Seven people who recently had heart bypass surgery in Europe volunteered for additional treatment: messenger RNA injections.
It was not one of the COVID-19 vaccines, in which the RNA code is used to teach the recipient’s immune system. Instead, RNA from operated patients was designed to heal their hearts – by promoting the growth of new blood vessels.
The study, a collaboration between drugmakers AstraZeneca and Moderna, is one of dozens underway to harness the potential of RNA. Some of them started before the pandemic, but with the real success of vaccines, they have now gained momentum.
At Duke University Medical Center, researchers are testing an RNA drug other than Moderna in patients with propionic acidemia, a rare condition in which the liver is unable to break down certain amino acids and fats. Others test messenger RNA against various cancers.
And, of course, RNA is being used to make more vaccines. Among those tested are vaccines against Zika virus, respiratory syncytial virus (RSV), cytomegalovirus and influenza.
All of these efforts rely on the ability of RNA to carry the recipe for proteins, the building blocks of life. In a vaccine, the protein is a harmless fragment of the virus in question, allowing the recipient’s immune system to work in the event of infection. In other drugs, RNA can trick patients’ cells to make beneficial proteins that they are unable to make on their own.
It’s too early to say how well the various non-vaccine RNA drugs will work, said cardiologist Howard J. Eisen, medical director of the Penn State Heart and Vascular Institute, who has been monitoring the research. Among other issues: RNA degrades quickly (remember how COVID vaccines require cold storage?), So it needs to be delivered to the right cells in a timely manner.
Still, the potential, he says, is vast.
“It’s going to revolutionize medicine, I think. “
In the cardiac study, patients did not experience any serious side effects following the injections, the drugmakers reported in November. This was no surprise, given that billions have now been safely injected with RNA vaccines, said Eisen, who was not involved in the study.
But with just seven people (and four more who received placebo injections), the study was too small to draw any conclusions about the drug’s effect on heart function. Larger studies are planned.
RNA contains the recipe for a protein called VEGF-A, a growth factor involved in the formation of new blood vessels. The hope is that patients will experience an improved “ejection fraction” – a measure of how much oxygenated blood is pumped with each heartbeat. Yet previous studies, in which researchers sought to stimulate this protein with a different approach called gene therapy, have had limited success.
Likewise, testing of the RNA-based drug for propionic acidemia is in its early stages, as are studies of RNA-based treatments for other metabolic diseases.
What is clear is that new approaches for these liver disorders are badly needed, said Dwight Koeberl, who oversees Duke University’s site for Moderna’s propionic acidemia trial.
For now, patients with this condition must seriously limit or avoid the consumption of meat, dairy products, and nuts, otherwise their body accumulates toxic byproducts that lead to neurological and heart damage, among other complications. To compensate for this restricted diet, they have to drink a special formula with vitamins and other supplements. And even so, some ultimately need a liver transplant.
Koeberl, professor of pediatrics at Duke University School of Medicine, has also studied the use of gene therapy to treat these patients. This approach is a long-term solution, as the instructions for making the corrective proteins are provided inside the nucleus of a person’s cells (whereas RNA is transient and degrades within days, which means that some treatments should be administered several times).
But like gene therapy treatments for heart disease, gene therapy for metabolic disorders remains a work in progress. One barrier to gene therapy is that it is usually delivered inside the recipient’s cells with a virus, which can be overcome by the immune system, Koeberl said.
RNA-based therapies, on the other hand, are usually packaged in tiny droplets of oily molecules called lipids, like with COVID vaccines. These lipid nanoparticles do not enter the cell nucleus. They only need to penetrate the outer cell membrane for RNA to do its job, and they do so easily. Koeberl was drawn to the possibility of a simpler solution.
“My interest is to try to help these patients with something as soon as possible,” he said.
Many, if not most, of the RNA drugs tested are vaccines, judging from a search of clinicaltrials.gov, a list of clinical studies maintained by the US National Library of Medicine.
Over traditional vaccines, one of the advantages of the RNA approach is that the genetic instructions can be quickly updated to match emerging threats. Pfizer and BioNTech, for example, are already developing a vaccine to match the omicron variant of the coronavirus, although large-scale production still takes time. The European Union has ordered 180 million doses of the modified vaccine, which should be available by March.
New generation RNA vaccines may also have the advantage of requiring lower doses. This is the idea behind a flu vaccine under development by Seqirus, which has operations in the United States in Summit, NJ, and is a subsidiary of CSL Limited, based in Melbourne, Australia.
The RNA in this vaccine is ‘self-amplifying’, which means that it is made up of two components: the genetic recipe for making influenza proteins that stimulate an immune response, as well as instructions for making multiple copies of. this recipe. In theory, this would mean that a lower dose of such a vaccine could be just as effective, but with a lower rate of side effects. Seqirus has been studying this approach in animal models for years and plans to test this type of influenza vaccine in human volunteers in the second half of 2022.
Patient support groups have watched the development of messenger RNA with great interest, whether the drug is used to prevent disease, such as with vaccines, or to treat it.
Many advocates were aware of the potential of RNA treatments long before the release of COVID vaccines. Among them is Kathy Stagni, executive director of the Organic Acidemia Association, which provides support to patients with propionic acidemia and others.
She said she set the record straight every time she heard someone say the technology behind COVID vaccines has been “rushed”.
“This is something that they have been working on for a long time,” she said.
Eisen, the Penn State cardiologist, was working at the University of Pennsylvania decades ago when Penn scientist Katalin Karikó was doing some of the first experiments that would pave the way for vaccines.
She wasn’t working on vaccines at the time, but on using messenger RNA to treat heart disease. Now that the technology has matured, AstraZeneca and Moderna are once again tackling heart disease.
“In essence,” Eisen said, “the circle has come full circle.”