Even before its RNA vaccine for COVID-19 made Moderna famous, the company’s founders had a vision for treating rare diseases.  

“When the pandemic hit, it slowed us down a little bit because we had other things on our minds,” said Kyle Holen, MD, Moderna’s head of development, therapeutics, and oncology. “But now we’ve been able to have a renewed focus on rare diseases, and it’s really exciting to see the impact this is having on some of our patients.” 

Through my conversation with a cheerful and optimistic Holen, nothing made him smile more than when sharing patient stories. He tells me a story about an exit interview with a young girl with a metabolic disorder known as glycogen storage disease type 1a (GSD1a) and her family. 

“We talked to her parents about us developing a therapy for GSD1a and the mom said, ‘We just never thought that anyone would care,’” Holen recalled. “This is why we do what we do, because we’re telling people that they matter and that we can help, and that just means the world to these patients.” 

Holen’s excitement leads him to another anecdote about a child with propionic acidemia (PA), requiring a very strict diet. “When they were on the study, they were able to eat a more normal diet, and she thanked us because this past Christmas was the first Christmas that the family ate their Christmas meal together,” Holen said. 

Moderna—a rare disease company  

The thing about rare diseases is that there are thousands of them, and they’re not even rare in aggregate. The Orphan Drug Act defines a rare disease as a disease or condition that affects less than 200,000 people in the United States, and according to the National Institutes of Health (NIH), there are more than 7,000 known rare diseases. These diseases affect about 400 million people worldwide, with 50% affecting children. In the United States, rare diseases affect about 1 in 10 people.  

Moderna chooses which rare diseases to treat based on several factors, such as the clear clinical outcomes and effects, how well their lipid nanoparticles (LNPs) target the indication, and how well the mRNA approach works compared to other options, like gene therapy. 

That is why Holen and his colleagues decided to investigate methylmalonic acidemia (MMA). This extremely rare organic acid disorder manifests in a variety of symptoms, including metabolic crises, seizures, and developmental delays. The most common form of MMA results from mutations in the MUT gene, which encodes the methylmalonyl-coenzyme that breaks down certain proteins and fats correctly. When methylmalonyl-coenzymes are missing, cell metabolism is disrupted, leading to the buildup of toxins in the bloodstream. At present, the treatment options for MMA include reducing daily protein consumption, taking antibiotics or nutritional supplements, or undergoing an organ transplant.  

“For disorders like MMA, there’s a clear biomarker response when patients have a liver transplant—you can see the MMA levels come down by 70%,” said Holen. “So, if we believe our mRNA is essentially a medical liver transplant, we should see the same impact on that biomarker. Lo and behold, we have patients with 70% reductions in their biomarkers. That’s great for our proof of concept and science to understand that impact immediately upon treatment. So, that’s another criterion we use—how can we get to a yes as quickly as possible?” 

Proof-of-concept for rare metabolic disorders 

To treat MMA, Moderna developed an investigational treatment called mRNA-3705. The company is testing the safety and effectiveness of administering mRNA-3705 through an IV to make functional methylmalonyl-coenzymes in MMA patients with MUT deficiency aged one year and up in the Landmark study. 

Treatment studies for propionic acidemia (PA) are also progressing at Moderna. Similar to MMA, PA is a rare disorder of organic acids marked by the lack of an enzyme called propionyl-CoA carboxylase (PCC), which is needed to break down proteins and fats. The Paramount Study for PA is a lot like the Landmark Study for MMA in that it looks at the safety and effectiveness of mRNA-3927, an IV mRNA therapeutic, to make a proper PCC enzyme. 

Along with these uncommon organic acid disorders, Moderna is also investigating GSD1a. A lack of a protein involved in sugar metabolism makes GSD1a patients regularly have low blood sugar and build up glycogen in certain organs and tissues, mostly the liver. Moderna’s LNP technology can effectively treat this condition. Moderna is testing mRNA-3745 in the Ba1ance Study to see if a single IV infusion can rebuild GSD1a’s ability to break down glycogen, raise blood sugar, and stop people from eating starch.   

“We’ve started to see what we believe is proof of concept across all three different programs with substantial reductions in metabolic decompensation events and reductions in markers,” said Holen. 

“It’s exciting and I think that we feel confident that this platform works for rare diseases. Now, the challenge is that there are 1,500 different inborn errors of metabolism. I am not sure we will mount 1,497 more programs, but we could, and the sky’s the limit of what we do next. And so, we’re excited to move this platform into other rare diseases where we can further impact patient lives.”  

Beyond the liver  

Moderna also does research and development on mRNA technology, including which sequences to use, how to make those sequences stable, and diverse ways to manipulate mRNA. They also focus on mRNA delivery, mostly through LNPs. Holen praises his colleagues who wake up every morning “thinking about how to make a better LNP. It means we can make novel discoveries and rapidly improve the technology with that intense hyperfocus on LNP.” 

A fitting example of a new advancement in Moderna’s LNP technology is an inhalable LNP that’s being used to develop a cystic fibrosis (CF) program in collaboration with Vertex Pharmaceuticals

“People think that making an inhaled LNP with an mRNA that can be stable, be delivered into the lungs, and get through all that mucus that CF patients have into the cells to create CFTR would just be a small step from the LNPs that we have today,” said Holen. “It was not a small step. It was a huge undertaking, and it makes me beam with pride to work with people who can figure this out, make it happen, and get this to patients.”  

“We’ve already started dosing CF patients in clinics,” said Holen. “This is the year that we’ll figure out if mRNA can help CF patients, so I’ve got my fingers crossed that it will have good data.” 

Moderna’s LNP research extends beyond inhaled and liver-directed forms. Holen said that Moderna is constantly looking for new ways to target other tissues and has ongoing business development efforts to find other technologies that other companies are developing. 

Fighting mRNA misconceptions 

According to Holen, there are a lot of misperceptions about RNA and a lack of education about what mRNA is, and that extends to all levels of people we talk to, even clinical trial investigators sometimes. “It’s been a while since they’ve thought much about mRNA and certainly aren’t familiar with LNP and the technology, so why might it not be useful for people with rare diseases of the muscle or the neurons,” said Holen. “We have a lot of education to do, and we’re happy to do it.” 

According to Holen, one of the main misperceptions is that people lump mRNA in with gene editing. As mRNA is self-limited and has a short half-life inside the cell—briefly to manufacture protein before being degraded—there are no changes to the patient’s DNA and likely no long-term side effects. 

But the effort is worth it, according to Holen, who has said he can’t wait for the next rare disease patient story he gets to hear being treated with Moderna’s mRNA therapeutics. 

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