ORIGINALLY PUBLISHED:
02 July 2021
Written by:
Head of Bioscience Cardiovascular, Early CVRM, AstraZeneca
Head of Translational Sciences and Experimental Medicine, Early CVRM, AstraZeneca
Being able to precisely target the underlying molecular cause of an individual’s disease in heart failure would be a fundamental change from current clinical management paradigms which rely mainly on clinical signs and symptoms. A growing understanding of the genetic drivers of heart failure is laying the foundations for precision medicine in what is a highly heterogeneous disease affecting 64 million people worldwide.1
At AstraZeneca, we are collaborating with world-leading experts to identify novel targets and biomarkers to discover and develop precision medicine in life-threatening diseases of the heart muscle, such as ischaemic cardiomyopathy (ICM) and idiopathic dilated cardiomyopathy (IDCM) and the inherited muscle wasting condition, Duchenne muscular dystrophy (DMD).
Identifying molecular fingerprints of heart failure
By harnessing the power of artificial intelligence and omics analysis, our aim is to unravel the complex disease biology of heart failure at the molecular level in individual patients. We are using machine learning to analyse large quantities of gene expression data from cardiac biopsy samples and stratify patients with heart failure into novel molecular sub-classes, irrespective of their clinical signs and symptoms. These insights have revealed that the ‘molecular fingerprints’ shared by patients in these homogeneous sub-classes are unrelated to the ICM and IDCM classification generally used in heart failure diagnosis. We are starting to link sub-class-specific gene expression profiles to dysregulated molecular pathways and processes indicative of distinct disease biology across the different sub-classes. We are also using gene expression data from past trials, linked with clinical data, to see whether they actually correspond to clinically meaningful phenotypes. Using all this new information, we plan to identify novel therapeutic targets that will form the basis of a precision medicine approach to the care of patients with different molecular sub-classes of heart failure.
Targeting impaired heart muscle contraction
Among the genetic drivers of the stretched and weakened heart muscle seen in dilated cardiomyopathy (DCM) is a mutation in the gene for phospholamban (PLN), a key protein for cellular calcium regulation. Excessive PLN activity is linked to faulty calcium cycling and impaired heart muscle contraction and relaxation. Whilst a key target for drug discovery, so far the structure of the protein has proved hard to target with conventional drugs.
Encouraging laboratory data have demonstrated the potential of antisense oligonucleotides (ASOs) to target PLN activity in DCM.2 The research, carried out in collaboration with Ionis Pharmaceuticals and international heart failure scientists at University Medical Center Groningen and Karolinska Institute, shows that ASOs – strands of synthetic DNA – can be used to deplete the formation of PLN linked to DCM.
In a preclinical model encoding the PLN R14 gene deletion, we used ASOs to reduce PLN activity, prevent cardiac dysfunction and improve survival.2 We also saw encouraging results with ASOs in other heart failure models, making it a promising precision medicine approach in cardiomyopathy and possibly other forms of heart failure.
Gene editing in DMD
Advances in the care of children born with DMD have improved the outlook for those living with the disease, but progressive wasting of heart muscle can lead to life-limiting DCM and heart failure when individuals reach their 20s.
Progress with gene therapy that targets the heart muscle has been limited.3 However, using our well established CRISPR-Cas9 gene editing expertise, our teams are investigating the removal of faulty sequences from the dystrophin gene, and using adeno-associated viruses to efficiently deliver targeted treatment into heart muscle cells. If this works, there is also the potential to extend this approach to other inherited diseases.
Learning from rare genetic drivers of heart failure
Through in-depth research into genetic drivers of heart failure we aim to advance understanding of why some patients with gene mutations develop the disease while others don’t.
In a recent collaboration, scientists at our Centre for Genomics research identified an increased frequency of rare variants in the cardiomyopathy gene, TTN, among 5000 people with heart failure compared to over 13,000 healthy individuals.4 In addition, variants were found in 21 different genes linked to cardiomyopathy, irrespective of whether patients had heart failure with preserved or reduced ejection fraction – the main clinical categories of the disease. This means that, although patients may go to their doctor with different symptoms, their underlying genetic drivers may be similar, with environment and comorbidities playing a bigger role than previously thought.
Right patient, right drug, right time
By exploring subtle genetic mutations, variations in gene expression and gene-environment interactions in more common forms of heart failure, there is a potential to stratify patients for clinical trials of biomarker-guided targeted treatment. Drawing on innovations in clinical trial design, and utilising an expanding toolkit of novel drug modalities we are aiming to target almost any type of underlying disease biology in heart failure so the right drug is available for the right patient at the right time.
