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Targeted MRNA Delivery Will Lead To Cheaper Cures For Many Diseases

Illustration of a lipid nanoparticle created to deliver mRNA into the body

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The technology in the mRNA covid-19 vaccines can be adapted to deliver genetic material to the blood stem cells in bone marrow, animal studies show. This should lead to better and cheaper treatments for a wide range of conditions, from inherited disorders and infectious diseases such as HIV to even ageing.

"With a single injection, you can modify the fate of cells," says Stefano Rivella at the Children's Hospital of Philadelphia. "This is the future of medicine. The sky is the limit."

mRNAs, or messenger RNAs, carry instructions for making proteins. They can be made to instruct cells to make any protein we want, including those needed for the various forms of CRISPR genome editing. Being able to get mRNAs into blood stem cells therefore opens up a vast range of possibilities.

Stem cells in bone marrow produce many types of cell, including red blood cells and the immune cells that fight disease. Some inherited diseases that affect blood cells, from beta thalassaemia to severe combined immunodeficiency, can already be cured by removing blood stem cells from an individual, correcting the mutations that cause them and replacing the cells in the bone marrow. For instance, a CRISPR gene-editing treatment for sickle cell disease is expected to be approved soon.

But there are two major issues with this approach. Firstly, the personalised nature of the treatment makes it very time consuming and costly.

Secondly, before modified blood stem cells are returned to the body, some of the existing blood stem cells in the bone have to be killed to make room for them. This is done with highly toxic drugs that can cause serious side effects and usually leave people infertile.

Modifying blood stem cells inside the body could solve both these problems, so many teams around the world are working on doing this.

Rivella and his colleagues started with tiny, fatty balls found in mRNA vaccines called lipid nanoparticles. When injected into muscles, these nanoparticles deliver mRNAs to muscle cells, which then produce the proteins encoded by mRNAs for a few days until the mRNAs break down.

If lipid nanoparticles are instead injected into the bloodstream, almost all of them get taken up by liver cells. This can be useful for treating liver conditions, but is a problem for most other conditions. To get the nanoparticles into blood stem cells, the team attached antibodies that bind to a protein found on the surface of the stem cells.

Unlike the viruses some groups have used to deliver mRNA into cells, lipid nanoparticles can carry very large mRNAs. "So far, whatever we wanted to encapsulate, we were quite able to," says Hamideh Parhiz at the University of Pennsylvania.

Rivella, Parhiz and their colleagues have done a series of experiments in mice to show these antibody-targeted lipid nanoparticles can deliver mRNAs to blood stem cells. For instance, after injecting nanoparticles containing mRNAs coding for a glowing protein called luciferase, the bone marrow cells in the femurs of the mice lit up.

Up to 60 per cent of the stem cells were modified, says Rivella. Many liver cells lit up as well, because the antibody-targeted lipid nanoparticles still got taken up by liver cells. For many purposes, this doesn't matter, he says. For instance, it isn't a problem if mutations causing sickle cell disease are fixed in the liver as well as in bone marrow.

But for some purposes, it does matter. So the team added a "switch" to the mRNAs that gets turned off by a molecule found only in liver cells. This prevented the liver producing luciferase, but the bone marrow still made it.

How mRNA is transforming the way we treat illnesses from flu to cancer

Next, the researchers used this approach to deliver an mRNA that causes cell suicide in order to kill off blood stem cells without harming other tissues. This means the technique could replace the highly toxic drugs currently used to "make room" for bone marrow transplants, eliminating the side effects.

"This is a coming-together of phenomenal technological advances that will not only improve curative approaches for genetic diseases in the well-developed countries, but also holds promise for global access," says Suk See De Ravin at the National Institutes of Allergy and Infectious Diseases in Maryland, who works on gene therapies.

Another potential use of the technique would be for "gene doping" in sports; for example, by increasing the production of red blood cells to carry more oxygen around the body, in ways that would be difficult to detect.

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Hybrid MRNA And Protein Vaccine Induce 5x More Antibodies In Mice

Caltech scientists have developed a new type of vaccine that works like a hybrid of mRNA and protein nanoparticles. In tests in mice, the prototype produced five times more antibodies than existing COVID-19 vaccines, and could be put to work against a range of diseases.

The general principle of a vaccine is to train a person's immune system to recognize a pathogen, such as influenza or SARS-CoV-2 viruses, so that they can more effectively fight them off during future infections. This is usually done by introducing proteins from the target to the body, so the immune cells create effective antibodies against them.

Protein-based vaccines, such as Novavax's COVID-19 vaccine, directly deliver inactivated versions of a pathogen's proteins that circulate and attract the attention of the immune cells. But mRNA vaccines, which have been in development for decades before being accelerated by the COVID-19 pandemic, take a different approach. These use mRNA molecules that teach the body's own cells to produce pieces of virus proteins, which in turn trigger an immune response.

The Caltech team has now developed a new technique that combines both methods into one vaccine. Known as ESCRT-and ALIX-binding region (EABR) technology, the vaccine uses mRNA to coax the recipient's cells to make protein fragments, but also includes little "tails" on these proteins. These tails trigger cellular processes that lets some proteins clump together into virus-like particles and circulate through the body. In this way, they then function like protein-based vaccines.

"During a natural infection, the immune system encounters both infected cells and free virus particles," said Magnus Hoffmann, lead author of the study. "Current mRNA vaccines mimic infected cells, while protein nanoparticle-based vaccines mimic free virus particles to stimulate immune responses. Our hybrid technology does both."

The team tested the new technique as a COVID-19 vaccine in mice, and found that mice given the hybrid vaccine produced five times more antibodies than existing vaccines. Only two shots rather than three were needed to induce robust antibody levels against Omicron variants, and these antibodies were also effective against the original strain and the Delta variant.

While there's plenty more work to do, the team says this hybrid vaccine technology could be put to use against other pathogens, like the flu and even HIV. Further afield, using the tails to build self-assembling nanoparticles could eventually be used to deliver drugs to targets like cancer cells.

The research was published in the journal Cell.

Source: Caltech

Here's Why Vaccines Probably Didn't Cause Bronny James' Cardiac Arrest—Despite Musk's Claims

Topline

Billionaire Elon Musk recently took to Twitter (recently renamed to X), which he owns, to imply that the Covid-19 vaccine may have played a role in LeBron James' 18-year-old son Bronny's recent cardiac arrest—here's why that is unlikely.

LeBron James' eldest son, LeBron "Bronny" James Jr, is in stable conditions after going into cardiac ... [+] arrest on Monday—a not so rare instance for young basketball players. (Photo by Alex Bierens de Haan/Getty Images)

Getty Images Key Facts

Musk—the richest person in the world—responded to Bronny James' cardiac arrest by tweeting: "We cannot ascribe everything to the vaccine, but, by the same token, we cannot ascribe nothing," adding that "Myocarditis is a known side-effect. The only question is whether it is rare or common."

Myocarditis—or inflammation of the heart muscle—is a rare side-effect of the mRNA Covid-19 vaccines made by Pfizer and Moderna, but it can be triggered by many other things, such as viruses like the coronavirus itself, bacteria and infections, according to the Yale School of Medicine.

Reports of myocarditis are extremely rare compared to the total vaccinated population: Of 192,405,448 people who received the mRNA-based Covid-19 vaccines between December 2020 and August 2021, 1,626 reported side effects that met the "case definition of myocarditis," research published in JAMA Network last year found.

Heart complications like myocarditis and pericarditis are actually more common after contracting Covid-19 than after receiving a vaccine, according to a study published by the Centers for Disease Control and Prevention last year—even among young men and teenage boys, who are more likely to face myocarditis from vaccines.

A 2021 CDC study found people who contracted Covid-19 are 15.7 times more likely to face myocarditis than their uninfected peers, with the risk of myocarditis higher among males, and a 2022 American Heart Association study found that "about 3 in every 1,000 patients hospitalized due to a COVID-19 infection developed acute myocarditis."

Bronny James' vaccination status is unclear, but the heart condition myopericarditis is most common within a week of receiving the second Covid-19 vaccine dose, a study published earlier this year in Science Immunology said, though federal health officials say side effects have also been reported after the first dose or a booster shot.

A 2022 study from the American Heart Association found that "about 3 in every 1,000 patients hospitalized due to a COVID-19 infection developed acute myocarditis."

Key Background

Bronny James is in stable condition after going into cardiac arrest Monday during a basketball practice at the University of Southern California, where the 18-year-old is an All-American athlete, according to a statement from his family. According to recruiting platform 247Sports, the USC Trojans' incoming point guard was among the top 30 college basketball recruits this year and is among the top five combo guard recruits. He played four seasons with Sierra Canyon School in California, the first state to mandate Covid-19 vaccines for students in 2021—which was Bronny's junior season. Athletes going into cardiac arrest is not unheard-of, Forbes recently reported. A sports medicine expert and physician at the University of Alabama in Birmingham's School of Medicine attributes notes that basketball involves "sudden bursts of cardiovascular effort" and many players have tall, long-limbed body types, making sudden cardiac arrest more likely. According to the Cleveland Clinic, myopericarditis is anything related to issues, including inflammation, of the myocardium (heart muscle) and pericardium (heart muscle's protection).

Crucial Quote

"The risk of SCD (sudden cardiac death) is higher in male and African-American athletes and appears to be disproportionately high in men's basketball players," according to 2016 research published in the Journal of the American College of Cardiology.

Big Number

132. That's how many cases of exercise-related sudden cardiac arrest were reported between July 1, 2014 and June 30, 2016 among middle, high school and college athletes–mostly among males (84%), high school athletes (59%) and basketball players (30%)—according to research from the Sports Health journal.

Tangent

A Twitter fact check of Musk's statement on Bronny James originally said: "Studies show that the risk of myocarditis is significantly higher after an actual Covid infection than with the vaccine. Among adolescent boys, the risk of myocarditis following a Covid infection was approximately twice that of the risk following the second vaccine dose." The note has since been removed from Musk's tweet for unknown reasons.

Surprising Fact

Earlier this year, Damar Hamlin, a 25-year-old defensive safety for the Buffalo Bills, shocked viewers when he went into cardiac arrest in the middle of the team's game against the Cincinnati Bengals. Hamlin's incident, which kept him in the hospital for over a week, also fueled anti-vaccine narratives on the Internet.

Poliomyelitis Treatment