This story was supported by a grant from the National Press Foundation in partnership with Fondation de France. For MedPage Today's related story on how families support rare disease research, click here.
One of the hardest things about managing Jordan Franks' propionic acidemia (PA) was feeding him.
Jordan never wanted to eat. His body seemed to know that food could poison him, so like many kids with PA, he was food-averse.
"My son didn't want to eat anything by mouth," his mother, Jill Chertow, told MedPage Today. "I think the most he would ever eat was like, two pieces of mac 'n' cheese. Or he would lick the salt off of a French fry."
Kids with this rare disease can't metabolize certain amino acids. So Jordan had a regular -- and intense -- schedule of formula feedings that he took in through his gastrostomy tube, or g-tube.
"There was a lot of stress in managing his nutrition," said Chertow, who is president of the . "He had three different powdered formulas. One was a baby formula, like a Similac. Then there was a second formula that had protein but didn't have the amino acids that were bad for him. And there was a third formula for calories."
The formulas had to be mixed and weighed to the tenth of a gram to deliver precise amounts of nutrients. Depending on the time of day, Chertow also had to mix in medications.
Jordan had six of these g-tube feedings each day, and because fasting is dangerous in children with PA, Chertow turned on a pump every night to make sure he didn't go too long without nourishment.
"It was challenging to manage all the feeds and within a timely manner," said Chertow. "You can't be too far off schedule, or it messes up the rest of the feeds for the day. Everything needs to be done pretty close to on time."
Jordan died in 2016 when he was only 16 years old. There was no treatment for PA during his lifetime, and there still isn't one. But families and researchers are hoping that the technology honed during the COVID-19 pandemic can help change that.
PA is one of a handful of rare diseases being targeted with mRNA therapeutics.
While mRNA mostly became known during the pandemic because of its use in COVID-19 vaccines, the technology had been investigated as a therapeutic long before then -- and it was hoped to have particular potential for rare diseases.
"I think there's great potential for treating monogenic diseases" with mRNA therapies, said P.J. Brooks, PhD, acting director of the Division of Rare Diseases Research Innovation at the National Center for Advancing Translational Sciences at the NIH. "That's what you're seeing with the propionic acidemia and methylmalonic acidemia trials."
One of the companies leading those efforts is, of course, Moderna, which became a household name during the pandemic for its mRNA COVID-19 vaccine (Spikevax). It is among a handful of companies that have advanced mRNA therapeutics for rare diseases into human clinical trials.
Moderna's PA trial is furthest along, followed by its trial for a sister condition, methylmalonic acidemia (MMA). Both conditions are considered ultra-rare, with estimates that each affect about 200 families in the U.S.
The company also just enrolled the first patients into its glycogen storage disease type IA trial, and is set to begin enrolling patients with cystic fibrosis in a clinical trial .
Other companies with human clinical trials of mRNA agents for rare diseases include Ultragenyx with its glycogen storage disease type III (GSD III) therapy, and Arcturus with its ornithine transcarbamylase (OTC) deficiency treatment. Several other mRNA therapies for rare diseases are in preclinical studies.
The technology has its limitations, but patients and families are watching the trials closely in hopes that they will yield a treatment.
A Step Forward
Paolo Martini, PhD, worked on rare diseases long before he became the chief scientific officer for rare diseases at Moderna. He liked the field because it felt more interconnected than working on diseases with large populations like cancer or cardiovascular disease.
"In rare genetic diseases, it's almost like a family," Martini told MedPage Today. "I set up a network of [experts] all over the world, and we know each other well. There's not much known on rare diseases, so people are very collaborative."
That collaboration includes patients, patient advocacy groups, doctors, researchers, pharmaceutical companies, and others, he said.
Moderna recruited Martini from Shire in 2015, and within 2 years, Martini and his team -- in partnership with NIH researchers -- had their first major success. Mice with MMA tolerated 5 weeks of treatment with an mRNA drug aimed at the disease.
Their findings, , garnered attention for being the first to show that an mRNA therapy can be given repeatedly without soliciting an immune response -- one that could be problematic in and of itself, or that eventually could render therapy ineffective. Martini and team had altered both the mRNA itself and its lipid nanoparticle coating to better evade the immune system and get the drug to the liver, where it is needed.
"With a small modification in one of the nucleosides, we were able to create an mRNA that was silent to the immune system," Martini said.
The animals didn't just tolerate the therapy; they thrived, said Charles Venditti, MD, PhD, chief of the Metabolic Medicine Branch at NIH's National Human Genome Research Institute, who was a co-author of the study.
"The mRNA therapy resulted in the expression of the enzyme in the liver of mice with MMA," Venditti told MedPage Today. "It has beneficial effects in the mice; it lowered metabolite levels and improved their clinical appearance."
It also works quickly, and the level of enzyme expression in mice can be measured in a matter of hours, he added, noting that Moderna conducted additional animal studies that were used to inform their human trials for MMA and PA.
The company was just about to enroll the first patient in its MMA trial in March 2020 when COVID-19 hit.
'They Can Get Sick So Quickly'
It would have been impossible to bring kids with MMA or PA into a hospital during the early, uncertain days of the COVID-19 pandemic.
"We could not put anyone at risk," Martini told MedPage Today. "These patients are very fragile. In some instances they are immune-compromised ... so we stopped everything."
Moderna also had to divert resources to making its COVID-19 vaccine, though Martini said his team always continued pushing ahead on their rare disease treatments in parallel.
MMA and PA fall into the category of organic acidemias. In both diseases, mutations in a single gene that produces a single enzyme prevents the body from properly metabolizing certain amino acids, which causes toxic metabolites to build up in the blood, potentially leading to a metabolic crisis that can be deadly.
The severity of the condition ranges from patient to patient, depending on their exact mutation: "There's an effect by the type of mutation and the amount of residual enzyme activity that a patient has," Venditti explained.
"There can be patients with a somewhat milder condition," he added. "That doesn't mean they don't have any symptoms or signs of the condition, but they can be not as unstable as someone who has two changes in the respective genes that totally inactivate the enzyme."
Children with more severe forms of MMA or PA usually have their first metabolic crisis early in life.
Jordan Franks, for instance, was born on a Friday. By Monday, he had to be rushed back to the hospital, his mother, Chertow, said.
"These children can't even have colostrum," Martini said. "They can have metabolic decompensation and die because they can't process it."
Some children with MMA and PA are frequently in and out of the hospital because of their metabolic challenges, Venditti said. Even a regular respiratory infection can turn into a metabolic crisis.
"Any little thing that happens to them, they can get sick so quickly," he added. "With these recurrent events happening so frequently, there comes a real chance of death and disability."
Kids with MMA and PA also can have lifelong neurological damage from these early metabolic crises, Martini said.
Jordan's early crisis and subsequent crises left him non-verbal, and he also had other behavioral issues, his mother said.
A Favorable Target
The missing or defective enzyme in MMA is methylmalonyl-CoA mutase, and in PA it's propionyl-CoA carboxylase. Both are made by the mitochondria, particularly those in liver cells. Without properly functioning enzymes, methylmalonic acid and propionic acid, respectively, build up in the blood.
Essentially, an mRNA therapy that can make it into the liver can allow the enzyme to be produced, and ultimately clear the toxic metabolites.
"mRNA goes into the liver, which is a favorable target, because most of everything that you inject into the blood goes to the liver," Brooks said. "The enzyme gets made, and metabolizes the toxic metabolite."
Martini explained how the therapy works. Once the mRNA, encased in a lipid nanoparticle, is given as an infusion, it enters the bloodstream and binds with lipid-like molecules in circulation that have an affinity for hepatocytes in the liver.
The whole molecule is then pulled into the cell, which takes it apart and releases the mRNA. The mRNA is recognized and gets taken up by the ribosomes, which translate it into a protein -- in this case, the missing enzymes in MMA and PA.
"You can imagine that the same approach can be used for a lot of other diseases where you need to correct a genetic defect in the liver," Brooks said.
Currently, there's no treatment for MMA or PA. Patients rely mainly on dietary control to restrict the amount of amino acids that can't be metabolized.
Some can also consider a liver transplant, which is usually reserved for more severe cases because, like any surgery, it has its risks, and there's a need for lifelong immunosuppression. Questions also remain as to how long a transplant can be effective, and whether it can truly curb damage to other organs over time.
Experts interviewed by MedPage Today said an mRNA therapy could be a replacement for liver transplant in MMA and PA patients, or it could be a bridge to any future treatments that might provide a permanent fix, such as gene therapy.
Martini said Moderna is seeing early signs of hope in its PA trial. At its , the company reported a decrease in the number of metabolic decompensation events after treatment started, according to preliminary data.
A total of 12 patients have been enrolled in four separate cohorts, he said, and all patients who have completed the study thus far are continuing into an open-label phase, "mainly because I think they believe what's happening with mRNA and potentially they're feeling better," he said.
No patient has discontinued the trial, and some participants have taken more than 15 doses so far and it appears they are still responding to treatment, he added.
"They have some encouraging biomarker evidence that the approach is working as they think it should," Brooks noted.
Moderna made some modifications to the protocol for the MMA trial that was set to start in March 2020. Martini said the first cohort of three patients has been dosed, and additional patients have been enrolled in the second cohort, totaling about five patients treated so far.
Initial data from both trials are expected in 2023, the company said.
Chertow is positive on the news, but remains cautious. Just because families decide to stay in a trial "doesn't mean it's helping," she said.
Chertow enrolled Jordan in a study of carglumic acid (Carbaglu), a treatment developed for a different condition, when he was about 6 years old.
"I knew it cut his glutamine in half, cut his glycine in half, and his ammonia was pretty good," she said. "I didn't see side effects, so I'm like, I don't know if it's helping or not, but it doesn't seem to be hurting."
"People continuing [into the open-label phase] means, 'Yeah, I guess it's safe,'" she said. "But the question is, will it change their quality of life if you have an infusion every 2 weeks?"
Other Rare Targets
Moderna is not the only company with mRNA therapies in human clinical trials for rare diseases.
Emil Kakkis, MD, PhD, is the CEO of Ultragenyx, a biotech that's focused on rare and ultra-rare diseases. Kakkis made his name in the rare disease field by developing an enzyme replacement therapy for the rare genetic condition of mucopolysaccharidosis in the 1990s when enzyme replacement therapy was an emerging treatment strategy.
Now, along with other gene therapies and treatment strategies for other conditions, Ultragenyx has an mRNA therapy for GSD III in human trials. The company has dosed patients in its phase I/II trial, which is currently testing different doses, and plans to have early results in 2023.
They focused on GSD III because it appeared that the treatment wouldn't need to be given as frequently, Kakkis said.
"We found with some others, the [protein or enzyme] didn't last long enough, and you'd have to give the treatment weekly," he said. "For GSD III, it appeared that if you could get rid of the toxic carbohydrate that's building up, it didn't matter if you didn't have the enzyme there for a few weeks. The toxic carbohydrate would build up slowly over time and you could clear it again, so there's the possibility of treating this disease less frequently, maybe once a month."
"We've been looking primarily at situations where you can treat less frequently, so that we don't keep tickling the immune system constantly," he added.
Ultragenyx has partnered with Arcturus on that compound, and the latter company is also independently investigating an mRNA therapy for OTC deficiency. That trial is in phase I/II and is expected to report interim data in 2023, . Arcturus did not respond to a request for comment.
This month, Vertex announced that the FDA approved its investigational new drug application for an inhaled mRNA therapy for cystic fibrosis. The company, which is developing the treatment in partnership with Moderna, said it plans to start a single ascending dose trial .
There are other mRNA therapies for rare diseases in preclinical trials. Moderna and the Institute for Life Changing Medicines are developing an mRNA therapy for Crigler-Najjar syndrome type 1. Moderna is also conducting preclinical work for OTC deficiency and phenylketonuria.
The Road Ahead
At this time, mRNA appears to be most promising for genetic diseases involving the liver, such as MMA and PA. That's because it's relatively easy to get the mRNA into liver cells.
"When you infuse something into the bloodstream, it gets to the liver first, and then it heads out to the rest of the circulation," Jerry Vockley, MD, PhD, chief of medical genetics at the Children's Hospital of Pittsburgh, told MedPage Today.
The lipid nanoparticles encasing the mRNA "are seen in the highest concentrations by the liver," Vockley said. "To get them into the muscle, for instance, in high enough levels, in clinically meaningful levels, it's just a technical challenge right now."
"We're very interested in finding better ways to deliver mRNA to other cell types," Brooks noted.
Even in PA or MMA, it might be better to deliver mRNA to both the liver and muscle cells, Vockley said. "The liver is only responsible for about a third of the branched chain amino acid metabolism in the body. Muscle is the bigger part. It's more like half to two-thirds."
"If you could get something that hits the muscle and the liver, you probably have something that would be close to curative," he added. "We still don't know if it would fix the brain completely. It's not clear if that's just tied to the metabolic decompensation events, or if it's something that just might show up later in life."
Another limitation to mRNA therapy is that it would need to be re-dosed often.
"It would be a recurrent therapy, and it's unknown how much they're going to need, what the interval is going to be, what the side effects are," Venditti explained.
Gerard Berry, MD, director of the metabolism program at Boston Children's Hospital, said the dosing for the MMA or PA trial could end up being about every 2 weeks.
"We're very enthusiastic about mRNA treatment," Berry said, "but we're paying attention to all of the different nucleic acid therapies."
Vockley echoed that mRNA is just one component of the rare disease therapy space. There's gene therapy, which delivers a copy of the gene that's broken or missing, but it has "had a lot of fits and starts," he said, due to both efficacy issues and side effects, including deaths.
But the gene therapy field has moved on from adenoviral vectors to adeno-associated viral vectors, which should improve safety, Brooks said.
There's also been a move to retroviral and lentiviral vectors for ex vivo gene therapy, which involves removing cells from the body, genetically modifying them, and returning them to the body, he added.
CRISPR also offers another means of gene therapy for rare diseases. Indeed, an ex vivo CRISPR-based treatment for sickle cell disease will be .
Four other gene therapies have been approved by the FDA in recent years: voretigene neparvovec (Luxturna) for retinal disease, onasemnogene abeparvovec (Zolgensma) for spinal muscular atrophy, etranacogene dezaparvovec (Hemgenix) for hemophilia B, and nadofaragene firadenovec (Adstiladrin) for a type of bladder cancer. Some approved cancer treatments, known as chimeric antigen receptor (CAR) T-cell therapy, are also considered gene therapy, as they involve ex vivo editing of a patient's own T cells to make them target cancer cells.
In MMA and PA, Venditti's team at the NIH is hard at work on gene therapies that are in the preclinical phase, but other companies are pursuing additional strategies as well. That includes two small-molecule drugs being investigated in human clinical trials: one by , and another by .
Chertow said the fact that there are three clinical trials that patients with PA can try is "exciting for the families." It's also a significant improvement over the state of research when Jordan was born in 2000, she said.
Since there were almost no research programs then, Chertow and four other families launched the Propionic Acidemia Foundation in 2002 to accelerate research.
The organization has funded about $1.5 million in PA research since then, she said. "A lot of our initial research led to PA being a good option for research like mRNA, because there was a mouse model and ... there was some basic science that was done."
Though that didn't happen quickly enough for Jordan to benefit, the hope is that researchers get closer to a treatment, in whatever form it takes.
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