Photo Credit: V. Altounian/Science

Biotech, Moderna Therapeutics has experienced a bit of scrutiny this year, but it is looking to change that by proving that its drugs are safe for long term use. 

Paolo Martini, who heads up rare disease research and his team are hoping to enroll children suffering from a rare metabolic disorder known as methylmalonic acidemia (MMA), in a clinical trial that delivers “messenger RNAs”. The company has gone on to raise billions of dollars on the promise of treating a variety diseases with RNA, reports Science.

In a study, published in Cell Reports, the company have confirmed that there were no obvious health problems in mice given repeated doses of its latest generation of messenger RNA (mRNA) drugs. Although there is a lot more that needs doing to prove that this process can be used in children, but it is however, some of the first published animal research supporting the use of this type of RNA as long-term therapy in diseases like MMA. 

Kathryn Whitehead, a chemical engineer at Carnegie Mellon University in Pittsburgh, Pennsylvania, who was not involved in the study, said, “It’s good news for the mRNA delivery field and an important step.

“I don’t know if I’ve ever been more excited about a class of drug than I am about MRNA.”

Despite the great prospects of MRNA, a lot can go wrong, especially when you try to sneak molecules into the body. This is largely because our immune system has evolved to recognise RNA from outside the cell as an invading virus and attack it. The protective nanoparticles made of lipids commonly used to encapsulate mRNA can also trigger immune reactions and damage the liver at high doses. Another problem can arise if you’re trying to replace a vital protein that’s missing, as the body may recognise the newly produced protein as foreign. 

In a bid to move away from those traps, researchers at Moderna have altered the chemistry of the mRNA itself so it doesn’t set off receptors on roving immune cells. As a result, they have started human testing of its mRNA drugs for cardiovascular disease and cancer, and for vaccines against the flu, Zika, and chikungunya viruses. They aren’t the only ones leading the way, German based biotech companies CureVac and BioNTech are also testing several mRNA-based cancer vaccines in clinical trials. 

Thanks to a careful redesign of their delivery vehicle, the lipid nanoparticle, Moderna has managed to overcome previous problems. This able to quickly shed one of its key lipid components upon entering the body, rendering it stealthier and less toxic.

To prove the success of this, Moderna worked with scientists at the National Institutes of Health in Bethesda, Maryland, in a new study to test how effectively that nanoparticle delivers mRNA encoding the protein that’s missing or defective in MMA patients. The enzyme, known as methylmalonyl-CoA mutase (MUT), is made primarily in the liver, and it helps break down proteins and fats in food. Without it, the buildup of methylmalonic acid in the blood can cause weakness and slowed development, kidney and liver damage, and even seizures and stroke. Children that are diagnosed with MMA must eat a restrictive diet, and some undergo liver transplants. 

Specifically in the study, the researchers gave intravenous injections of MUT-encoding mRNA to mice lacking the enzyme. The treatment reduced blood levels of toxic acid by up to 85%, they revealed. Furthermore, after getting weekly injections for five weeks, the mice did not have elevated levels of liver enzymes that signal toxicity, and there was no increase in certain markers of inflammation, or in antibodies that indicate an immune response. 

Martinu explained, “We saw these mice not only surviving but gaining weight, turning almost into a normal mouse. These data I think [are] the validation, at least in animal models, that this messenger RNA therapy could work.”

However, other researchers do want to see a lot more evidence of long term safety. Some would like to see the mice followed for longer and given even higher doses.

President of Moderna, Stephen Hoge has expressed his confidence that the drug’s safety can exceed that factor-of-10 standard. “Seeing the hope in the eyes of these physicians…of potentially having something to test was incredible.”