A cure for an extremely rare disease called progeria may be in sight. The condition causes children to age faster and significantly shortens their life expectancy. But until recently, there was no effective treatment.
Today, a small group of academics and government scientists, including Dr. Francis Collins, former director of the National Institutes of Health, are working without hope of financial gain to stop progeria using an innovative gene-editing technique.
If gene editing is effective in slowing or stopping progeria, the researchers say, the method could also help treat other rare genetic diseases that have no treatment or cure and, like progeria, have attracted little interest from pharmaceutical companies.
After a quarter-century of research, the group is approaching manufacturers and considering seeking regulatory approval for a clinical trial of gene editing for progeria.
The project “has merit, but also risks,” said Dr. Kiran Musunuru, a gene-editing researcher at the University of Pennsylvania who also advises a gene-editing company. He cautioned that while the editing worked well in mice, there’s no guarantee it will work in human patients.
Dr. Collins became interested in progeria while training in medical genetics at Yale University in 1982, nearly three decades before he was appointed head of the NIH. One day, he saw a new patient, Meg Casey. She was less than four feet tall, bald under her wig, and wrinkled like an older woman. She was only in her early twenties.
She suffered from progeria.
Dr. Collins was both saddened and moved. Little was known about the disease, which affects only one in 18 to 20 million people. According to the Progeria Research Foundation, there are only 18 patients still alive in the United States. While Ms. Casey and others have survived into their 20s, people with the disease often live only 14 or 15 years, and many die of heart attacks or strokes.
“I thought, ‘Oh my God, someone should take care of this,’” Collins recalls. “Then I moved on.”
Nineteen years later, Dr. Collins, then leading a federal project to map the human genome, was at a party when he was approached by Dr. Scott Berns, a pediatric emergency physician, who told him that his little boy, Sam, had a fatal disease.
“I don’t know if you’ve heard of it,” Dr. Berns said. “It’s called progeria.”
“I know a little more about that,” Dr. Collins replied.
He remembered Mrs. Casey.
Dr. Collins invited Dr. Berns, his wife, pediatric resident Dr. Leslie Gordon, and 4-year-old Sam to his home. Dr. Collins told Sam’s parents about the disease and played Frisbee with the boy. Sam lived to be 17.
Dr. Gordon told Dr. Collins that she had no illusions: the disease was a curiosity, but not a research priority because of its rarity. That’s why she, Dr. Berns, and her sister Audrey, a lawyer, created the Progeria Research Foundation to support promising studies.
“There was nothing else,” she said.
Dr. Collins was inspired. Although he was an administrator at the NIH, he also had a small laboratory and was free to study whatever he wanted. He decided to tackle progeria.
But it took years and the emergence of a new era of molecular medicine with advances in gene editing for the prospect of a cure for progeria to seem possible.
The new types of genetic modification are “potentially the answer to a dream we all want to see come true,” Dr. Collins said. “There are about 7,000 genetic diseases for which we know the mutation.”
Of these genetic diseases, 85% are ultra-rare, affecting less than one in a million people.
And of those, according to Dr. Collins, “only a few hundred are receiving treatment.”
The easy part
Dr. Collins began by giving a new postdoctoral researcher in his lab a mission: find the cause of progeria.
“Let’s give it a year,” he said.
That turned out to be the easy part. It took only a few months for researcher Maria Eriksson. Just one letter out of the three billion individual letters—each a G, A, C, or T—that make up human DNA was altered. At a specific location in a gene called lamin A, one of those letters is replaced by another. The result is the production of a toxic protein, progerin, that disrupts the scaffolding that holds a cell’s nucleus in its proper shape.
Dr. Eriksson, Dr. Collins and their colleagues published a paper explaining this discovery in 2003.
The lamin A mutation occurs in a sperm or egg before fertilization. It’s just a stroke of luck.
With aberrant progerin, cells begin to deteriorate after a few divisions, becoming increasingly unusual in appearance. Eventually, the deterioration triggers a self-destruct signal in the cells.
The next step in the research was to introduce the lamin A mutation into mice. As in humans with the disease, the animals aged rapidly, developed heart disease, developed wrinkled skin and lost their hair. And they died young.
But it wasn’t until the emergence of CRISPR, a DNA-cutting technology, in 2012 that the small research group thought a bold new treatment could be developed. CRISPR can cut DNA and turn off a gene. But it was far from ideal: what was really needed was something that could repair a gene.
The solution was born in 2017 in the lab of David Liu, a Harvard professor and director of the Merkin Institute for Transformative Technologies in Healthcare. His group invented a gene-editing system that acts like a pencil at the site of a mutation, using an enzyme to erase one of the letters in DNA—adenine, or A—and write in a guanine, or G. That’s exactly what’s needed to correct the progeria mutation.
This gene-editing enzyme doesn’t exist in nature. Nicole Gaudelli, who was a postdoctoral researcher in Dr. Liu’s lab at the time, produced one anyway, through a survival-of-the-fittest experiment: Dr. Gaudelli forced bacteria to make the enzyme or die. (Dr. Liu is a co-founder of several gene-editing companies aimed at treating more common diseases.)
Dr. Liu called the system invented by his group “base editing” because it directly changes the letters, or bases, that make up DNA.
In one experiment, Luke Koblan, a graduate student in Dr. Liu’s lab, tried to fix the progeria mutation in patient cells grown in petri dishes. His experiment was successful.
Dr. Liu was delighted. He had watched documentaries about progeria and the patients had touched his heart.
In 2018, Dr. Liu was invited to give a seminar at the NIH. He knew Dr. Collins would be in the audience, so he added some slides on base editing of cells from progeria patients.
Dr. Collins was fascinated. He called Dr. Gordon to tell him what he had heard.
“It was like a flash of lightning,” Dr. Gordon said.
Here at last is some real hope.
“I thought, ‘Oh my God, let’s do this,’” Dr. Collins recalls.
The hard part
NIH researchers first sought to improve the health of mice with progeria. They started with a simple infusion of the base editor.
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 appeared healthy. They kept their hair. And they lived to the onset of old age in mice — about 510 days — instead of dying at 215 days of progeria.
To streamline manufacturing and minimize potential side effects of the delivery method, Dr. 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 vector. This was a difficult task, because even the original CRISPR DNA-cutting scissor system from nature does not fit into a single delivery mechanism of this type.
Once the shrinkage was achieved, the researchers had to test the new gene-editing enzyme on mice and see if the editing still worked.
They are now conducting a longer experiment to see if the mice live to a ripe old age.
In the meantime, the researchers are considering next steps to use their innovations to cure children with progeria. The team meets on Zoom every Monday at 4 p.m.
Their goal is to obtain approval from the Food and Drug Administration to start a clinical trial.
A key step will be finding a manufacturing partner to make the base editor for use in humans.
“We want to start this trial in two years or less,” Dr. Collins said.
What if it works? What if editing progeria genes helps pave the way for thousands of other untreated genetic diseases?
“So wow,” Dr. Collins said.