Anissa Merriam was a vibrant teenager, a talented artist who loved anime and excelled in difficult classes. But at 14, she started dropping her pencil and her hairbrush, and struggled with her studies. Something wasn’t right, she told her parents.
Eventually, Anissa was diagnosed with a rare, neurodegenerative form of epilepsy that strikes in early adolescence, causing intractable seizures and dementia. Most patients die before 30. Today, Anissa, at 22, likes to dress up like 1930s child star Shirley Temple, watch Disney movies and tap dance.
Not long ago, her mother, Jenifer Merriam, had reason to hope, as scientists pursued three or four different approaches they were confident would lead to a treatment, perhaps even a cure, for the disorder called Lafora disease. Some researchers were planning clinical trials for early next year. But those efforts have been imperiled by the coronavirus pandemic, as many labs remain shuttered or are operating at low capacity. For the Merriam family, it’s an especially cruel turn.
Since March, medical research on diseases other than covid-19 (the disease caused by the novel coronavirus) has taken a huge hit, with countless experiments abandoned and clinical trials suspended or postponed. This singular focus will inevitably delay much-needed advances for other life-threatening ailments, including cancer, stroke and heart disease, experts say.
“Anytime you slow down a rapidly progressing field of medicine, there is some long-term decrease in how fast new therapies get approved and used,” said Benjamin Neel, director of the Perlmutter Cancer Center at NYU Langone Health.
The Cleveland Clinic’s Steven Nissen, who is overseeing several major cardiovascular trials, said every study has been hurt in some way. One trial, now shut down, involves a therapy for a fatty particle linked to a higher risk of having a heart attack, a condition Nissen said he has wanted to treat for three decades.
Now, as medical institutions explore resuming non-coronavirus research, they say it will be hard to make up for lost time. Some researchers have to rebuild their colonies of specially bred animals. Many labs are implementing staggered work shifts to limit the number of employees at any one time. “I don’t see how we can maintain the levels of activity we had in the past,” said Craig Jordan, a leukemia researcher at the University of Colorado Anschutz Medical Campus.
The pause is especially difficult for families with relatives who have rare diseases. Often, these are devastating genetic disorders that, like Lafora, do more and more damage as time passes. The National Institutes of Health estimates that as many as 30 million people in the United States, many of them children, have one of 7,000 rare diseases. Only 5 percent of the diseases have approved treatments. And many hoped-for therapies may work only when patients are young and a disease has not progressed too much.
“Often, you have a window when you have to act, or otherwise the situation is harder to salvage,” said Anne R. Pariser, director of NIH’s Office of Rare Diseases Research, which focuses on conditions that affect fewer than 200,000 people.
For Jenifer Merriam, who lives with Anissa and her two other children in Gilbert, Ariz., the passage of time is terrifying. She is desperately hoping a treatment will not only save her daughter’s life but maybe even bring back some of the old Anissa.
“Cognitively, she is like a little girl,” Merriam said. “This is a disease where we watch them go backward.”
“How can this research be ‘nonessential’?” she said. “Everyone deserves a chance, whether they have covid-19 or cancer or Lafora disease.”
Before the pandemic struck, University of Kentucky College of Medicine biochemist Matthew Gentry had been racing to complete animal experiments in hopes that human trials using an enzyme compound could be launched by early next year. But in March, most of his lab was shut down, and he had to switch gears to focus on covid-19.
With his Lafora timetable blown up, Gentry worries delays in producing a treatment could mean some youngsters will be lost forever. “There is very likely a point of no return, but we don’t know what that point is,” he said. “The fear is that you have a patient who would have been in the good zone who has now moved into the non-recoverable zone.”
Lafora researchers in Los Angeles, Indianapolis and Europe also have had their work disrupted.
Jeri Kubicki, who lives in Cincinnati, is also alarmed by recent research delays. Her 7-year-old son, Blake, is one of fewer than 1,000 boys in the United States with Lowe syndrome, a genetic disorder that damages the eyes, brain and kidneys, and reduces life expectancy to 30 to 40 years. Blake functions like a 3-year-old, playing with his toy cars and dog — “a goofy kid who loves to laugh,” his mother said.
Last month, families affected by Lowe syndrome and a dozen researchers from throughout the world were scheduled to meet at the University of Montreal to decide how best to develop a treatment for the disease, but the gathering was canceled. “It was pretty deflating,” Kubicki said.
“People say, ‘What’s a few more months?’ “ said Robert Nussbaum, a former researcher at the University of California at San Francisco who identified the genetic cause of Lowe syndrome. “But a few months mean a lot to these families. They face a constant message that there is little we can do — but that could be changing.”
The disease that afflicts Anissa Merriam was named after Spanish neurologist Gonzalo Rodríguez Lafora. More than a century ago, he described abnormal substances in the brain. Today, scientists know genetic mutations cause abnormal glycogen, a form of sugar, and result in damaging aggregates, or clumps, called Lafora bodies.
Children with the disorder develop normally until early adolescence, then deteriorate and die within a decade of diagnosis.
“Your child sort of disappears in terms of who they are,” said Frank Harris, president of Chelsea’s Hope, a nonprofit dedicated to Lafora disease. “It’s very similar to what you would see with an elderly Alzheimer’s victim. Imagine seeing it with a 16-, 18- or 20-year-old child.” His daughter, Kelsey, died at 18.
For the past four years, Gentry, the Kentucky researcher, has led an NIH-funded collaboration called the Lafora Epilepsy Cure Initiative, made up of researchers in the United States, Canada and Europe. In animal studies, the scientists have discovered ways to eliminate the Lafora bodies and prevent their return.
In a breakthrough experiment in 2018, Gentry infused a novel enzyme-antibody drug into the brains of specially bred mice for seven days. The enzyme is found in saliva and the gut and breaks down complex sugars in food. The results were stunning: Nearly all the Lafora bodies were eliminated, and the animals’ brain chemistry was returned to normal. The results, published last year in the peer-reviewed journal Cell Metabolism, raised hopes the therapy may be able to not only stop the disease but reverse some of the damage it causes.
Based on Gentry’s work, a small biotech company, Valerion Therapeutics, has recently begun drug-safety studies in macaques. But that work can’t be completed until Gentry concludes experiments on mice to determine the right dose of the drug — information he won’t be able to provide until August or later. His lab is operating at 25 percent capacity, and his mice are now too old; a fresh group needs to reach the right age for the experimental therapy.
Lafora researchers at other universities in Gentry’s collaborative also have been pursuing gene therapy and traditional drugs. Yet another approach, with Ionis Pharmaceuticals, involves using antisense oligonucleotides, which are pieces of nucleic acids designed to bind to cells’ RNA — in this case, to fix a problem that leads to the production of abnormal glycogen.
Gentry and several other Lafora researchers said it’s important to develop different types of treatments, given the risk of failure. In addition, they said, a combination of therapies might work best. Ionis, which expressed confidence in its drug, said its research has not been delayed by the pandemic and that human trials may start next year.
Whether any treatment will be able to restore capacity to a seriously affected patient like Anissa Merriam is unknown.
Gentry believes that, even late in the disease, patients will be able to regain at least some of their abilities. But he acknowledged that only clinical trials will provide the answer.
Jenifer Merriam, who once owned a preschool, has tried hard to give her daughter a happy life, taking her to Japanese tea gardens and festivals and enrolling her in acting and tap dance classes. She remembers Anissa as a highly intelligent teenager who produced stunning drawings and had lots of friends.
In recent years, Anissa’s closest companions have been her family and the nurses and therapists who, before the pandemic, came several times a week. Her daughter’s high school friends stopped visiting years ago, another painful loss.
“You wake up every day, and all your friends’ daughters have gone off to school and are doing adult things,” Merriam said.
In 2018, Merriam was surprised to learn at a Lafora conference that researchers were making significant progress. At their request, she enrolled Anissa last December in a “natural history study” of the disease being conducted at a handful of hospitals. They went to the University of Texas Southwestern Medical Center in Dallas.
Such studies follow a group of people to understand how a disease develops and how best to treat it or design trials. In Dallas, Anissa underwent tests including an electroencephalogram and was told to return in six months. Researchers say the study may serve as a comparison group for trials, instead of a group given a placebo, though that ultimately will be up to federal regulators.
When a nurse at the hospital explained to Merriam about efforts that were being pursued to develop treatments, “I just sat and cried,” she said. “I was given a death sentence for my daughter 10 years ago and sent home. They gave me hope that I will not have to bury my daughter.”
But because of the coronavirus outbreak, participating hospitals put the natural history study on hold or scaled it back, as medical centers kept non-emergency patients out of their facilities to protect them from infection. It’s another delay that concerns researchers. Jenifer Merriam was worried that her daughter’s appointment for mid-June would be canceled, but she recently learned that they will have their next appointment in a little more than a week.
With nurses and therapists no longer coming to Merriam’s home because of the pandemic, Anissa’s 13-year-old brother and 20-year-old sister are helping their mother care for Anissa. Merriam sleeps with a baby monitor to make sure her daughter isn’t having a seizure or respiratory distress, which is typical of the disease.
For her 22nd birthday last month, Anissa wanted to have a dance party. Her mother agreed but insisted on physical distancing. As Anissa danced to Michael Jackson and Ariana Grande in the big entryway of their home, relatives and a few family friends took turns dancing with her, six feet apart.
“She might not be able to dance for her next birthday, so I’m going to let her dance and laugh and celebrate 22,” Jenifer Merriam said. “We will live today and enjoy today.”
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