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
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
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.
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.
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
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
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