As the chief scientific officer of Moderna’s International Therapeutics Research Centers, Paolo Martini travels all over the world visiting newborn patients with rare metabolic diseases, their families, and their doctors. Most of the kids that he sees have the genetic disorder propionic acidemia (PA) or methylmalonic acidemia (MMA). After every visit, Martini returns to his team of scientists with the same report.

“It's devastating. Every time I leave, I'm in tears. To see these little nuggets, they're adorable, and they're full of tubes. They cannot be fed,” he said. “I bring back that image all the time because I want to remind them that we're doing this for a reason.” 

PA and MMA are recessive genetic diseases that arise when a child inherits mutations in genes for enzymes that convert certain proteins and fats into Krebs cycle metabolites (1). Because these metabolic pathways are critical for converting nutrients into energy for cells, symptoms usually appear soon after birth. Caregivers can manage the disease by feeding children a low protein diet to prevent the buildup of toxic metabolites, but there are no therapies that treat the underlying causes of these diseases. 

While Moderna may be famous for their COVID-19 mRNA vaccine, Martini and his team started working on mRNA therapies for rare diseases long before the start of the pandemic. With Moderna’s mRNA therapies for PA and MMA both currently in Phase 2 clinical trials, Martini hopes to provide patients with the first ever treatment options for these devastating diseases.

How did the rare disease program at Moderna begin?

I was working on a rare genetic disorder at the drug discovery company Shire. One day in 2015, a recruiter from Moderna called me and said, “Would you like to start our rare disease unit at Moderna?” I said, “Uh, no thank you. ”Moderna’s reputation at the time was not the best, mainly because people wondered about what Moderna was doing. There was a lot of secrecy, which was dictated mainly by the fact that they were pioneering new ways of making RNA.

The recruiter who reached out to me was the same person who had recruited me to Shire, who said that I owed a favor to at least interview at Moderna. So I went, and when I saw that the CEO was French and I'm Italian, I said, “Great, we won't get along!” But, I met Stéphane Bancel, and we loved each other from the very first moment. Then I met Stephen Hoge, the president, and I saw that they had a clear vision in mind, and more importantly, incredible data, particularly for rare diseases. They were also thinking about rare diseases in the right way: patient centric. All those things made me feel good about making the decision to move to Moderna. There I had full freedom to build the rare disease pipeline.

How did you decide to develop treatments for PA and MMA in particular?

We wanted to focus on severe diseases. Patients with PA and MMA can die because of a metabolic decompensation event (high levels of toxic metabolites in the blood) or acidosis (excess acid build up in the blood). The level of acid in their bodies affects their central nervous systems, so they can become cognitively impaired. These patients have a life span of months to six years, and for severe mutations, the quality of life is horrible because they’re bed bound and fed by tubes. In the case of PA, the mortality is very high, and nobody was even approaching it.

Why use mRNA as a therapy for PA and MMA?

There are two key characteristics of mRNA that people didn’t appreciate much initially: We can multiplex mRNA, and we can put as many mRNA molecules in a lipid nanoparticle as we want. In a disease like PA, patients have a mutation in one of the two subunits of the enzyme propionic carboxylase. Both subunits form an important structure to metabolize the substrate. If someone has a severe mutation in one subunit, the body tends to produce a lower level of the other subunit at a certain point. By placing mRNA in a lipid nanoparticle, we can dose it to elicit the same protein response every time. I call the mRNA the prodrug because we give that, and the protein that’s created is ultimately our drug.

What were some of the challenges your team faced in developing these therapies?

Lipid nanoparticle delivery was one of the biggest challenges. For PA and MMA, we wondered whether we were reaching the hepatocytes. We saw that we were curing mice, but we can always cure mice. Fortunately, we did a study in nonhuman primates to understand the distribution of lipid nanoparticles in the liver, and we realized that our lipid nanoparticles delivered the mRNA therapy to dendritic cells, which were not the right cell type.

We then focused on understanding delivery to the hepatocytes rather than dendritic cells, and three months later, we had the right lipid nanoparticle. 
– Paolo Martini, Moderna

This is where I really appreciated Moderna. Sometimes investors put pressure on researchers to move a program forward despite the results. But Moderna leadership said no, and that we could not move forward with this until we understood why things were not working. This mentality is especially important in rare genetic disorders because the moment we say, “Let's try something,” we create hope for families and patients. If we don't have the right therapy, it’s not right to move forward. We then focused on understanding delivery to the hepatocytes rather than dendritic cells, and three months later, we had the right lipid nanoparticle.

Now, there are patients who have been on the mRNA therapy, for example for PA, for more than a year and a half. They are continuing the treatment. I cannot say anything, obviously. I don't want to jinx it. More importantly, what is beautiful to see is that all the patients currently on this treatment have decided to continue in the open label Phase 3 study, which is remarkable.

What do you find most rewarding about developing these therapies for rare diseases?

The beauty of working in rare diseases is the community. Physicians know patients by name. Patient advocacy groups come together, and they include families who find out that their child is going to be born with a disease and need to know how to manage it. For me, working on rare diseases is more like working with a family. I’ve established incredible friendships and collaborations with physicians where the focus is to help patients. Hopefully, there will be a reward in seeing that these patients eventually have better quality of life.

The most exciting part will be the first approval either for MMA or PA because that will open the door for a plethora of diseases that we can work on. Moderna now has an incredible infrastructure for rare diseases that can support the future of mRNA delivery in other organs. There's still a lot to do, but I love that we are doing it. It's been the best time of my life so far.

This interview has been condensed and edited for clarity.

Reference

1. Forny, P. et al. Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision. J Inherit Metab Dis  44, 566-592 (2021).