Research into new treatments for CHD boosted by funding awards

Two new grants will further BHI research into progeria and pulmonary hypertension:

MRC: Gene-inspired therapy to rescue cardiovascular disease in progeria: awarded to Professor Paolo Maddedu

Hutchinson-Gilford progeria syndrome (HGPS), characterised by a rapidly ageing appearance, is a rare disease caused by an abnormal gene and related protein. Because there is no effective cure, children with HGPS will, on average, die of cardiovascular disease at around 14 years old.

This project proposes a new treatment where a gene – found in people who live a long and healthy life – is transferred to rescue the premature cardiovascular senescence typical of HGPS patients.

Professor Paolo Madeddu’s team has discovered a beneficial variant of the BPIFB4 gene, and shown in animal models that transferring this gene reduces the suffering from a heart attack, diabetes and high blood pressure. Preliminary studies showed that the longevity BPIFB4 mutation can benefit some molecular mechanisms that are dysfunctional in children with HGPS.

Paolo says:

“We will determine the efficacy of BPIFB4 gene therapy in HGPS mice, looking at the treatment’s ability to preserve heart and blood vessel function. In addition, we will investigate the mechanisms underpinning this benefit, using human cells from HGPS patients. If results are positive, we will continue our research confirming the lack of toxicity, defining the best dose and timing of treatment for prolonged benefit and the advantage of adding BPIFB4 therapy to current drugs, in view of obtaining permission for a clinical study in patients.”

HRUK: Targeting
pericytes for halting pulmonary hypertension in infants with CHD: awarded to Professor Paolo Madeddu, Professor Massimo Caputo and Dr Elisa Avolio

 Some children are born with a ventricular septal defect: a hole in the wall between the two lower chambers of the heart, where blood can flow across the hole from the left side of the heart to the right. If the defect is not corrected in time, children are likely to develop pulmonary hypertension (high pressure in the blood circulation to the lung).

Surgical correction of the ventricular shunt usually allows the blood pressure in the lungs to return to normal levels. In some cases, however, the pressure may stay higher than normal after surgery.

At least five to 10 per cent of patients with congenital heart disease develop pulmonary arterial hypertension (PAH), which can lead to heart failure. The risk of developing pulmonary hypertension is higher for children living in poor countries and areas of social deprivation, because of the limited access to specialist centres where the cardiac defect can be recognised and corrected before complications arise.

Recent research indicates pericytes – multi-functional cells embedded within the walls of capillaries – could be targeted for the treatment of PAH. Paolo says:

“Our research will investigate why pericytes from children with CHD constrict and block the pulmonary circulation. It will also test a new treatment to reduce the contraction of pulmonary pericytes and prevent pulmonary hypertension occurring.”

First use of ROB2 in Cochrane Review of Exercise Interventions for CHD

Graham Stuart and Guido Pieles collaborated with Craig Williams at the University of Exeter to publish a Cochrane Review, which gathered evidence for the effectiveness of physical activity interventions for people with congenital heart disease.

The Review compared three types of interventions from 15 trials, including programmes designed to increase physical activity, aerobic fitness and health-related quality of life. It found some evidence for increased physical fitness and physical activity, although there are no data yet to suggest this results in fewer hospital visits.

Read the Review in the Cochrane Library

Graham says:

Exercise used to be discouraged in patients with CHD. This was poor advice and led to an increase in cardiovascular and psychosocial morbidity.

Our Cochrane Review has shown that there is a need for further research to demonstrate why  exercise benefits disordered cardiovascular  physiology and to establish whether the  multiple theoretical benefits of exercise training  can translate into improved clinical outcomes.

All authors of Cochrane systematic reviews are now expected to use the Cochrane Risk of Bias tool (ROB2) to assess the risk of bias in any  randomized controlled trials they identify, to help people understand the trustworthiness of the findings. This was the first Cochrane Review to use ROB2 methodology.

Read the Cochrane editorial on ROB2

This post first appeared in the March 2021 BHI Newsletter