Cardiovascular disease (CVD), in all of its forms, is the number one killer in the UK, Europe and the US. More often than not, it has long-term effects, including an enlarged, damaged and less efficient heart muscle which naturally leads to other disabilities and a notably decreased quality of life.
While the affected person certainly bears the burden of such diseases, society as a whole does as well. In a 2006 study, researchers found that CVD cost the UK economy £29.1 billion in 2004, with healthcare costs accounting for 60% of the total. This number is even higher in the US, with healthcare costs associated with CVD just under $300 billion per year.
It’s worth mentioning that CVD encompasses all diseases and conditions that affect the heart or blood vessels. But the focus here is on coronary heart disease, which often results in heart attacks and heart failure.
Coronary Heart Disease
According to the NHS, patients suffering from coronary heart disease can be prescribed a combination of medications that help to reduce blood pressure, lower cholesterol or widen the arteries or blood vessels. Unfortunately, many medications have negative side effects and, given that they must be taken long-term, can be costly.
Blocked arteries could require interventional procedures, including bypass grafts, angioplasty and even transplants. Success rates depend on numerous factors, including age and lifestyle and, in the case of transplants, there’s understandably a higher demand than there is supply.
What About Prevention?
Currently, prevention of CVD is directed at lifestyle changes. The Mayo Clinic recommends a healthy diet, exercise and stress management for heart health. Of course, their number one recommendation is to stop smoking.
But what about medical prevention? It’s clear that there’s a need for preventative methods that will limit ischemic injury and regenerate tissue that’s been damaged before the patient suffers a heart attack, heart failure, or another life-threatening condition.
Regenerative Medicine and the Future of Treatment
Scientists around the world are working tirelessly to turn research into effective treatments and, in the past decade, we’ve witnessed a surge of scientific enthusiasm for regenerative medicine. And it’s well and truly a group effort as it requires scientists and clinicians with different expertise, from cardiology to cell biology to engineering.
California’s Stem Cell Agency has awarded over $202 million to researchers looking into heart disease, in particular how to create stem cells that can replace the damaged heart muscle and restore the heart’s ability to efficiently pump blood around the body. Other researchers are focusing more on tissue engineering technologies by building artificial scaffolds in the lab, loading them with stem cells and placing them in the heart with the goal of stimulating the recovery of the muscle.
In terms of prevention, Cardiology News reported Dr. Andre Terzic of The Mayo Clinic believes that regenerative medicine will protect against chronic disease and help match healthspan with life span in aging patients.
And there is Celixir, a company which is developing its own life-saving therapies, including heartcel, an immunomodulatory progenitor (iMP) cell therapy for the treatment of adult heart failure, which has been approved for clinical trials in both the UK and the US.
EU Phase II trials were completed back in 2016 with overwhelmingly positive results. Most notably, 100% of patients were free from any major adverse cardiac event (MACE), 30% of patients experienced improved heart function and 50% of patients experienced improvements in their quality of life.
Over the next several years, we should see more and more regenerative therapies leaving the research pipeline to be used in clinical environments and, in time, we can hope that deaths and healthcare costs associated with CVD will decline thanks to new treatments.
Deadly heart disease
Heart disease, even while being curable comes as one of the biggest threats to one’s health in today’s modern world. Being one of the biggest causes of death around the world, heart disease kills one in six men and one in six women, and largely impacts the health of around 7.4 million people in the UK alone.
Generally, when a person experiences heart failure, the organ often comes up with scars which further complicate the situation each and every passing day. Until now, the damage caused by heart disease has been considered irreparable. But thanks to the continuing efforts in the field of regenerative medicine, the healing of the heart tissue is fast becoming a real possibility.
Celixir the technology platform
Celixir, the company researching regenerative medicine for life, was founded by Nobel laureate Sir Martin Evans and Ajan Reginald, an MBA graduate from Kellogg School and former chief of emerging technologies for the pharma giant Roche.
‘I always had this interest in innovation and how you invent stuff. And I think the pharmaceutical industry is probably the best example of how you monetize an invention.’
(Ajan Reginald quoted in one of his interviews to a renowned online weekly.)
Ajan and Sir Martin met when they were both speakers at a conference panel back in 2007, and after two years of collective efforts and innovative approaches to stem cell research, they launched Celixir under the business name, ‘Cell Therapy Ltd’.
Ajan Reginald defines Celixir’s regenerative medicine techniques as a ‘technology platform,’ which can be compared to the so-called ‘Internet of Things,’ for instance.
“That’s a platform technology that allows lots of devices to communicate with each other across multiple platforms. Our core technology is the ability to identify medicine that can regenerate parts of the body that until very recently have been irreparable…[it] allows us to look at the cellular damage that is in a scar, to identify what has gone wrong and design a medicine that may fix it.”
Today Celixir has more than 20 specific medicines in the pipeline, but its onus is on finding a cure for heart disease. In particular, the above-mentioned heart treatment process, which has been in the market for the last two years.
This is how the pharma industry works. Each of the products goes through a series of research and clinical trials before getting ‘ready to use’ in public. The process has been the same for decades, but still comes as a big challenge for every startup that has to secure enough investment funding before getting into the same business.
“The UK is not a brilliant place to find that sort of risk capital, Europe is worse. The US was better but the market conditions aren’t great at the moment,” says Ajan, though his company Celixir has managed to secure money from all of those regions, along with Asia, where it bagged a contract worth £12.5m from Daiichi Sankyo, which secured the rights of distributing the heart medicine made by the company in Japan.
So if you’re thinking of putting your money into a long-term pharmaceutical venture, then one created by a Nobel Prize winner sitting at the very top is certainly going to be your best bet.
But that isn’t Celixir’s only investment. They have also raised £691,000 via equity crowd funding website Crowdcube. Ajan said in his statement to potential investors:
“Nearly all of us know somebody who’s affected by one of these chronic diseases and we think of regenerative medicine as being for everybody so we thought crowdfunding was a way to allow anyone to participate in [this] innovation.”
The agile nature of startups
If we look into the current situation, the pharma industry is dominated by some of the biggest names in medicine such as Novartis, Roche, Pfizer and the UK’s very own GSK. Each of these companies employs tens of thousands of people, which when compared to Celixir’s tight, but mighty team of 46, should come as a surprise that Celixir have achieved so much in such a short space of time.
Ajan says that even though the big names have an edge in terms of better marketing and more established technologies, the small firms, such as his own, have an upper hand at the innovation part. Small startups have the ability to be agile, to test new ideas quicker, to make turnarounds faster, they aren’t held up with processes and bureaucracy like the big companies.
Ajan says, “the kind of stuff we’re good at – new thinking, new ideas, the things that need a different approach where you need small, innovative teams. The field of regenerative medicine is all quite new and therefore if you want to have a significant breakthrough with a new technology that probably happens in small companies like ours. It’s about focus, we’re highly focused in a field of technology and we don’t do anything else.”
Celixir – a British company
Ajan is incredibly proud of the fact that Celixir is achieving all this in the UK. “We’ve developed it in Britain, we’ve funded it in Britain, we’re hopefully going to bring it to market in Britain and we’ve got lots of foreign direct investment into our company.”
As Ajan says, there’s something unique about the innovation culture here in the UK. “We quietly get on with world-class science. We quietly get on with earth-shattering medical innovation. In the US they have great innovations but everybody has to jump up and down and tell you all about it. That’s probably for me the most important thing about us. We have a culture of combining that excellence in science and that belief that we can do things that nobody else can do, but we do it with a certain degree of humility.”
But will he be selling this to a foreign buyer if there’s a right price on board?
“There’s no need for us to do it, we’re not looking for that. But if a big company did come along that was really good for my shareholders… and we could treat ten times as many patients, of course, we’d consider it.”
A typical day in Ajan’s life
So just what does a typical day look like for the founder of a world class, regenerative medicine startup?
Well, says Ajan, I clear my inbox before going to sleep, but as we work with our clients in the US and Japan, I still get about 30 or 40 emails by 6am in the morning. I try to finish them all by 6:30am. I play hockey for the England Masters team (for those aged 35 to 50) so I need to go through a fitness regime which involves hardcore training in the gym until 7am. This gets followed by some quality time with my son until he goes to nursery.
That provides a chance for everyone to catch up with their emails – generally, the emails which I get generates a lot of work for me and my team. I reach my office by about 8:30am and try to finish up with all the work by 6:30pm so I can get home and put my son to bed by that time.
My usual working day is split into three parts. One third of that goes into checking the progress of specific projects. Another third is reserved for meeting with all my colleagues and subordinates. I conduct one to ones with everybody that reports to me on a weekly basis. Even though it’s quite hard, it’s really important as the business we are in is quite complicated and cutting edge so we have to talk about it frequently.
The third part I always keep free because there’s always something important coming my way and I must pay attention to it with immediate effect. It may be reviewing the FDA filing, having a look at analysts’ reports or something else – it’s a bit like how Mark Zuckerberg still gives a part of his day to programming. It’s quite important as it keeps your feet on the ground. I also travel quite often – including my weekly visit to Europe, to Japan probably once a month and the US every two months.
Celixir and the British Heart Foundation
The British Heart Foundation announced in the summer of 2019 that heart failure could be treated with stem cells. This announcement was welcomed gladly by the team at Celixir who are dedicated to researching the use of stem cell based therapy to treat heart failure too.
Cambridge-based researchers found that by transplanting heart muscle stem cells alongside other supportive cells from the outer wall of the heart, into the area of damaged heart tissue, the stem cells could potentially help the damaged heart to recover after becoming injured following a heart attack.
As mentioned earlier, cardiovascular disease is the number one cause of death around the world, taking over 17 millions lives annually. Heart failure affects over 25 million people worldwide, and in the UK alone, there are approximately 7.4 million people who live with heart disease, and just under 1 million living with heart failure.
What is heart failure
Heart failure is a syndrome of the heart being impaired. Heart failure is not caused by one specific condition, nor are the signs and symptoms of heart failure alike for each individual person.
Common signs and symptoms of heart failure:
- Shortness of breath
- Swelling in the lower legs
- Irregular heartbeat
- Sudden shortness of breath
- Coughing pink, foamy mucus
- Chest pain caused by heart attack
Heart failure doesn’t tend to happen out of the blue, it is usually a result of other illnesses, conditions and issues that have weakened the heart, damaging it and preventing it from working efficiently. Heart failure is not always a result of a weakened heart, however, it can also occur following the heart becoming stiff (caused by high blood pressure).
Other common causes of heart failure:
- Coronary artery disease – this is one of the most common forms of heart disease that causes heart failure due to a buildup of fatty deposits in the arteries, reducing blood flow, leading to a heart attack.
- High blood pressure – hypertension causes the heart to work harder than usual to pump blood around the body, which over time can result in overworking the heart muscle, making it stiff and ineffective at pumping blood.
- Damaged heart valve – heart valves prevent blood from flowing the wrong way through the heart, but when a valve becomes damaged, through coronary heart disease for example, the heart has to work harder to keep blood flowing the right way. Resulting in a weakened heart.
- Myocarditis – inflammation of the heart tissues, most commonly caused by a virus, result in the failure of the left side of the heart to work.
- Congenital heart defects – if the heart has never worked properly, over time it has to work harder to get the blood pumped around the body, leading to heart failure.
In any case, heart failure is the result of the heart’s inability to keep up with the regular demands the body places on it, rendering it unable to pump blood all around the body.
Heart failure typically begins on the left side of the heart, more specifically, it occurs in the left ventricle – the heart’s main chamber for pumping blood and spreads from there.
And the heart is not able to regenerate, like the liver. So once damaged, the healthy tissue becomes scar tissue, leaving patients with reduced cardiac function and can lead to heart failure.
The current treatment for heart failure
Heart failure is not something that typically can be treated overnight; heart failure is a chronic disease that currently requires lifelong management, to ensure the symptoms don’t worsen.
There are of course exceptions to this – for example, in the case of faulty heart valves, if replaced, the heart can return to normal function.
But for the vast majority of people living with heart failure, it needs to be treated with a combination of medications such as Beta blockers or ACE (angiotensin-converting enzyme) inhibitors, and in some cases the use of devices and/or surgery.
Surgical treatments can include:
- Coronary artery bypass – where the blocked artery in the heart is bypassed using other blood vessels.
- Valve repair – where the faulty valve is repaired to prevent blood flowing the wrong way, or an artificial valve replaces the damaged valve.
- Pacemaker – a small electrical device that is inserted into the chest or abdomen in order to control the heart’s beating rhythms.
But despite these treatments managing heart failure, none of them are able to slow the progression of heart failure, nor can they prolong life, and nor do they address the issue of the root problem, the actual cause of the heart failure – the loss of functioning heart muscle cells.
Because once heart muscle cells are lost, they cannot be replaced by the body.
Stem cells could treat heart failure
Stem cells are being researched to help treat heart failure in two ways. Firstly, the heart muscle derived stem cells can be used to research and test potential new drugs, and secondly, as a way to replace the damaged heart tissue.
Which is where the recent BHF research fits in. By introducing new, functioning heart tissue stem cells into the damaged tissue, they might be able to help the heart to recover following significant damage caused by, for example, a heart attack.
The problem of this approach up until recently has been that the transplanted stem cells have not survived beyond a few days following transplantation. And the Cambridge scientists have been looking into how to extend the life of the transplanted cells, recently finding epicardial cells to be supportive in helping the heart muscle stem cells to survive, to grow and to restore the damaged heart tissue.
Celixir itself received clinical trial application approval in January 2018 to initiate a Phase IIb human clinical trial using its Heartcel medicine, to help treat moderate to severe heart failure in adults.
Heartcel™ – Treating Heart Disease
Celixir is in the vanguard of cell gene therapy technology. This world leading biotechnology company, founded by Ajan Reginald and Nobel Laureate Sir Martin Evans, just keeps on delivering innovative solutions for seemingly untreatable ailments.
In its short 10 year existence, Celixir has fast become a powerhouse renowned for developing various stem cell therapies, and is acknowledged as being at the cutting edge of regenerative medicine.
As mentioned above, the team at Celixir have been working tirelessly, discovering over 20 tissue specific regenerative medicines, focussing on stem cell therapies and gene based therapies, all of which are (or could be) trialled to potentially treat currently incurable diseases, or aid in the better management of known untreatable diseases.
And it all began with heart disease.
Heartcel – the trial
Celixir set out to find a way to tackle heart disease, and with the help of the British Heart Foundation, they are currently conducting a human clinical Phase IIB trial of their cardiac regenerative medicine, Heartcel™.
This trial is underway at Imperial College London’s Royal Brompton hospital and is due to compete in 2020, with potential entry to market expected in 2021.
Heartcel™ has been developed to aid in the treatment of moderate to severe heart failure, a condition thought to affect over 20 million adults worldwide, currently the leading cause of death in Western Europe.
Readily available medicines have not proven effective at slowing this killer disease’s progression, nor are they capable of prolonging the life of patients with heart disease. Almost 45% of all patients admitted to hospital with heart failure die within the first year.
Which is why Celixir has placed Heartcel™ front and centre, as their lead investigational regenerative medicine.
Heartcel™ is a tissue engineered medicine made up of allogeneic immunomodulatory progenitor (iMP) cells, and has been designated by the European Medicines Agency as an advanced therapeutic product.
iMP cells have been engineered to help reduce scarring on the heart (a result of heart failure), and to regenerate the damaged muscle tissue in patients suffering with heart failure. Heartcel™ is currently administered during a coronary artery bypass graft, but delivery via catheter is in development in order to open up the treatment to include all heart failure patients and those with cardiomyopathy.
Heartcel™ – changing the landscape of heart disease
The results from the Heartcel™ Phase II trial that were presented at the 2016 International Society of Stem Cell Research Annual Conference clearly demonstrated that the Phase II study had not only met all of its endpoints, but that the initial results were statistically and clinically positive.
The results showed at the 12 month endpoint there was a 100% MACE (major adverse cardiac event) free survival, a 30% (on average) improvement in patients’ left ventricular ejection fraction, a 40% (on average) reduction in patients’ left ventricle scar size, and a 50% (on average) improvement in patients’ quality of life.
Even better, at a four year follow up, MACE-free survival rates continue to be 100% with imaging analysis revealing further scar reduction and a regeneration of heart tissue in over 70% of patients.
But Heartcel™ isn’t Celixir’s only product in the testing pipeline. Celixir’s team of world class scientists are working nonstop to bring to market other life saving regenerative medicines, including Tendoncel – a platelet lysate-based therapy, and Myocardion – a progenitor cells of mesodermal lineage (PML) therapy.
- Tendoncel. This off the shelf topical gel has been designed to be applied directly to the skin above the site of injured tendons to enable them to regenerate, negating the need for surgery. Tendoncel has had incredibly positive results following on from its Phase 2 testing trial, and has now entered a Phase 3 trial, which is currently underway.
- Myocardion. A progenitor cells of mesodermal lineage (PML) therapy. Myocardion is considered a follow-on regenerative medicine that has been produced for use in percutaneous coronary intervention and is clinical trial ready. It is being considered as a potential treatment for patients suffering with mild to moderate heart failure.
Stem cell research
Our bodies are made up of different types of cells, but out of all of them, stem cells are the most remarkable. Stem cells are distinguishable from all other types of cells as they have no specific speciality – they are capable of becoming anything, regardless of their source.
Stem cells can proliferate through cell division, with no limit, and with every new cell created, each cell has the ability to either become a specialised cell – from a red blood cell to a brain cell to an organ or bone cell, and everything in between, or remain an unspecialised stem cell.
Which makes stem cells incredibly unique and vital for all living organisms. In embryos, stem cells are the foundations from which the entire body is created, and in adults, stem cells replace lost, injured or diseased cells.
And it’s because of their ability to create life and to auto-renew that means stem cells have the potential to treat seemingly incurable diseases such as diabetes and cardiovascular disease.
Stem cells could be the difference between someone with a spinal cord injury spending the rest of their life in a wheelchair, or walking again. In short, stem cells have the potential to give life and hope where it seemed there was none.
Different types of stem cells
Embryonic stem cells – these are stem cells, as the name suggests, that come from embryos. Most embryonic stem cells are sourced from fertilised eggs that have been created through in vitro fertilisation (IVF). These eggs have been donated for research.
Non-embryonic (adult) stem cells – these stem cells are found in the body, in all tissues and cells, and can renew themselves to become any cell in that tissue or organ. The role of adult stem cells is to repair and maintain the tissue in which they’re found.
Induced pluripotent stem cells – as the name suggests, these are adult stem cells that have been reprogrammed to become like embryonic stem cells i.e. capable of becoming any type of cell. It’s not yet known what significant clinical differences exist between induced pluripotent stem cells and embryonic stem cells.
Cord blood stem cells – these stem cells are taken from the discarded cord of a newborn baby. Collecting cord blood stem cells poses no risk to the mother or the baby as the cord is harvested for these stem cells once it is no longer needed by the baby. Cord blood is important because it contains haematopoietic stem cells which are incredibly rare and normally found in bone marrow. These cells can make any type of blood cell – red, white and platelets. They’re the cells responsible for our blood production throughout the course of our life.
Amniotic fluid stem cells – stem cells derived from amniotic fluid may not be pluripotent, but there is increasing evidence that stem cells found in amniotic fluid are incredibly valuable, capable of being used in cell therapy and for regenerative medicine.
Why research stem cells
By observing stem cells throughout their life cycle, developing from stem cells into the final body part, researchers can learn how certain ailments and conditions develop.
As well as observing the development of stem cells, scientists can grow healthy cells in a lab and use them to replace damaged or diseased ones.
Researchers can even test new drugs on these lab grown stem cells to check for their safety and efficacy, before moving onto human drug trials. In particular, new areas of study have involved looking at the effects of drugs on induced pluripotent stem cells.
Conditions that might be treated with stem cell therapies
Spinal Cord Injuries
Spinal cord injuries are damage to the spine causing temporary or permanent reduction in its ability to function. Your spinal cord consists of 31 pairs of nerves that travel from your brain down your back, feeding different parts of the body, enabling the brain to give instructions to body parts, from your fingers to your toes, even your heart, bowel and lung function are all controlled by the spinal cord.
Spinal cord injuries can be caused by falls, diseases such as spina bifida, car accidents, sports injuries and much more. Spinal cord injuries can include a loss of muscle usage, being able to feel physical sensations or autonomic function. These symptoms occur below the level of the injury to the spinal cord and are either complete (i.e. complete loss of sensation) or incomplete (partial loss of sensation, with some function remaining).
At present, there is no way to undo damage that has occured to the spinal cord – the spinal cord can not repair itself. Although plenty of work and research is being carried out looking at nerve cell regeneration that aims to improve nerve function following a spinal cord injury. Current treatment involves preventing the condition from worsening.
In January 2019, Japan approved stem cell treatment for spinal cord injuries, which sees mesenchymal stem cells, extracted from the patients’ own bone marrow, injected intravenously, helping them regain some of their lost sensations and even movement.
A stem cell trial that is currently underway is a phase 1 clinical trial researching treatment for trauma induced spinal cord injuries. The FDA has already approved phases 2A and 2B for this trial, which will see randomise control crossover trials.
In the current trial, participants will receive intrathecal injections of adipose derived mesenchymal stem cells (cells that can be used to reduce the likelihood of cell death caused by the body’s inflammatory response to injury). If successful, the treatment would drastically improve patients’ lives, negating the need for them to undergo further surgery or require permanently implantable devices.
While it’s known that stem cell treatment can be incredibly effective in treating spinal cord injuries, it’s the how, when and why stem cell treatment works in spinal cord injuries that needs further investigation.
Approximately 10% of diabetes sufferers worldwide have type-1 diabetes. This equates to roughly 42.5 million people living with the disease globally. In the UK, type-1 diabetes sufferers number 400,000, with just under 10% of those being children.
For some sufferers of type-1 diabetes, they can manage the disease through lifestyle changes, but for most, they require daily insulin injections to keep their blood glucose levels in check. Type-1 diabetes, unlike type-2, can’t be prevented. And worst of all, it can occur at any age.
Not knowing what the root cause of type-1 diabetes was has plagued scientists for years, but now they understand that the destruction of beta islet cells inside the pancreas causes the disease.
And without knowing exactly what causes type-1 diabetes, has prevented scientists from finding a cure.
At present, patients with type-1 diabetes have to take immunosuppressant drugs to prevent the body from attacking the beta cells and simply replacing diseased islet cells with healthy ones (islet cell transplant) isn’t a cure. If left unchecked, diabetes can cause kidney failure, blindness, even heart disease and death.
Stem cell research has opened up a range of diabetes specific research including growing insulin producing beta cells in the lab, enabling better availability of the beta cells to be used in future research.
There is plenty of research trying to uncover a cure for diabetes currently, including encapsulation research, immunotherapy research, and regeneration research. There have even been successful experiments in mice showing that induced pluripotent stem derived beta cells can reverse the damage caused by diabetes.
So who knows, maybe a cure for diabetes is just round the corner, like there could be one for heart disease.