Meet the CureHeart team

“I'm a Professor of Neuroscience at the University of Oxford. My background is in medicine and neurology, but I've largely spent the last 25 years of my career in drug development. This has mostly been targeted at neuromuscular diseases. I focused a lot of my efforts on Duchenne muscular dystrophy (DMD). And then as that has been more successful, we've worked on related diseases.”

Professor Wood makes this sound simple. In reality, he was integral to the development of the first disease-modifying drug for DMD, which was approved in 2016. He has also launched 5 companies, been involved in the development of multiple therapies and made substantial contributions to medicine across several neuromuscular diseases.

Admirable, but how does this translate to genetic cardiomyopathies – the inherited heart muscle conditions that affect over 30 million people across the world?

“DMD mostly affects skeletal muscle” he explains, “but it also affects the brain and the heart. So without being a cardiologist I've always had an interest and tried to develop drugs to treat the heart because of its involvement in these neuromuscular diseases. I've actually had several research grants over the last 20 years from British Heart Foundation (BHF).

These links into heart medicine at the University of Oxford mean Professor Wood has had a long working relationship with BHF Professor Hugh Watkins - head of the CureHeart programme and one of the world's leading lights on genetic cardiomyopathies.

“Hugh and I were talking about the possibility of a collaboration years ago, but the timing wasn't quite right. Then came BHF's Big Beat Challenge and its promise of £30m. We knew that winning that competition could provide transformational support from BHF. By this time, knowledge of the genetics of cardiomyopathy had come on, the therapeutic technologies had come on, and developing a therapy now seemed possible.”

The treatment Professor Wood is talking about could be CureHeart's first therapy to reach clinical trials. Unlike the gene-editing cure also being developed, this treatment will use a technology he has already employed to develop drugs for muscular diseases. This technology is already used in 20-30 drugs benefitting people right now across the globe. In short, it's a technology that could fast-track a revolution in the care of genetic cardiomyopathy.

“Antisense oligonucleotides (ASOs) are short, DNA-like molecules, that target specific genetic sequences. But DNA is rapidly broken down when it is free in our body, either in the bloodstream or inside cells, so we alter the properties of these ASO molecules to make them more like a drug. This means they can be injected into the bloodstream and carried around the body to where they are needed, without being broken down first.”

Our DNA contains genes which are the master instruction manuals for building proteins in our cells. When the cell needs to build a protein, a copy of the instructions for that specific protein is made. ASOs target these copies for destruction without affecting the master instructions in the DNA.

“The majority of ASOs used in medications modify how a gene’s message is used, to overcome problems caused by a mutation in that gene. That’s where I have contributed to several drugs for muscular dystrophy, and one for muscular spinal atrophy. Another ASO option is to turn a gene’s message on or off. There are very few examples of silencing a gene in the heart, and that’s exactly what we’re doing in CureHeart.”

A spelling mistake (called a mutation) in a single gene causes disease in many people with a genetic cardiomyopathy. Because we inherit a copy from each of our parents, it is often possible to live without one of them. The problem is that the protein made by the mutated gene not only doesn’t work, but may also actively interfere with the healthy version. Professor Wood and the CureHeart team aim to develop ASO treatments that only target the instructions that contain a spelling mistake, and label them for destruction. If there’s no mutated instructions, there will be no disease-causing proteins.

This opportunity is not without its difficulties, as Professor Wood explains: “the majority of ASO-type drugs that are currently approved work in the liver. If you put one of these drugs into the body it reaches this site very easily, so there's been quite a lot of progress over the last 10 years. But nothing like this has ever been successfully done in the heart.

“We also need to modify the ASO to stop it being broken down in the body before it can do its job. But if you change it to make it bullet proof, it may be less effective at the job we need it to do. So we have to understand where that balance lies.

“The ASO also has to be incredibly specific to the instructions with the spelling mistake. We need it to remove enough of these instructions to stop the disease, but not affect the healthy instructions at all. Combining that specificity, the stability to not be broken down too quickly, and a treatment that only affects the heart – it’s never been done before. It’s completely unique and a huge challenge.”

Despite the hurdles to overcome, Professor Wood sees real potential in this approach. “It's a very mature technology, we know a lot about how to develop these ASO drugs. We also know a lot about how to make them safe. People should think about them more like everyday drugs, compared to the gene-editing approach which could be a permanent cure, and therefore is very tantalising but also comes with more challenges that the team are addressing.

“The ASO treatments aren’t permanent, you wouldn’t have long-term effects if you stopped taking them. Ideally it would be given like an insulin injection either at the doctor’s surgery or even self-administered at home. We don’t know yet how often the treatment would need to be repeated, but some of the ASOs already used for other conditions only need administering every 6 to 12 months.

“We’d start by treating people who already have symptoms, but in time, we hope this could be safe enough to be given as a preventative. We’re not quite there yet, but ideally this would be a drug you took every few months, by very simple means. It would get into the heart and prevent the production of faulty proteins, so that people who carry disease genes could take this ASO treatment and never develop symptoms at all.”

It sounds like science fiction, but Professor Wood is bringing years of expertise to the international dream team of CureHeart researchers. Gene-silencing treatments for genetic cardiomyopathy could be just around the corner.

“I’m not from a family of scientists,” says Jack, “But I latched on to science when I was in high school in Minnesota. I focussed on chemistry and maths as an undergraduate but became much more excited by the promise of biological therapeutics, and so shifted gears for my PhD to work on gene editing technologies.”

Jack couldn’t have picked a better place to undertake his training. He works in the lab of Professor David Liu, one of the world’s leading gene editing experts.

Reflecting on his team, Jack says, “It’s a fantastic assembly of scientists. PhDs last five or six years here, rather than the three or four in the UK, and I just started my fourth year. I’m at the halfway point in my studies, and every day, it feels like we’re branching into new avenues of discovery.

“We all benefit from each other’s work; a lot of optimisation spills over from one project to another. So, as a colleague is developing a system, I can say, ‘OK, let’s work together to include this discovery in my work.’ It’s really exciting to be surrounded by so many experts and benefit from so many perspectives, especially starting from a young age.”

Jack may be young, but his field is younger still. Professor Emmanuelle Charpentier published a monumental discovery in 2011. In 2020, Professor Charpentier, along with Professor Jennifer Doudna, received the Nobel Prize for harnessing a bacterial tool capable of chopping up the DNA of invading viruses. This tool, called CRISPR/Cas9, combines molecular “scissors” capable of cutting out DNA with a guidance system that specifies which sections of DNA are to be cut.

Since then, the field has grown exponentially, with increasingly engineered versions improving on the original. Now, versions of CRISPR/Cas9 include base editors capable of changing a single letter of DNA and prime editors capable of changing a whole sequence.

“The CRISPR/Cas-based techniques we’re currently using were popularized around the time I was graduating high school,” explains Jack, “But since then, the platform has gone through six or seven monumental upgrades, yielding better editors all the time. Now we’re looking to see how we can tweak existing discoveries or start from the ground up to design new ones to suit particular diseases.”

As our understanding of these gene editing systems has progressed, so too has our ability to modify and tailor these tools for various applications. Scientists now have more ways to modify gene editing tools to be more efficient, precise, and, in some cases, more compact. The ability to optimize along these various parameters is especially critical for therapeutic applications of gene editing to treat or potentially cure human genetic diseases.

“In around a decade, we’ve gone from being able to change perhaps ten parameters to billions. You could waste a lot of time trying to screen billions to trillions of these optimisations. That’s where I can draw on the years of expertise our lab has gained, which helps me to navigate that landscape.

“Initially, the field had to poke around in the dark, but now there are massive data sets that allow us to make quicker and more informed decisions. We can design an editor that has the characteristics we want and is capable of targeting a specific change in the DNA. But to reach that end product, we have to go through a multi-stage selection process.

“We rule out sub-optimal options at each stage, iteratively honing our strategy through screening thousands of options until we settle on a final set of editing tools with the best combination of qualities for our particular application. After choosing an optimal variant, we make sure they behave properly in mice and cells derived from human patients with cardiomyopathies.”

Jack’s work in tailoring gene editors is a critical undertaking as the CureHeart team collectively work towards developing cures for inherited heart muscle diseases.  To be successful as medicines, gene editors must be precise, efficient, and capable of safe delivery into cells. Given that inherited heart muscle diseases can arise from various mutation types across different genes, the ability to tailor gene editing tools is critical.

Professor Liu’s lab is one cornerstone in the multinational collaboration that is CureHeart. Researchers from groups thousands of miles apart are working together to stand the best chance of finding cures for inherited heart muscle diseases.

“It’s impossible for a single person to be an expert on all parts of a given project, so it’s important for experts in gene editing technology to work closely with experts in disease pathology or human genetics.

“That’s where the Watkins group and others across the pond have been very good. They can identify and prioritise faults in the DNA of people living with these conditions. We also work with Christine and John Seidman’s group here at Harvard to devise gene editing strategies, which they help us implement.

“Coordinating collaborations across continents really gives you a breadth that you wouldn't get in many other fields. And that's something that I always appreciate, and our CureHeart updates are always very exciting to see.

“As an individual lab, you can fixate on one method for solving a problem. But when you zoom out you can hear from all these collaborators who can inform future research and go about solving the problem in different ways.”

“Novel approaches to edit the genes associated with cardiomyopathies and deliver these editors to human cells offers numerous possible therapies we did not think possible just years ago. How we decide to prioritize and implement each new discoveries into our therapeutic designs will be critical for the success of the project at large. CureHeart—representing a unique collaborative of engineers, biologists, geneticists, and clinicians —both stimulates world-class research to cure cardiomyopathies and enables critical evaluation of the scientific and regulatory pathways for advancing our discoveries to the clinic.”

For people living with a known DNA fault, precise editing of a short stretch of faulty DNA could halt or even reverse the symptoms of their inherited heart muscle disease.

Developing this therapeutic strategy is not trivial. Editors must only act in the heart muscle cells, and only edit a very specific region of DNA. As there are many different mutations leading to these conditions, a single gene editor can’t cure everyone. Nevertheless, Jack is excited by the potential his field offers.

“There’s great hope for the future of genome editing technologies, and CureHeart takes a very practical approach to finding use for them in treating cardiomyopathies. We explore a broad range of the newest technologies we feel are most promising, and ground them in what we can currently test in relevant models of human disease. We don’t want to optimise something that won’t be well received as a human therapeutic or won’t scale well to industry-level production demands.

“The CureHeart team’s approach to developing multiple therapeutic lead candidates, both genome editing and more traditional approaches, is one that can realistically change patients’ lives in the near-term and be a linchpin for the future use of precision genome editing to correct the underlying cause of cardiomyopathies.”

I started my career in Sydney, where I studied medicine and practised as a junior doctor. Right from the start I wanted to experience research too. I decided to come to Oxford for a placement during my medical degree, because there’s nowhere better for meeting clinician scientists: those who practise medicine and also conduct research. While in Oxford I spent more and more time in the genetics clinics, and had the chance to see Professor Hugh Watkins’ inherited heart conditions clinic, but I never thought I’d come back as his PhD student.

My time in Oxford was fantastic, but I had to go back home to finish my medical degree. I loved being a doctor and particularly like talking to patients. You can have a huge impact on each of their lives, not just through diagnoses and treatments, but also just by listening if they need someone to listen. That's the kind of approach I try to take in my clinical care and I think it makes you a better doctor.

No matter how much I enjoyed the clinic, I wanted to stay involved in research. I guess what I’m doing is unusual, because I’m trying to develop my training in both quite early on in my career. This means I’m not a clinician who's come to science, or a scientist who's come to medicine. I wanted to have both from the start because I think it can be really valuable to apply a clinical lens to science and a scientific lens to medicine. I applied for a Rhodes Scholarship and spoke to Hugh about coming back to Oxford.

I was successful, and suddenly I was doing the dream PhD in one of the best labs in the world for studying genetic diseases affecting the heart. I was really lucky to join CureHeart just as it started, meaning I had the chance to contribute to the project right from the beginning.

Our aim is to develop cures for inherited heart muscle diseases, or ‘genetic cardiomyopathies’, which stop your heart muscle working as it should. They affect around 30 million people around the world, leading to heart failure or sudden cardiac death. The problem stems from mistakes in your DNA. These mistakes can affect different genes, which are the blueprints for how to build the molecules that grow and run a body.

Lots of different mistakes in lots of different genes can cause genetic cardiomyopathies, but we can think about them in two categories: mistakes that mean a molecule is built but defective, and mistakes that mean not enough of a molecule is made.

If the problem is that not enough of a molecule is produced, we can potentially treat the disease by boosting production. That’s what I’m trying to do in my research. If I can show that we can boost production of molecules made by one gene, then we could apply the same technique to boosting production of molecules from other genes too. This could mean that people whose cardiomyopathies are caused by mistakes in completely different genes could be treated with the same technique.

A lot of my work at the moment is about growing cells with DNA mistakes seen in real people with genetic cardiomyopathy, and making sure they behave in the lab as they do in the body. It’s a really important foundation to build the rest of my PhD work on. I find consistency is the key, and I’m in the lab at the same time every day to treat the cells and keep them happy. The project is in its early stages, but it is going well so far.

I love genetic medicine and cardiology, and found the clinical side really interesting. Now, I have the chance to be part of the research too, in a project that could translate to help patients soon. I find that so exciting, especially coming from a clinical background, where I know how life-changing it can be when someone gets the right treatment.

The work can be very busy, but I love it and I think I gain a lot of inspiration from day-to-day role models. I had an amazing GP supervisor in Medical School who always had time for his patients and showed me how seemingly small kindnesses can hugely impact on patients. Similarly, I meet people in the lab who are so dedicated to their work, and have such insight, that you can’t help but be inspired.

I also get to work with Hugh Watkins and the other inspirational scientists in the CureHeart team. These are researchers who have built incredible careers by pairing their clinical and scientific work so effectively. Although I have a long career ahead of me, I’d like to follow in their footsteps, and I feel that CureHeart is helping me towards that goal.

Professor Hugh Watkins (University of Oxford) and Professor Christine Seidman (Harvard Medical School)  

Hugh and Christine are cardiologists and experts in the genetics of inherited heart muscle diseases and the care of patients who live with them. 

Both of their labs have produced pioneering work in this area – often in collaboration – having led the discovery and understanding of mutations causing inherited heart muscle diseases. Their findings have resulted in the development of diagnostic tests that have since been widely adopted in clinical practice, with significant impact on the lives of patients and their families. 

Professor Jonathan Seidman (Harvard Medical School)

Jonathan is a geneticist and computational biologist who co-directs a laboratory with Professor Christine Seidman and has co-led their ground-breaking research on the genetics of inherited heart diseases. 

Professor Stuart Cook (National Heart Centre Singapore)

Stuart is a clinical and molecular cardiologist. He is known for his important discoveries towards understanding the process of thickening and scarring of heart muscle, known as cardiac fibrosis. 

Professor Eric Olson (University of Texas Southwestern Medical Centre)

Eric is a world-leading expert in muscle biology. He has led important discoveries in heart regeneration, and the correction of gene defects in other genetic muscle diseases such as Duchenne muscular dystrophy. 

Professor Matthew Wood (University of Oxford)

Matthew is an expert in genetic therapies for neuromuscular diseases. His work with the UK Nucleic Acid Therapy Accelerator and industry collaborations will give access to new technology and appropriate treatment options for clinical development. 

Professor David Liu (Harvard University)

David is a chemist globally renowned for developing revolutionary gene editing technologies. His laboratory will lead work to adapt his pioneering method of base editing and prime-editing technologies to make safe and precise corrections in the faulty genes that contribute to cardiomyopathy. 

Professor Luk Vandenberghe (Harvard Medical School)

Luk is a molecular biologist with expertise in the delivery systems of gene therapy. He will provide expertise in the viral delivery technologies to target gene-editing tools specifically to heart muscle cells. 

Insight from patients will be central to CureHeart’s aim of delivering safe and effective therapies. From the start, scientific progress will be guided and followed by networks of patients suffering from inherited heart muscle diseases on both sides of the Atlantic.

Cardiomyopathy UK

This specialist charity, led by Joel Rose, supports people in the UK who live with heart muscle diseases. The charity will lead patient advocacy for CureHeart in the UK.

Find out more about Cardiomyopathy UK's role in the CureHeart project.

Wendy Borsari

Wendy is the Lead Patient Advocate for the Sarcomeric Human Cardiomyopathy Registry. She is a cardiomyopathy patient with extensive experience in patient advocacy in research and will ensure the involvement of patients and their families in the United States.

This Panel comprises international leaders in relevant areas of science, medicine and health innovation from both academia and the biopharma industry and will provide independent overview and advice to support the CureHeart team’s progress towards achieving their bold ambitions.

The Panel is chaired by Sir Patrick Vallance, who helped the UK government navigate the COVID-19 pandemic as the Government Chief Scientific Adviser and also chaired the main selection panel of BHF’s Big Beat Challenge competition which CureHeart won. He brings into the role a lifetime of scientific leadership experience from academia, industry and government.