For 14 years, Meredith “Meri” Gussin has never really slept. At night in their Miami home, her husband stays awake long enough to give their son Jamie his midnight dose of cornstarch. Meri takes the next shift, waking at 4 a.m. to deliver another dose through his feeding tube, followed by another in the morning. The cornstarch isn’t simply nutrition (Box 1). For Jamie, who has a metabolic disorder known as glycogen storage disease type Ia (GSD1a), it keeps his blood sugar from crashing while he sleeps—a potentially fatal situation.
Hypothetical mishaps pop into Meri’s mind in an endless game of whack-a-mole for worries: What if her phone doesn’t charge? What if she accidentally mutes it? What if, after years of interrupted sleep, she simply doesn’t wake up? To ensure she never misses a feed, Meri has several fail safes: one alarm beside the bed and another across the room. The alarms are staggered a few minutes apart in case she silences one and drifts back to sleep.
The consequence has been a never-ending spell of anxiety and exhaustion. “We’ve never slept through the night for 14 years,” Meri told Inside Precision Medicine. “There’s this constant fear that some minor human errors can occur, and it could have consequences that could be fatal. That’s no way to live.”
But Meri’s nerves don’t get to sleep during Jamie’s waking life. Even with a continuous glucose monitor (CGM), Jamie’s blood sugar can behave unpredictably. Meri checks his Dexcom CGM while he’s at school, worries about whether he ate enough lunch to make it to his next cornstarch dose, and makes sure he leaves home carrying his pouch of “uncooked” cornstarch.
That fear reflects the peculiar cruelty of GSD1a: only with management that’s meticulous to a fault can people with this rare inherited metabolic disease appear perfectly healthy. But their bodies lack the normal ability to maintain blood glucose during fasting, making going without eating for hours—something that doesn’t constantly nag the consciousness of most—life-threatening. As Meri put it, “The issue is that there is no margin for error.”
For decades, treatment has therefore revolved around an unforgiving schedule of meals and raw, uncooked cornstarch. Now, for the first time, there is an approved therapy designed to change the underlying biology.
The first GSD1a gene therapy
On August 19, the FDA granted accelerated approval to Ultragenyx’s Genglycos (pariglasgene brecaparvovec-opnr, formerly DTX401 prior to being acquired from Dimension Therapeutics in 2017) for adults and children ages eight and older with GSD1a. It is the first approved treatment designed to address the underlying cause of the disease.
GSD1a is caused by pathogenic variants in G6PC, which encodes glucose-6-phosphatase (G6Pase), an enzyme critical to the final step that allows the liver to release glucose into the bloodstream. Patients with insufficient G6Pase activity cannot mobilize glucose during fasting, causing severe hypoglycemia, liver glycogen accumulation, and other metabolic abnormalities.
Genglycos uses an adeno-associated virus serotype 8 (AAV8) vector to deliver a functional copy of G6PC to liver cells with a single infusion. Eric Crombez, MD, chief medical officer of Ultragenyx, who began working on the program when it belonged to Dimension Therapeutics, explained that AAV8 was selected in part for its ability to traffic to the liver. (The program, which launched in 2015, predated the FDA approval of a drug using lipid nanoparticles to deliver genetic medicines—the first being Alnylam’s patisiran (Onpartto) in 2018—which are now known to have formulations that preferentially target the liver).
The G6PC gene also happens to fit comfortably within the limited cargo capacity of AAV, according to David Weinstein, MD, who has worked on GSD1a gene therapy since 1998 and served as global lead for the Phase I/II study. It seems simple to provide liver cells the genetic instructions they need to perform a missing metabolic function, but it raises a more unusual question: How do you measure success when the existing treatment comes from a packet of cornstarch?
In the Phase III GlucoGene study, patients treated with Genglycos reduced their daily cornstarch intake by an average of 41% at Week 48, compared with a 10% reduction in the placebo group, while maintaining glycemic control. By Week 96, treated patients had reduced their daily cornstarch intake by an average of 61% from baseline.
The nighttime results were particularly striking. By Week 96, nighttime cornstarch use had fallen 70% among participants originally assigned to the therapy and 75% among those who crossed over from placebo. Two-thirds eliminated at least one overnight cornstarch dose while maintaining low levels of hypoglycemia and improving fasting tolerance. Three eight- to 17-year-old Japanese patients discontinued daily cornstarch while maintaining or improving glycemic control in a small open-label study.
BOX 1. How cornstarch became a lifesaving treatment for GSD1a
For a disease caused by a missing liver enzyme, one of the most important therapeutic advances came not from a pharmaceutical laboratory, but from the kitchen. Before modern dietary management, glycogen storage disease type Ia (GSD1a) was often fatal in childhood. Because patients cannot adequately release glucose from stored glycogen, fasting can rapidly trigger severe hypoglycemia.
By the 1970s, managing GSD1a required continuous overnight nasogastric glucose infusions or highly disruptive, frequent round-the-clock feedings to prevent severe, life-threatening hypoglycemia. Researchers then began searching for a carbohydrate that could provide glucose gradually without continuous feeding. Uncooked cornstarch proved remarkably effective. Its complex starch molecules are digested slowly, providing a prolonged supply of glucose rather than the rapid spike produced by simple sugars.
In 1984, Y.T. Chen, Martin Cornblath, and John Sidbury reported uncooked cornstarch therapy for GSD1a in The New England Journal of Medicine, helping establish an approach that would become the backbone of treatment for the next four decades. The “uncooked” aspect is critical. Cooking gelatinizes starch, making it easier for digestive enzymes to break down and shortening its glucose-releasing effect. Raw cornstarch is absorbed more slowly, allowing appropriately dosed patients to maintain blood glucose for several hours.
Cornstarch dramatically changed the natural history of GSD1a, helping children who once faced life-threatening fasting intolerance survive into adulthood. But the breakthrough came with an important limitation: cornstarch does not repair the defective metabolic pathway. It substitutes for it. Patients may therefore require scrupulously timed doses around the clock, even throughout the night.
Cornstarch as an endpoint
Both Crombez and Weinstein stress that focusing only on grams of cornstarch misses what those numbers actually represent. Before cornstarch became standard management (Box 1), Crombez said, GSD1a was considered universally fatal. Depleted glucose levels prevent patients from accessing liver glycogen, so they must eat cornstarch every few hours.
When a gene-therapy recipient reduces that external glucose source yet continues maintaining blood glucose, something much more biologically significant is happening. “It’s important to talk in full sentences,” Crombez told Inside Precision Medicine. “It’s the reduction of cornstarch and the ability to maintain normal glucose levels.” If patients can fast longer without cornstarch and maintain glucose, their livers are performing a metabolic function that they previously could not. “It’s really about being able to maintain normal glucose levels by yourself for the first time in your life,” Crombez said.
Weinstein goes further. “Cornstarch reduction is not, to me, the most clinically meaningful endpoint,” Weinstein told Inside Precision Medicine. “The most important part of this is avoidance of hypoglycemia and avoidance of severe hypoglycemia.” Among patients he has followed, Weinstein said even those with severe mutations avoided severe hypoglycemia during study testing, with some fasting for as long as 15 hours—something he described as “unheard of in GSD.” That gets much closer to what families actually fear.
Meri knows what is at stake. At a patient-focused meeting hosted by the FDA that Meri helped to lead, two mothers described losing their children after missing nighttime alarms. One couple later divorced amid mutual blame over the death, Meri said.
Weinstein has seen the same tragedy clinically. “People with GSD1a, especially the people with the severe mutations, go to bed at night and worry about whether they’re going to be alive or whether their child is going to be alive in the morning,” Weinstein said. “There is a fear of going to bed because I have had patients, unfortunately, who died because they missed the overnight cornstarch.”
That, he argues, is the real therapeutic target. “With the gene therapy, I think we will prevent that fear,” Weinstein said. “To me, that is the biggest benefit of this gene therapy. It’s not the cornstarch reduction.” Crombez makes a similar distinction. “This isn’t about cornstarch,” Crombez said. “This is about these patients being able to sleep through the night and live their lives.”
Durability unknown
For all the early enthusiasm, Genglycos does not completely correct GSD1a. “I think it’s not perfect. It’s not a cure, but it should have the potential to be a life-changing treatment for many of the patients,” Weinstein said.
One important variable may be genotype. Weinstein said patients entering treatment with some residual enzyme activity appear to respond particularly well, while those with mutations resulting in no enzyme activity can still improve substantially but may not achieve the same results.
Long-term durability also remains an open question. Crombez said Phase I/II participants have now been followed beyond five years, and the benefit has so far held up. But exactly how long a single treatment can remain effective will require continued observation. “We’ve always wanted at least five years of durable treatment,” Crombez said. “I think if we can get to 10 or 15, that’s fantastic. Anything beyond that, great.”
The issue becomes particularly important in young children. AAV generally does not integrate its therapeutic payload into the genome. As a child’s liver grows and hepatocytes divide, the proportion of cells carrying the therapeutic DNA could decline. That helps explain why the therapy is currently approved starting at age eight—even though the risk from hypoglycemia can be particularly intense during early childhood.
“If we dose really young patients, we do need to be mindful that they are going to need a dose two based on liver growth alone,” Crombez said, adding that even several years of protection could ultimately prove worthwhile in particularly vulnerable children. That possibility, however, still needs to be tested.
Nor is it clear whether restoring some glucose regulation will prevent the long-term complications of GSD1a, including hepatic adenomas, kidney disease, and neurological problems. “We don’t have enough experience yet to know if gene therapy is going to increase or decrease the risk of complications,” Weinstein said.
Receiving the therapy does not mean walking out of an infusion center and forgetting about GSD1a. Weinstein believes post-treatment management—including how clinicians reduce cornstarch and adjust patients’ diets—can substantially influence outcomes. According to Weinstein, as investigators accumulated experience, results improved. “It’s not going to be just give the gene therapy and walk away, which I think for some reason people think that’s how gene therapy works,” Weinstein said.
An advance, but no cure
Genglycos likely represents the beginning, rather than the endpoint, of genetic treatment for GSD1a. Beam Therapeutics is pursuing a different strategy: gene editing designed to correct the R83C mutation, which is the genotype of Jamie Gussin. Unlike AAV gene addition, a successful edit could theoretically create a permanent genetic correction that persists as liver cells divide. “Gene editing is exciting because it offers the chance of a cure,” Weinstein said.
But its precision is also its limitation. The approach targets one particular mutation, meaning it cannot address the broad spectrum of G6PC variants responsible for GSD1a. Even if gene editing succeeds, Weinstein argues, mutation-agnostic gene addition could therefore continue serving a much broader patient population.
For now, even Ultragenyx is careful about describing what its first-generation approach has accomplished. “We understand that for all patients we are not completely, fully treating this disease,” Crombez said. “I’m a firm believer that if you start with perfect as a requirement, you’re going to get nowhere. This is a really good place to start.”
Jamie, however, didn’t qualify for the Ultragenyx or Beam Therapeutics trials. Fourteen-year-old Jamie has hardly experienced the independence many teenagers take for granted. He rarely spends nights away from his parents. He’s never attended a sleepaway camp, and only recently did he recently have his first experience with the childhood staple of sleepovers.
For families like the Gussins, success does not necessarily require perfection. Meri can comfortably send her two daughters off to college without worrying about their safety. With Jamie, she has never been able to take that basic assumption for granted. “I hope that he gets to go to college and live independently and enjoy life without fear,” she said. “For all people with GSD, the biggest gift would be able to have a full night’s sleep without that worry.”
With today’s sophisticated biomedical research, the ambition to be able to go to bed, close your eyes, and assume morning will come is almost ludicrous. “That seems so basic,” Meri said. “You want to take a nap on the couch, you fall asleep, and you don’t need to set an alarm. But you can’t miss a feed!”
After a lifetime organized around the next dose of cornstarch, gene therapy may finally give some patients permission to miss one—and get a good night’s sleep.
