05 May 2020

PVRI celebrated World PH Day with The Dinosaur Trust

About The Dinosaur Trust

The Dinosaur Trust is a UK registered charity that was set up by Jamie and Julia Strachan as their son Archie was born with PAH. The Dinosaur Trust funds research into PAH in order to save and improve the lives of children and adults who suffer from the disease.

The PVRI and The Dinosaur Trust have been working together over many years and various Research Grants have been sponsored by The Dinosaur Trust.

Projects funded by The Dinosaur Trust in collaboration with the PVRI

Correction of a BMPR2 Mutation using CRISPR/Cas9-assisted Genome Editing in Familial Pulmonary Arterial Hypertension Patients

Awardees: Soni Savai-Pullamsetti and Werner Seeger, Justus-Liebig University, Giessen, Germany

Abstract

80% of the cases of familial pulmonary arterial hypertension (PAH) are connected to heterozygous mutations of the BMPR2 gene but most mutation carriers will never develop PAH in their lives. Although PAH pathogenesis has been addressed in many studies the reason for the low penetrance of the mutation is unknown and molecular mechanisms underlying the devastating disease hallmarked by severe remodelling of the pulmonary arterial vasculature are yet to be deciphered.

The aim of our project is to decipher the functional consequences of the BMPR2 mutations found in patients on the regulation of the whole set of genes that concur to the physiological control of the vascular cells, in particular those that are suspected to participate in the pathological process. It is hypothesized that environmental impacts that lead to epigenetic rearrangements in pulmonary arterial cell types, so called second hits, alter the regulation of whole gene sets, which then, in combination with a defect in the BMPR2 gene leads to vascular remodelling and PH.

Thus, to investigate molecular mechanisms underlying PAH pathogenesis we would like to work on four levels and employ different in vitro and in vivo models to dissect the molecular basis of PAH and design a patient-specific approach for gene therapy.

  1. In vitro differentiation of patient PBMC derived iPSCs to endothelial-like cells (iPSC-ECs) to study functional consequences of the BMPR2 mutation in vitro in comparison to non-affected (heathy) BMPR2 mutation carriers and healthy family members without BMPR2 mutation.
  2. Correction of the BMPR2 mutation in patient derived iPSC-ECs with the CRISPR/Cas9 system for in vitroassessment of the molecular consequences of a “therapeutic” gene editing approach.
  3. Employing the personalized iPSC-EC in vitro system for drug screening and validation of the molecular phenotype by RNA sequencing.
  4. Development of CRISPR/Cas9-based gene therapy approaches. Different strategies such as engagement of in situ CRISPR effects by aerosol or intravascular application of adenoviral vectors or transplantation of vascular cell types with a “corrected” version of BMPR2 will be established using a BMPR2 deficient mouse model.

Hyung Chun, Yale University, USA

We have tremendously benefited from the funding support of the PVRI/Dinosaur Trust in making key new discoveries into our understanding of the disease mechanisms that are involved in pulmonary arterial hypertension, as well as function of the BMPR2 gene that is strongly associated with PAH.

First, we discovered a novel mouse strain, which lacks a key protein that interacts with BMPR2, to develop spontaneous pulmonary hypertension. Moreover, human mutations in this gene have also been recently described, and we are actively seeking better understanding of the role of this gene in human PAH. Second, we have identified a new function for BMPR2, where it serves as a key sensor of blood flow by the cells lining the blood vessel. This may be a key role for BMPR2, and disruption of this role may play an important role in development of PAH in humans. Third, we continue to seek better understanding of proteins that are associated with BMPR2 that may be critical for regulating its function in the context of PAH. Lastly, we are heavily invested in determining how the right side of the heart responds to the increased blood pressure in the lungs, as ultimately most patients with PAH will suffer from right heart failure that may lead to poor disease outcomes.

Overall, while we have made key important discoveries through our work supported by the PVRI/Dinosaur Trust, we will continue to dedicate our efforts to advancing this body of knowledge so that we can find ways to better understand and treat this devastating disease in the near future.

BMPR2 mutant rats develop pulmonary and cardiac characteristics of pulmonary arterial hypertension

Frédéric Perros, INSERM U999 – University of Paris-Sud, France 

Through the funding support of the PVRI/The Dinosaur Trust grant, we were able to characterise at the haemodynamic, histological, electrophysiological, and molecular levels, the first rat lines ever created with monoallelic mutations in the ge e encoding bone morphogenetic protein receptor 2 (Bmpr2), the main genetic risk factor for heritable pulmonary arterial hypertension (PAH). The results of this study were published in a high- ranked cardiovascular journal: Hautefort A et al. Circulation. 2019.

Noticeably, we were able to show a not-yet-studied effect of Bmpr2 mutation specifically on the right ventricle (RV), which compromised intrinsic function, even in non-overloaded states, suggesting that BMPR2 mutations may have a negative effect on RV function in patients with PAH. To date, differences in survival and disease severity in BMPR2 mutation carriers have been explained mainly by more severe pulmonary vascular involvement, leading to a more severe and faster disease trajectory. However, because RV function is the main determinant of prognosis and disease severity, RV function may play a significant role in the different clinical phenotypes of BMPR2 mutation carriers and noncarriers. This is a shift in paradigm from an exclusive role of BMPR2 dysfunction in vascular remodelling to its highly probable involvement in RV failure/maladaptation.

Our studies now focus on a more detailed evaluation of the cardiovascular function, which will determine to what extent the RV (and the left ventricle) of the Bmpr2 mutant rats is compromised and the adaptability of these hearts to increased load.

BMPR2 mutant rat model unexpectedly develops spontaneous breast tumour but no obvious pulmonary hypertension

Sébastien Bonnet, University Of Laval, Quebec, Canada

Thanks to the support of the PVRI/ The Dinosaur Trust, we have initiated an international (North America, Europe) collaborative effort aimed to better understand the role of BMPR2 signalling network in PAH.

Specifically, in France, Dr Perros and his colleagues have established the first rats’ model with disrupted BMPR2 signalling and demonstrated that these rats exhibit a phenotype similar to the one seen in humans with BMPR2 mutations (25% or so spontaneously developed PAH). In Canada, after establishing the rat colony, Dr Ranchoux, a post-doctoral fellow, was able to duplicate Dr Perros findings. Based on this, Drs Nadeau, researcher associate, and Victoria Toro, PhD student, have explored the consequences of aging in this rat population in order to better understand the clinical complications that may arise in PAH patients with BMPR2 mutation, as well as healthy carrier.

 During this, they have demonstrated that 20% (95%CI:12-28) of the 82 Bmpr2+/ß71 rats versus 4% (95%CI:0-9) of the 84 age-matched wild-type littermates spontaneously developed mammary masses and ulcerations requiring euthanasia. Mammary masses were histologically diagnosed by an anatomical veterinary pathologist as fibroadenomas (hormone-dependent benign breast tumours predisposing to cancer) and adenocarcinoma in 83% and 17% of cases, respectively. Tumours predominantly occurred in females (93%of cases), were generally observed after postnatal day 322. We also demonstrated that female with tumours had greater PA pressures, suggesting that tumours development may accelerate/promote PAH development in BMPR2 mutant rats. We are now investigating this further.

In conclusion, we demonstrated for the first time that BMPR2 mutated animals are predisposed to breast cancer. Development of breast cancer promotes the development of PAH.

Articles on World PH Day

Call it by the correct name - pulmonary hypertension not pulmonary arterial hypertension. Growing recognition of the global health impact for a well-recognised condition and the role of the Pulmonary Vascular Research Institute

Professor Paul Corris, Emeritus Professor of Thoracic Medicine Newcastle University Newcastle Upon Tyne UK. Chairman of Board of Pulmonary Vascular Research Institute

Professor Werner Seeger, Chief of the Department of Internal Medicine, Section Head of Respiratory and Critical Care Medicine, Chairman of the German Center for Lung Research (DZL), Chairman of the Universities of Giessen & Marburg Lung Center (UGMLC)

Abstract

May 5th signals World Pulmonary Hypertension Day and, whilst the world is currently focusing on the coronavirus pandemic, it is important to remember our patients with this condition, which continues to exert a major disease burden in all low, middle and high income countries.

Although pulmonary hypertension has long been recognised to complicate many common diseases, especially left-sided heart disease and lung disease, most basic, translational and clinical scientists together with the pharmaceutical industry have, to date, focused predominantly on pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension1. Both entities are rare, leading to the erroneous belief that pulmonary hypertension in general is a rare condition, and not worthy of major global focus.

This editorial summarises the global incidence and prevalence of pulmonary hypertension and considers implications for health-care providers, policy makers, and future research strategies.

Pulmonary hypertension: a silent killer ignored no more

Dr Bradley A. Maron,  Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston MA USA;

Professor Paul Corris, Emeritus Professor of Thoracic Medicine Newcastle University Newcastle Upon Tyne UK. Chairman of Board Pulmonary Vascular Research Institute.

Elevated blood pressure in the lung artery system is a condition known as pulmonary hypertension (pulmonary, for lung and hypertension, for high blood pressure) (PH), which is an important non-communicable cardiopulmonary disease that causes heart failure, hospitalisation and shortened lifespan. In contrast to ‘hypertension’, which is primarily a disease of aging affecting non-lung arteries and already well-known to the global health community, PH is distinct in several important ways.

  • First, the epidemiology and demographic profile of PH is unrelated to hypertension.
  • Second, the diagnosis of PH cannot be accomplished using a regular blood pressure assessment, but instead requires ultrasonographic or other methods.
  • Third, even minimal elevation in pulmonary artery pressure is associate with cardiac dysfunction and a substantial increase in adverse clinical events.  
  • Finally, as much as 70% of the lung circulation may be abnormal prior to the development PH symptoms.

PVRI shines spotlight on pulmonary hypertension in the Lancet Respiratory Medicine Journal

Stuart Rich, Sheila Glennis Haworth, Magdi Yacoub and Paul Hassoun

Pulmonary hypertension: the unaddressed global health burden

The history of pulmonary hypertension is unique among non-communicable diseases (NCDs). Although recognised for centuries, only the development of cardiac catheterisation in the 1950s allowed the diagnosis to be made clinically. The initial case series characterised it as a rare disease of young women that was progressive and fatal. After the European epidemic of pulmonary hypertension in 1965, attributed to the diet pill aminorex, WHO held a symposium on pulmonary hypertension in 1973, which created international awareness. The National Institutes of Health sponsored the first registry on primary pulmonary hypertension in 1980, providing information about sex (1-7 times more frequent in women), onset (mean age 36 years), and survival (mean 2.8 years from diagnosis). In 1992, another epidemic of pulmonary hypertension attributed to diet pills, this time fenfluramines, brought pulmonary hypertension to world attention again. A second WHO symposium on pulmonary hypertension in 1998, established the clinical classification of five groups of pulmonary hypertension, but it was largely designed to serve the needs of North America and Europe. Pulmonary hypertension as a disease of low-income and middle-income countries was never addressed.

Heightened awareness among physicians in North America and Europe has resulted in a dramatic rise in pulmonary hypertension diagnosis and the establishment of centres of excellence. A cohort study from Canada reported a 28% increase in prevalence from 1993–2012 to 127 cases per 100,000 population. A population-based study from the USA found that 20% of cohorts of older participants (72-96 years) had echocardiographic evidence of pulmonary hypertension, and that increasing pulmonary artery pressure was associated with increased all-cause mortality independent of both age and the presence of cardiopulmonary disease. The diagnosis of pulmonary hypertension carries a 7-times increase in mortality, regardless of cause.

News from our partners

NCD Alliance

The NCD Alliance has brought attention to "Raising awareness of pulmonary health and COVID-19".

Support from individuals and organisations around the world including the PH community is key to protecting the health of our lungs and those living with PH worldwide particularly through the COVID-19 pandemic. The COVID-19 pandemic presents many unique challenges when caring for patients with pulmonary hypertension (PH).

The NCDA is encouraging people to share PH day activities and messaging on social media via the hashtag #WorldPHDay2020 and tag along @worldphday

Research funding for our professional network

If you would like to apply for a grant from the PVRI to support a regional PH meeting in your country or to carry out research, please complete the online Sponsorship Application Form. 

PVRI GoDeep Registry

The PVRI GoDeep Registry, led by PVRI President, Werner Seeger at the Justus-Liebig University Giessen, Germany, is a worldwide deep phenotyping pulmonary hypertension (PH) database spanning over all continents. The data offers insights into specific geographical and ethnical profiles of this disease. Furthermore, researchers can utilise the registry to identify possible study participants for clinical trials. Normal values, prevalences and incidences of specific pathologies can be derived.

PVRI Members

We would like to take this opportunity to encourage all of our professional members to ensure that their membership is up to date. You can do so by visiting My PVRI.


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