A cure for the ultra-rare disease progeria may be on the horizon. The disease accelerates the aging of children and significantly shortens their lives. But until recently, there was no path to a highly effective treatment.
Now, among them, Dr. Francis CollinsThe former director of the National Institutes of Health is working on an innovative gene-editing technique to stop the disease progeria, with no expectation of financial gain.
If gene editing is effective in slowing or stopping progeria, the researchers say, it could help treat other rare genetic diseases, such as progeria, that have little interest from pharmaceutical companies and for which there is no cure or treatment.
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After a quarter-century of research, the group is approaching manufacturers and plans to seek regulatory approval for a clinical trial on progeria gene editing.
Dr. Kiran Musunuru, a gene-editing researcher at the University of Pennsylvania who also consults for a gene-editing company, said the project was “valuable but also risky.” She warned that while the editing worked well in mice, there was no guarantee it would work in human patients.
Collins first became interested in progeria while studying medical genetics at Yale University in 1982, nearly three decades before he was appointed to head the NIH. One day, he saw a new patient, Meg Casey. Less than 4 feet tall, balding under her wig, and wrinkled like an old woman. She was only in her 20s.
He had progeria.
Collins was saddened and emotional. Almost nothing was known about the disease, which affects only 1 in 18 to 20 million people. According to the Progeria Research Foundation, there are only 18 known living patients in the United States. While Casey and others survive into their 20s, people with the disease typically live only to age 14 or 15, and many die of heart attacks or strokes.
“I thought, ‘Oh my God, someone’s got to work on this,'” Collins recalls. “Then I moved on to other things.”
Nineteen years later, Collins, who was then heading a federal project to map the human genome, was approached at a party by pediatric emergency room physician Dr. Scott Berns, who told Collins that his toddler, Sam, had a terminal illness.
“I don’t know if you’ve heard of this,” Berns said. “It’s called progeria.”
“I know a little bit about that,” Collins replied.
He remembered Casey.
Collins invited Berns, his wife, pediatric resident Dr. Leslie Gordon, and 4-year-old Sam to his home. Collins talked with Sam’s family about the disease and played Frisbee with the boy. Sam lived to be 17.
Gordon told Collins he was under no illusions — the disease was a curiosity, but because of its rarity, it wasn’t a research priority. So he, Berns, and his sister Audrey, a lawyer, founded the Progeria Research Foundation to support promising studies.
“There was nothing else,” he said.
Collins was inspired. Although he was a director at the NIH, he also had a small laboratory and was free to study whatever he wanted. He decided to focus on progeria.
But it took years for a cure for progeria to appear possible, and advances in gene editing have ushered in a new era of molecular medicine.
Collins said new types of gene editing were “the potential answer to a dream that we all want to see come true.” “There are about 7,000 genetic diseases that we know the mutations for.”
85 percent of these genetic diseases are very rare, affecting less than 1 in 1 million people.
Of those, “only a few hundred have received treatment,” Collins said.
The Easy Part
Collins began by giving the new postdoctoral researcher in his lab an assignment: Find the cause of progeria.
“Let’s wait a year,” he told her.
This turned out to be the easy part. It took Maria Eriksson, your friend, just a few months. Of the 3 billion individual letter sequences that make up human DNA—a G, A, C, and T each—a single letter was changed. At a specific point in a gene known as lamin A, one of these letters was swapped for another. The result is the production of progerin, a toxic protein that disrupts the skeleton that holds the cell’s nucleus in place.
Eriksson, Collins and colleagues published a paper describing their findings in 2003.
The mutation in Lamin A occurs in a sperm or egg cell before fertilization. It’s just random, terrible luck.
With abnormal progerin, cells begin to deteriorate after a few divisions and appear increasingly unusual. Eventually, the deterioration triggers a self-destruct signal in the cells.
The next step in the research was to put the lamin A mutation into mice. Like humans with the disease, the animals aged rapidly, developed heart disease, wrinkled skin and hair loss, and died young.
But it wasn’t until the DNA-cutting technology CRISPR emerged in 2012 that the small research group thought a bold new treatment could be designed. CRISPR can cut DNA and disable a gene. But this was far from ideal — what was really needed was something that could repair a gene.
The solution emerged in 2017 from the lab of Harvard professor David Liu, director of the Merkin Institute for Transformative Technologies in Health. His group invented a gene-editing system that acts like a pen at the site of a mutation, using an enzyme to delete one of the DNA letters—adenine, or A—and write in a guanine, or G. That’s exactly what’s needed to fix the progeria mutation.
This gene-editing enzyme has never been seen in nature. Nicole Gaudelli, then a postdoctoral researcher in Liu’s lab, created one anyway, using a survival-of-the-fittest experiment: Gaudelli forced bacteria to either produce the enzyme or die. (Liu is the co-founder of several gene-editing companies aimed at treating more common diseases.)
Liu called the system his group invented “base editing” because it directly organizes the bases, the letters that make up DNA.
In one test, Luke Koblan, a graduate student working in Liu’s lab, tried to correct the progeria mutation in patients’ cells growing in petri dishes. His experiment was successful.
Liu was excited. He had seen documentaries about progeria and the patients had touched his heart.
Liu was invited to give a seminar at the NIH in 2018. He knew Collins would be in the audience, so he included a few slides about base-editing cells from progeria patients.
Collins was fascinated and called Gordon to tell him what he had heard.
“It was like a lightning strike,” Gordon said.
Here, at last, real hope has emerged.
“I thought, ‘Oh my God, let’s go,'” Collins said.
The Hard Part
The NIH researchers first tried to improve the health of mice with progeria, starting with a single transient infusion of the base regulator.
The results, documented in a 2021 paper, far exceeded their cautious hopes. Nearly all of the damage to the large heart arteries that is a hallmark of the disease was reversed. The mice looked healthy. They kept their hair. And they lived to the onset of old age — about 510 days in the case of mice — instead of dying in 215 days with progeria.
To make manufacturing easier and minimize potential side effects of the delivery method, Liu’s group had to shrink the size of the gene editor, which was too large to be delivered to cells in a single molecular carrier. This was a challenge because even nature’s original DNA-cutting CRISPR scissors system doesn’t fit into a single delivery mechanism.
Once they had managed to shrink it, the researchers had to test the new gene-editing enzyme in mice to see if the editing still worked. It did.
They are now running a longer-term experiment to see if the mice can survive to old age.
While they wait, the researchers are working on figuring out the next steps for using their innovation to treat children with progeria. The team meets every Monday at 4 p.m. on Zoom
Their goal is to get permission from the Food and Drug Administration to begin clinical research.
One important step will be to find a manufacturing partner to produce the core regulator for use in humans.
“We want to start this trial in two years or less,” Collins said.
But what if it works? Progeria base editing could help lead to thousands of other genetic diseases that have no cure?
“Then wow,” Collins said.
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