Your COVID Vaccine Could Be The Cure For a Heart Attack
That’s right! With the mRNA technology that powers Pfizer and Moderna vaccines, we can combine this with injectable hydrogels to promote cardiac regeneration.
The first organ to live, last to die. Before we were even born, at 6 weeks old, it was already doing its job; the job that it will continue to work hard at until we die. There is never a day off for this organ as it pumps continuously and provides all the tissues and organs in our body with blood and oxygen through a 60,000-mile network of vessels.
The heart.
Not only is the heart life-giving and vital, but it is more than just an organ. It represents emotion, affection, and love.
But this organ that works tirelessly with no breaks or days off sometimes breaks down. Cardiovascular diseases (CVD) are the leading cause of death worldwide, killing over 17.9 million people in 2019 [1]. That’s around the population of the Netherlands [2]! In the US alone, it accounts for nearly 1 in 4 deaths [3].
Table Of Contents:
- The DL On Heart Attacks
∘ The Standard Treatments for Heart Attacks - Regenerative Medicine and Tissue Engineering
- mRNA Therapeutics X Hydrogels For Cardiac Regeneration After An MI
- The Main Character: Messenger RNA
∘ Benefits of mRNA Therapies Vs. DNA
∘ Chemically Modified mRNA: The Solution To The Limitations Of mRNA
∘ Benefits of VEGF-A For Angiogenesis - The Delivery Mechanism: Injectable Chitosan-Collagen Hydrogels
- Conclusion
The DL On Heart Attacks
“You almost gave me a heart attack!”
It’s a common phrase that we use all the time whenever someone scares us, but it’s more than an expression. A myocardial infarction (MI), more commonly known as a heart attack, is when a part of the heart does not get enough blood, therefore not getting enough oxygen and nutrients [4]. An MI leads to ischemia, which means part of the heart muscle becomes damaged and dies [5]. The most common cause of an MI is coronary artery disease (CAD) [6]. CAD develops when the main arteries in the heart accumulate a buildup of fat, cholesterol plaques, and other substances that narrow and eventually clog the arteries [7].
In most cases after an MI, people recover and continue to live their lives. Depending on the time between the heart attack and treatment, some heart attack survivors are able to go back to their regular lifestyle, with a couple of adjustments in diet, exercise, and medication [8]. The heart is able to heal itself after an MI in several weeks by forming scar tissue around the damaged tissue area [9].
However, the scar tissue stays there for life and it is not like the regular heart muscle because it does not contract [10]. Excessive scar tissue on the heart reduces the heart’s ability to pump blood and adds extra strain to the remaining healthy heart muscle and may cause heart failure. This additional pressure on the rest of the muscle means that there is a higher risk for people with larger scars to have heart rhythm problems and sudden cardiac death [11].
The Standard Treatments for Heart Attacks
There are multiple treatments for healing the heart after a heart attack, and they vary depending on how severe the MI was.
Lifestyle changes: The development of CAD and eventually a heart attack can be caused by many factors including age, smoking, high blood pressure, obesity, high cholesterol levels, physical inactivity, high stress, and unhealthy diet [7]. All of these factors can cause a heart attack, so lowering the risk of reoccurring heart attacks can be done by making a couple of lifestyle changes. Changes like eating a low-fat and low-sodium diet, getting at least 30 minutes of physical activity, quitting smoking, and limiting alcohol intake can reduce the risk of another heart attack [12].
Medications: Sometimes, making lifestyle adjustments post-heart attack isn't enough. Doctors may prescribe medications like thrombolytic (helps dissolve blood clots), blood-thinning medications, beta-blockers to relax the heart muscle and make pumping easier, and ACE inhibitors to reduce stress on the heart and lower blood pressure [12, 13].
Procedures or Surgery: In severe cases, or when medication and diet are not enough, doctors will recommend procedures or surgery. Coronary angioplasty and stenting are when doctors will guide a catheter through an artery in your groin to the blocked artery to open up the blocked coronary artery using a balloon. Coronary artery bypass graft (CABG) surgery is sometimes needed to sow veins or arteries in place beyond a blocked or narrowed coronary artery which allows the blood flow to bypass the narrowed section [13].
Cardiac Rehabilitation: After a heart attack, cardiac rehabilitation or rehab will be necessary to help avoid future heart attacks. It’s designed to improve cardiovascular health post-heart attack. Rehab involves three main parts: exercise counselling and therapy, healthy living education, and counselling to reduce stress [14].
However, lifestyle changes, medication, and cardiac rehabilitation is mostly managing the symptoms of a damaged heart and preventing future heart attacks instead of tackling the damage that the MI already caused. Surgical procedures can better help restore blood flow to the ischemic area of the muscle, but open heart surgery is highly invasive, has a long recovery time, and there is a chance of dying during the surgery. There has to be something better, right? Well, there is…
Regenerative Medicine and Tissue Engineering
If you have been reading any of my previous articles, you would know that I am currently diving deep into Regenerative Medicine (RM) and all of its applications for a variety of diseases. Previously, I’ve talked about turning liver cells into pancreatic progenitors to cure diabetes, increasing the healthspan of humans with RM, and leveraging mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) to treat a variety of diseases.
For those who don’t know, regenerative medicine (RM) is a field of medicine that has the main goal of repairing or replacing damaged tissues and organs to establish or restore lost function. RM is an overarching field with 3 main subfields: Stem cells, gene therapy, and the main one we will be focusing on in this article, tissue engineering [15, 16]. Tissue engineering (TE) in the field of biomaterials development with the goal of restoring, maintaining or improving damaged tissues or whole organs. TE combines scaffolds, cells, and biologically active molecules to create things like artificial and 3D printed organs.
mRNA Therapeutics X Hydrogels For Cardiac Regeneration After An MI
After doing a ton of research into regenerative medicine for the past couple of months, I have come up with an idea that uses tissue engineering to repair damage post-MI.
Using chemically modified mRNA (cmRNA) and injectable hydrogels comprised of chitosan and collagen, doctors can inject the hydrogels containing the mRNA directly into the heart. Once injected, the mRNA can enter cells and produce human vascular endothelial growth factor-A (VEGF-A) to promote the production of new blood vessels and cardiac regeneration.
There are two main components of the solution: the mRNA, and the injectable hydrogels. Let’s dive deep into how it works.
The Main Character: Messenger RNA
The central dogma of biology states that DNA gets transcripted into RNA, then the RNA gets translated into functional proteins [17].
We all know about the double-stranded nucleic acid that is DNA. It’s the molecule that instructs all of the cells in our body to produce certain proteins. Then there is the end product, proteins. Proteins are made up of multiple amino acids and the functions of our bodies are usually carried out by proteins [18]. DNA cannot leave the nucleus of the cell, so mRNA is required to be the middle man to the ribosomes to create the proteins. mRNA is a single-stranded nucleic acid that transcribes a complementary strand from one strand of DNA [19]. It then swims over to the ribosomes, which is the protein-making machinery that reads the base pairs on the RNA strand and translates them into the corresponding amino acids [19].
Benefits of mRNA Therapies Vs. DNA
Recent studies have shown that mRNA could be an alternative strategy to gene therapy and tissue engineering, compared to the standard of DNA. Since mRNA carries out its mission outside of the nucleus in the cytoplasm of the cell, there is one less physical barrier compared to DNA because it has to enter the nucleus too [20]. In addition, mRNA does not carry the risk of insertional mutagenesis because it does not permanently insert itself into the DNA, and is only in the cell long enough to produce lots of proteins before it degrades [21]. mRNA also is able to transfect non-dividing cells unlike DNA, and since the cells in the heart stop regenerating early in life, efficiency would be low for DNA [22]. In the case of MI, while the production of beneficial proteins for an extended time period but not permanently, mRNA is the better choice.
Even though mRNA is a better option than DNA for cardiac regeneration, there are a few barriers that may limit the efficiency of mRNA. First, naked mRNA molecules are very unstable and in vivo, only have a half-life of 7 hours [22]. This means that it doesn’t last very long in vivo, limiting its effect. Second, it has innate immunogenicity and can easily be detected and degraded by immune cells and enzymatic responses [23]. Third, mRNA has a high molecular weight and negative charge density. The high molecular weight limits the delivery mechanisms that can be used to carry the mRNA. mRNA also has a negative charge density so it makes it very difficult for mRNA to enter the negatively charged cells [22].
Chemically Modified mRNA: The Solution To The Limitations Of mRNA
To solve these problems of natural mRNA, we can use chemically modified mRNA (cmRNA). The cmRNA can be divided into 5 main parts. There is the m7G cap at the 5' end, the 5' untranslated region, the open reading frame, 3' translated region, and the poly(A) tail at the end.
m7G Cap: The 7-methylguanosine cap (m7G) on the 5' prime end of the mRNA strand is critical in the protection of the transcript. It protects against the degradation by exonucleases and facilitates translation [22].
5' and 3' Untranslated Regions (UTR): Both of the UTRs on both ends of the strand of mRNA can be modified with the use of alpha/beta-globin genes to increase stability and translation efficiency [24].
The open reading frame (ORF): The open reading frame is the coding nucleotides that the ribosomes read and then transcribe the mRNA codons into proteins. Unmodified nucleotides can be detected by the immune system, so adding modified nucleotides can be shown to decrease the immunogenicity of mRNA [24].
Poly(A) tail: The poly adenine tail is made up of 50–250 adenosines and it plays an important role in translation efficiency and mRNA stability. The optimum length is around 120–150 nucleotides [22, 24].
Benefits of VEGF-A For Angiogenesis
The protein that the mRNA will be coding for is called vascular endothelial growth factor-A (VEGF-A). VEGF-A is a key protein that is responsible for providing adequate blood supply to all parts of the body and promoting angiogenesis [25]. Angiogenesis is the production of new blood vessels and when VEGF-A binds to receptors, it starts to promote cell production, differentiation, and assembly in all of the types of cells to make new blood vessels [26]. Zangi et. al [27] showed that in a MI mouse model that mRNA coding VEGF-A resulted in the expansion and directed differentiation of heart progenitor cells (heart stem cells). It also improved heart function and enhanced long-term survival [27]. This is just one of many studies that prove how effective VEGF-A is for treating MIs.
The Delivery Mechanism: Injectable Chitosan-Collagen Hydrogels
Hydrogels are 3D networks made up of hydrophilic polymer-based materials that can hold a large amount of water while maintaining their structure [28]. They can be used for tissue engineering scaffolding, drug delivery, and biomaterials. Hydrogels can be made up of natural polymers or synthetic polymers and can also be tailored for specific applications by tuning their biodegradability, physical, and mechanical properties [22]. They can also be engineered to respond to specific stimuli like pH levels, temperature, light, electricity, and enzymatic activity [29]. Their benefits include being biodegradable, biocompatible, and bioresorbable to prevent triggering an immune response[22].
Injectable hydrogels are able to be delivered directly into the tissue source via a needle and are the most effective because it is injected directly into the source of the damage. It’s a minimally invasive procedure and only electrophysiological guidance is needed to direct the injections instead of surgery [22]. The hydrogels and mRNA will be injected intramyocardially, right into the myocardium (muscular tissue of the heart) where it can work its magic.
Chitosan hydrogels modified with collagen have shown promising results in tissue engineering and repairing MI damage [30]. The benefit of these natural chitosan hydrogels is that it has high biocompatibility, low toxicity, and solubility in an acidic environment [31]. Chitosan-based hydrogels have been shown to protect transplanted cells, promote angiogenesis, reduce MI size, and improve cardiac function, all because they have the ability to interact with various bioactive molecules. Lu et al. [32] used a MI rat model and injected temperature-sensitive chitosan hydrogels and results showed that there was a significant improvement in infarct size, wall thickness, and both end-systolic diameter and end-diastolic diameter [32]. Furthermore, since mRNA has a negative charge, cationic hydrogels like chitosan offer advantages in delivery and can also self-assemble.
Conclusion
There is a ton of research that’s been done in the past couple of years on the future of mRNA technology. mRNA has practically limitless applications ranging from different types of vaccines beyond COVID-19, cancer vaccines, immunotherapy, and even localized regenerative therapeutics [33]. Major pharmaceutical companies that are researching a similar idea to mine include Moderna and AstraZeneca.
These two companies have partnered up and are looking into using mRNA to code for VEGF-A to treat not only heart disease but kidney and metabolism diseases too. For cardiovascular diseases, these two companies inject only the naked mRNA that is coated in a simple solution because lipid nanoparticles are not needed [34]. However, this approach makes it difficult for the mRNA to enter the cells, and the release of the protein does not last very long. Using hydrogels, we can control the release of the mRNA, leading to better healing over a longer period of time.
There may not be a lot of research yet on the intersection of mRNA and hydrogels for cardiac regeneration, but I think that in the coming years with more research into mRNA applications and new delivery mechanisms for mRNAs, that hydrogels might become a viable option. The COVID-19 vaccines may become the next cure for a broken heart.
Hi, I’m Erica! A 15 y/o super passionate about biotech and medicine. Thank you so much for reading my article! I hope you have learned something new or interesting. Don’t forget to subscribe, hit the clap button, and connect with me on Linkedin. If you have any questions, feel free to leave a comment.
