Bringing precision medicine to heart failure care

Written by:

Kenny Hansson

Head of Bioscience Cardiovascular, Early CVRM

Benjamin Challis

Head of Translational Sciences and Experimental Medicine, Early CVRM

Bringing precision medicine to heart failure care
Precisely targeting the underlying molecular cause of an individual patient’s disease in heart failure is a radical change from current clinical management paradigms. A growing understanding of the genetic drivers of heart failure are laying the foundations for precision medicine in a disease affecting 64 million people worldwide.1

At AstraZeneca, we are collaborating with other leaders in precision medicine to identify novel biomarkers to guide and treat life-threatening diseases of heart muscle, such as dilated cardiomyopathy (DCM) and the inherited muscle wasting condition, Duchenne muscular dystrophy (DMD).

Targeting impaired heart muscle contraction
Among the genetic drivers of the stretched and weakened heart muscle seen in 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, but this mechanism has proved hard to target with conventional drugs.

Now, encouraging laboratory data, to be presented at the Heart Failure 2021 congress, demonstrate 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. 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. Pre-clinical studies are now underway to further investigate such a therapeutic strategy as both a personalized medicine and as a more generalised treatment for patients with heart failure with reduced ejection fraction.

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.

Safety issues have limited developments with gene therapy to correct the defective dystrophin gene in the skeletal muscle of affected individuals, and progress with gene therapy targeted at heart muscle has been even more limited.3 However, using our well established CRISPR-Cas9 gene editing expertise, tour teams are investigating removing faulty sequences from the dystrophin gene, and to use 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 AstraZeneca’s 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.


References

1. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1211-1259.

2. Grote Beverborg N, Spater D,Knoll R, et al. Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy. Heart Failure 2021 Congress.

3. Xu L, Lau YS, Gao Y, et al. Life-Long AAV-Mediated CRISPR Genome Editing in Dystrophic  Heart Improves Cardiomyopathy without Causing Serious Lesions in mdx Mice. Molecular Therapy. 20189 27(8): 1407-1414.

4. Povysil G, Chazara O, Carss KJ, et al. Assessing the Role of Rare Genetic Variation in Patients With Heart Failure. JAMA Cardiol. 2021;6(4):379–386.



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