RNA Therapy Enhances Cardiac Self-Repair After Injury

Scientists are working on an RNA-based therapy to help the heart recover from damage caused by heart attacks and other forms of cardiac damage. This new approach involves using self-amplifying RNA to deliver a precursor to the natural hormone atrial natriuretic peptide (ANP), which the heart produces to stop inflammation. The precursor will be activated predominantly in the heart, using heart-specific enzymes that are not active elsewhere in the body. The aim is for this simple outpatient injection to become a standard addition to current emergency treatments to save more heart tissue and enhance heart tissue healing to reduce the risk of developing heart failure in the years that follow.

Why It Matters

The human heart has a limited capacity to generate new tissue to replace tissue lost following injury or disease. The sudden occlusion of a coronary artery followed by an acute decrease in distal myocardial oxygen tension leading to myocardial cell death within hours is a common clinical scenario. While reperfusion of the occluded artery can reverse ischemia and restore myocardial function acutely, some amount of heart muscle loss is inevitable and permanent. Following removal of the dead tissue, fibrosis and scarring of the remaining myocardium occurs and forms a wall of connective tissue scar. This supporting tissue does not contract and can disrupt normal heart muscle electrical properties and overall heart shape. Remodeling of the heart after acute myocardial infarction can also result in reduced left ventricular function, increasing the risk for chronic heart failure and arrhythmias and decreasing quality of life due to recurrent hospitalizations.

Present acute treatments for heart attack are excellent for stopping further injury to the myocardium by restoring blood flow. The treatment of heart attack has experienced a large leap in quality in recent years, with earlier diagnosis and better treatment. There is a selective role for thrombolytics, rapid catheterization and angioplasty with stent strains, and emergent surgery for acute occlusions of bypass grafts. Post-myocardial infarction medications have been shown to improve survival and reduce myocardial workload, but they cannot regenerate lost myocardium into viable heart muscle. The fact remains that significant heart muscle is lost irreversibly due to the ischemic insult, and that the heart’s morphology is changed permanently.

There is considerable interest in regenerative and protective approaches to manage acute myocardial damage. Most current therapies for left ventricular replacement following myocardial injury have significant translational deficiencies. Heart transplantation is the current gold standard, however, the donor organ supply is limited and patients require lifelong immune suppression. Cell-based and tissue engineering-based approaches have been tested in small patient cohorts and while promising, have significant variability in clinical outcome and face challenges related to scalable and cost-effective manufacturing that are best performed in a centralized clinical setting. Thus, an RNA-based approach has significant appeal due to its relative simplicity and potential for administration and distribution to peripheral centers if safe and effective.

We are actively investigating one such pathway, the ANP (Atrial Natriuretic Peptide) pathway. ANP is a circulating peptide that is currently used clinically to lower blood pressure and promote the excretion of fluids. In addition to these hemodynamic effects, ANP has been shown to modulate key immune and fibrotic pathways that are critical for tissue healing and cardiac muscle repair. The goal of wound healing is to clear away dead tissue, immediately stabilize the wound, and then slowly return to baseline levels of inflammation. Development of a therapeutic agent that promotes this healthy healing process may allow for increased amounts of functional heart tissue, and less non-contractile scar that impairs heart filling or pumping.

Scientists are seeking to improve efficiency to outpatient therapies by utilizing self-amplifying RNA, but important safety and efficacy issues need to be addressed. Currently messenger RNA-based therapies consist of a predicable amount of mRNA that is translated by cells for a period of time. Self-amplifying RNA (sRNA), on the other hand, contains all of the elements required for a virus to replicate, thus multiple generations of mRNA can be made from a small dose of sRNA. This potentially enables more effective outpatient therapy with fewer and less painful injections. However, longer lasting signals need to be demonstrated to safely turn off the signals, not over-stimulate the immune response, or have off-target effects elsewhere in the body.

Rather than relying on skeletal muscle as an extended production facility to generate precursor hormone that is subsequently delivered to the heart, direct delivery to the heart, though potentially advantageous, is not feasible for a number of clinical reasons, especially following myocardial infarction. However, here muscle serves merely as a transient factory producing a protein that is subsequently activated, predominantly within the heart, to give improved tissue targeting. This simple strategy has practical advantages and is within the bounds of current medical biology and practice.

Even with the most advanced targeting of high-risk patients, monitoring of patients on ANP will not cease. Patients with a heart attack are on medication to lower blood pressure, as well as to alter their kidney perfusion pressure and their levels of various electrolytes. Most of these medications increase levels of natriuretic peptides, which will increase urine production and affect salt and water circulation. Patients on ANP therefore have the potential to develop hypotension, lightheadedness, dehydration, or to have an abnormal sodium or potassium level. Monitoring these patients clearly will not be trivial, particularly in the older patient, or in those with chronic kidney disease. As more information becomes available, future studies will be needed to help clarify which of these patients would be best to treat with this approach, who might be at greater risk of serious side effects, and how such patients could be monitored in the ambulatory setting.

Both RNA and lipid nanoparticle-based delivery systems have the potential to activate the immune system inducing an innate immune response. A small level of immune activation is generally acceptable; however extreme activation may lead to increased inflammation, symptoms of fever, and complicate the recovery of a patient experiencing a myocardial infarction. The degree of immune activation can be diminished by modifying the RNA or through formulation to decrease innate immune activation. It would be helpful to have a better understanding of the symptoms experienced by a patient post administration, relevant laboratory tests, and discrimination between mild transient side effects and serious adverse reactions.

Innovative injections designed to enhance repair could potentially change the face of post heart attack therapy forever. Current treatment of a heart attack focuses first on reversing the initial damage to the heart, then subsequently fighting for heart function in the critical days following the event. For months thereafter, patients struggle to regain full physical function, while at the same time taking medication to help prevent future heart attacks. But what if we could intervene during the period of post-operative recovery to facilitate better, more restorative tissue repair?

Treating patients with reduced ejection fraction who are at risk for developing symptomatic heart failure can be cost-effective and potentially yield large savings given the high cost of caring for patients with heart failure. The payer may be more interested in the long-term benefit, as opposed to a short-term cost savings.

This real world application is not as simple as the randomized controlled trials that provide evidence of the effectiveness of this therapy. The infarct size, the delay to treatment, the degree of comorbidity, and the varied presentation of patients over time all need to be considered. Patients will present early in their course of illness with minimal deficit versus late with atypical presentation. A framework for application will need to be established to address the time from injury to treatment over several days or weeks, or the need for multiple doses of this therapy. Additionally, application in inpatient hospital/clinical settings may differ from application in rehabilitation settings.

Who It Affects

Those most likely to benefit from advances in post-MI remodeling are the patients who suffer a MI (especially those at highest risk for adverse remodeling). These are typically the very elderly, as well as diabetic and hypertensive patients with kidney disease, obesity, hyperlipidemia, or prolonged hypertension and prior coronary artery disease. Despite optimal therapy for heart failure, the advances in post-MI remodeling could improve exercise tolerance and reduce symptoms in these patients, and allow for a more rapid return to normal activities.

Currently, this treatment is applied to patients who have experienced a heart attack, but other types of cardiac muscle injury may also be treated with this approach in future, pending further investigation. These other conditions include other forms of cardiac injury, myocarditis, chemotherapy induced cardiac toxicity, certain cardiac surgical procedures, and severe, uncontrolled hypertension. Each of these diseases causes injury to the heart muscle, leading to scarring, but through inflammation-induced remodeling, they all target the same pathway as heart attack. As more safe and effective treatments for heart attack are developed, these additional indications may be considered for use as well.

Participants include all levels of healthcare providers. Interventional cardiologists could administer the therapy. Emergency physicians and paramedics could initiate the treatment during a patient’s acute myocardial infarction. Hospital cardiology teams, primary care providers and those involved in cardiac rehabilitation could manage follow-up care after the patient is released from the hospital. Follow-up care could include taking a patient’s blood pressure and symptoms and ordering necessary labs. Pharmacists would participate in medication reconciliation as many patients with heart disease take a variety of different medications some of which are used to control blood pressure and manage fluid status.

A number of practical challenges need to be addressed in order to administer TPA to patients with acute ischemic stroke within the time constraints of an already busy health care system. Administration of injection in hospital does not have to prevent other indicated treatments, such as reperfusion therapy, or patients’ receipt of primary and secondary prevention medications. Administration of the injection in the out-patient setting requires a practical and reliable system for timely identification and scheduling of patients for treatment as well as adequate follow-up. In addition, education of all health care providers and use of standardized processes are required to assure that thrombolytic therapy is not limited to the major stroke centers.

There is a great need for treatments targeting cardiovascular disease in rural and underserved communities. While outpatient, easy-to-administer injectable new biologic therapies have the potential to reach patients beyond the poor and minority populations most in need of them, the treatment could potentially worsen cardiovascular health disparities if not distributed with equity in mind. The scale of manufacturing, the need for a cold chain, and the training of community-based physicians in use of the drugs will all influence which patients will have access to these promising treatments. Health systems, providers, and payers will be called upon to address these challenges to ensure that the benefits of new cardiovascular therapies are not denied to the patients who need them most.

As self-amplifying RNA vaccines and treatments move towards wider use, higher quality and greater scrutiny will be placed on regulators and manufacturers. Consistent and reproducible manufacturing is crucial for these RNA medicines. Smaller changes in formulation between lots of drug can have large effects on potency and reactogenicity, which will need to be well characterised. In addition, long-term follow-up registries will be required for some treatments and must be set up as soon as the treatment is released for wider use.

What Changes

Future heart failure patients may require weeks or months of outpatient treatment as their heart heals from the first stages of its recovery. A patient with a heart attack would receive standard initial reperfusion therapy and treatment with cardioprotective medications. After discharge from the hospital or at first follow-up, the patient might get an RNA shot to prevent damaging inflammation and scarring as the heart undergoes remodelling.

Although the treatment window in which to intervene may remain acute, there are potential benefits to treatment provided in the days and weeks following an injury in patients who, for a variety of reasons, have been delayed in seeking specialized care for injury. Many patients do not receive timely referral to an injury treatment service for a variety of reasons including barriers to accessing care, delay in recognizing the symptoms of injury, or atypical presentations of injury. Administering treatment in settings such as cardiac rehabilitation facilities or other community-based hospital outpatient clinics could provide physicians with additional treatment options for patients who need injury rehabilitation but are not receiving timely care for their injury.

Future investment in health systems could be targeted at primary and secondary prevention of progression to heart failure and reduction of future hospitalisations for patients with heart failure. Investment in early post-discharge monitoring and rehabilitation as well as nurse-delivered community-based programmes could also be a priority area. There may be a decrease in demand for expensive technology for treatment of severe heart failure and hospital readmissions for patients requiring these technologies. In the short term, there will be investment required to up-skill staff in cardiac clinics to safely administer, monitor and document the effects of RNA therapy in heart failure patients.

Monitoring and follow up should be included in routine care and intensified in the early days. Patients and their carers should be told the symptoms of illness caused by these drugs that require immediate medical attention. Doctors should also tell patients for whom rivaroxaban is recommended, the appropriate doses of other common post myocardial infarction medications that can be given at the same time without adverse effect. Patients and their carers should be informed of the symptoms of illness that require urgent medical attention eg dizziness, shortness of breath, recent change in urine production, recent change in vision. Patients and their carers should be informed of the need for regular measurement of blood pressure and for evaluation of any reported dizziness and shortness of breath. Patients and their carers should be informed of the need for monitoring of kidney function tests and electrolytes when relevant.

However surveillance of approved RNA therapies is not going to be straightforward. Since these are treatments that have been developed to, in part, work by new mechanisms of action, it is important that some safety follow-up is carried out to detect any rare immune events or unusual longer-term safety signals. Health systems will also wish to make use of registries, normalise reporting of outcomes and enhance their pharmacovigilance capacity. These measures are not a barrier to delivering these potentially very powerful treatments to large numbers of patients; they are just part of the package.

The way we think about post-infarction rehabilitation could shift towards “repair support” in myocardial injury. While restoring blood supply, preventing thrombosis, controlling risk factors, and promoting physical training through cardiac rehabilitation have remained major goals of post-infarction recovery, their outcome benefit could be significantly enhanced by supporting the healing process itself. The potential to do so could lead to new clinical recommendations, quality measures, and patient education regarding risk post-infarction and long-term left ventricular function.

References:

https://pmc.ncbi.nlm.nih.gov/articles/PMC9732118/ https://www.hsci.harvard.edu/news/modified-rna-offers-drug-approach-regenerating-heart-tissue