Breakthrough for debilitating heart and lung disease

British Heart Foundation logo British Heart Foundation logo A protein that targets the effects of a faulty gene could offer the first treatment targeting the major genetic cause of Pulmonary Arterial Hypertension (PAH), according to research funded by the British Heart Foundation (BHF).

Genetic evidence dating back to 2000, from research the BHF helped to fund, indicated that the absence or reduced activity of a particular protein, bone morophogenetic protein type II receptor (BMPR-II), leads to PAH. BMPR-II is important to the normal function of the blood vessels of the lungs. PAH is thought to affect around 6,500 people in the UK.

This new study led by BHF Professor of Cardiopulmonary Medicine Nick Morrell and including expertise from Dr Rajiv Machado at the University of Lincoln, UK, is the first to use a protein, called BMP9, to reverse the effects of reduced activity of BMPR-II and to reverse the disease itself. The study was conducted in mice and rats, but also using cells from patients with PAH. It is published today in Nature Medicine.

PAH is a chronic and debilitating disease that affects the blood vessels in the lungs, leading to heart failure, and leaves sufferers feeling breathless and exhausted. Current treatments only target the symptoms and prognosis remains poor. The only effective cure is a lung, or heart and lung, transplant, which has associated risks and complications.

Once diagnosed with PAH, a person has a 30 per cent chance of dying within three years and the condition affects more women than men. Researchers speculate that this gender disparity is caused by pregnancy triggering the disease in genetically susceptible women or that oestrogen can affect the function of BMPR-II.

A team at the University of Cambridge, with contributions from researchers at the University of Lincoln, Switzerland and the US, searched for a BMP protein that could enhance the function of BMPR-II to target the condition. The researchers firstly trialled different BMP proteins on lung blood vessel cells grown in a dish. This process showed BMP9 to be most selective, and therefore less likely to have negative effects on other cells.

This study used the first animal model, a mouse, which closely mimics the human genetic form of the disease. The University of Lincoln’s Dr Machado was instrumental in designing the strategy for development of this experimental model employed in the study.

Using a specific set of molecular tools, Dr Machado replicated a mutation frequently observed in human PAH patients which, subsequently, was introduced into the mouse genome. This facilitated the generation of a mouse model that naturally mirrored the human disease state critical for the assessment of therapeutic options.

Ultimately, the team showed that BMP9 treatment reversed PAH in three separate mouse and rat models. They found that the treatment works in mice with both the genetic from of the disease, and in acquired forms of PAH, where the cause is unknown.

BHF Professor Nick Morrell, who led the research, from the Department of Medicine at the University of Cambridge School of Clinical Medicine, and Director of the BHF Cambridge Centre for Cardiovascular Research Excellence, said: “The next step for our research is studies in people with pulmonary arterial hypertension – first, safety testing to ensure the compound can be given to people. But we’re confident of passing this phase because BMP9 exists naturally in the body. We’re just giving patients more of it.”

Professor Jeremy Pearson, Associated Medical Director of the British Heart Foundation, which funded the research, said: “We’re very excited by these results. This condition is horrible and an effective treatment that prevents the need for a transplant would be a game-changer. Clinical trials of the treatment in patients are still needed but these findings, from years of research supported by the BHF, offer real promise of a cure.”

One gene closer to helping sufferers of rare genetic disorder

A new study has separately confirmed and significantly built on recent research, identifying mutations of a gene that causes the uncommon but potentially fatal Adams-Oliver syndrome.

A leading team of medical and genetics experts from institutions across Europe independently identified a gene called NOTCH1 while also discovering the largest range of mutations, both consolidating and expanding previous research published in 2014.

The new findings, published in the journal Circulation: Cardiovascular Genetics, solidify Notch signalling as a major factor in Adams-Oliver syndrome (AOS) and further advance diagnosis and treatment of this neonatal disorder – characterised by limb and scalp defects, accompanied by a host of cardiac and vascular complications.

The identification of the gene was driven by Professor Richard Trembath and Dr Laura Southgate, from Queen Mary University of London, with subsequent functional analyses primarily conducted by Dr Rajiv Machado and colleagues at the University of Lincoln, UK.

The study’s joint senior author Dr Machado, from the School of Life Sciences, University of Lincoln, said: “Our study, which provides the largest collection of NOTCH1 mutations to date, clearly places this gene as a major causal genetic factor in AOS and in particular when associated with major cardiovascular defects, both developmental and structural.

“This insight into NOTCH1 offers the potential to explain its function in the development of key systems in the body – notably cardiovascular, skeletal and pulmonary systems. The ultimate hope is further research in this area will result in more effective diagnoses, but most importantly treatment therapies, for those affected with this debilitating condition.”

The initial gene identification process was based on sequencing the genomes of 12 families affected with AOS. They found that two people from different families had mutations in the NOTCH1 gene. Confirmation of these findings was obtained by screening a cohort of 52 additional patients, which led to the identification of a further eight unique mutations.

This study, combined with the earlier publication of NOTCH1 mutations in AOS, is a significant breakthrough in the understanding of this developmental disorder, which currently has no cure.

In 2011, Dr Machado and Dr Southgate were integral to efforts that led to the discovery of the ARHGAP31 gene – the first identified molecular defect associated with AOS. This finding was noted by international publications including the American Journal of Medical Genetics which provided an editorial to mark the work.

Since then four additional genes, including NOTCH1, have been identified indicating this is a disease underpinned by multiple genetic factors.

The collaboration is currently further examining the impact of NOTCH1 mutations described in this study and exploring the possibility of additional mutations in as yet unidentified genes in an extensive cohort of patients.

This work was supported by the British Heart Foundation, the German Research Foundation and a Wellcome Trust Strategic Award.

Lincoln researcher to join prominent scientific debate

A leading cardiovascular disease researcher from the University of Lincoln, UK, has been invited to take part in a debate comprising top thinkers from science, medicine, health, economics, government and the media.

Dr Rajiv Machado, from the School of Life Sciences, is one of a group of prominent scientists invited to join the audience for the Astellas Innovation Debate 2015 at the Royal Institution of Great Britain in London.

Dr Machado is an eminent voice in the fight against Pulmonary Hypertension and has published breakthrough research into the causes of this debilitating vascular disease.

The debate brings together some of the world’s most progressive thinkers to discuss the role of innovation in solving the greatest challenges of our time. Past panellists have included Nobel Laureates Professor Sir Andre Geim and Dr Elizabeth Blackburn, Lord Robert Winston, Baroness Sally Greengross and Professor Brian Cox.

This year’s debate entitled ‘I-Genes: What the DNA and Data Revolutions Mean for our Health’, chaired by Jonathan Dimbleby, will explore whether science and technology can deliver truly personalised healthcare for all. George Freeman MP, Minister for Life Sciences, will give the keynote speech.

With the price of DNA sequencing plummeting, and the increasing ‘smartness’ of handheld electronics and point-of-care diagnostics, the prospect of personalised medicine fine-tuned to a patient’s genetic make-up no longer seems a far-off dream. Already health apps are giving the public unprecedented opportunities to monitor and manage their own fitness; in the future, we are promised, technology and genomics will combine to utterly change the patient’s experience.

As major projects like the UK government’s 100,000 Genome Project gear up to provide the fundamental medical science this future will need, the panel of world-leading experts will debate just what differences this new era of personalised healthcare will deliver.

The Innovation Debate 2015, which takes place at 6.30pm on Thursday, 29th January, will be broadcast live through and

​Student awarded specialist equipment


A Biomedical and Medical Sciences student has won more than £3,000 worth of specialist equipment and training

PhD Student Anastasios Karountzos, who was nominated by supervisor Dr Rajiv Machado, was one of just 20 winners chosen for the 2014 Gold Sponsored Student programme by Primerdesign Ltd.

He will receive qPCR kits (quantitative polymerase chain reaction), which is a laboratory technique used to amplify and simultaneously quantify a targeted DNA molecule.

Dr Machado, from the School of Life Sciences, University of Lincoln, UK, said: “In the context of disease this is important to understand the effect of identified mutations and, also, the potential deregulation of gene/protein networks affected by the initial mutational defect. In our work, three independent projects will benefit greatly from this award based around pulmonary vascular disease.”

Overall 20 ‘Gold’ level sponsorships were awarded this year to research students in various institutions across the UK.

On receiving the award, Anastasios said: “I feel honoured that our research group has been selected for this generous sponsorship from Primerdesign, which will provide us with professional support and training in qPCR based experiments from experts in the field.”

Primerdesign will also be offering to present two seminars which will be available to the whole institution.

These seminars, given by qPCR experts, will demonstrate ways for life scientists at the University of Lincoln to improve standards in their real-time PCR experiments and generate better quality data.

Dr Jim Wicks, Managing Director Primer said: “We aim to help qPCR students obtain the best possible data from their experiments and publish in accordance with the MIQE guidelines. Being former researchers ourselves we want to make qPCR as painless as possible and give something back to fellow students.”

Primerdesign is a successful spin-out from the University of Southampton. They specialise in the supply of assays, kits and reagents for use in real-time PCR.​

Research breakthroughs advance understanding of genetic causes of vascular disease

The world’s leading voices in the fight against Pulmonary Hypertension have compiled a special publication detailing the breakthrough research into the causes of this debilitating vascular disease.

Co-author Dr Rajiv Machado, from the School of Life Sciences, University of Lincoln, UK, attended the World Symposium on Pulmonary Hypertension in 2013 as an invited member of the symposium’s genetics and genomics task-force.

Papers arising from this conference, which brought together the most respected clinicians and scientists in the field, have now been compiled in a special edition of Journal of the American College of Cardiology.

The symposium, which discussed several forms of resistance in lung vessels including those associated with common disorders such as congenital heart disease and HIV, resulted in a powerful consensus around key issues and recommendations.

The replication and extension of these studies should serve to further define the genetic landscape surrounding vascular disease.

Dr Machado said: The aim of the symposium was to report new information and how this could then be translated into clinical medicine by providing novel targets for therapy. The results have now been published as the definitive scientific consensus on this area of disease.”

Dr Machado’s main research focusses on Pulmonary Arterial Hypertension (PAH), a progressive disorder characterised by abnormally high blood pressure (hypertension) in the pulmonary artery, the blood vessel that carries blood from the heart to the lungs.

Symptoms include shortness of breath, dizziness, swelling (oedema) of the ankles or legs, chest pain and a racing pulse.

Dr Machado was part of a team that discovered the primary gene that causes PAH and has since gone on to investigate the disease pathway, isolating more contributory genetic mutations.

As reported at the symposium, Dr Machado’s investigation of 300 patients with disparate forms of PAH – the largest study of its kind – resulted in the identification of three novel genes which appear to cause pulmonary dysfunction.

A process called next generation sequencing (NGS) was used to exclude the likelihood of the observed genetic variation being present in the general population.

In a separate study, colleagues reported two additional genetic causes of disease present only in PAH patients and, intriguingly, a genetic variant enriched among patients but present in all of us.

Dr Machado said taken together the findings presented promising new avenues for research.

“It is extremely rare to find this form of variation in a disease like this,” he said. “Identification of this alteration may provide a new target for PAH treatment. It has wide ranging significance to our understanding of lung disease. It all contributes to the genetic architecture of the disease and our understanding of what causes it.”

Dr Machado is now working on population-specific genetic patterns, looking at two subsets of PAH, including an Indian group which has no family history of the disease. He will use next generation sequencing to drive a baseline genetic profile of this previously unstudied population.

Dr Machado will also carry out full DNA sequencing to interrogate the causes of childhood PAH, a particularly severe form of disease which is currently not well understood.

The full paper ‘Genetics and genomics of pulmonary hypertension’ can be viewed at