $13 billion.

Recently, the pharmaceutical industry has developed an interest in developing drugs for rare diseases where the science was previously considered to be too complex and the return on investment small. However, there are around 7,000 rare diseases and treatment can command a premium price; for example, US-based rare disease specialist Alexion charges $400,000 per patient per year for Soliris to treat a kidney condition called atypical haemolytic-uraemic syndrome, generating over $2 billion in sales in 2014.

We are in the midst of a genomics revolution as better bioinformatics, greater access to knowledge bases and improved tools for interpretation drive growth. Yet, the pharmaceutical industry is only just scratching the surface.

Knowledge gained from the study of sclerosteosis has led to the development of a treatment for osteoporosisMike Furness is head of sales and marketing at Congenica