A cure for an extremely rare disease, progeria, may be on the horizon. The disease accelerates the aging of children and dramatically shortens their lives. But until recently, there was no path to a highly effective treatment.
Now, with no expectation of financial gain, a small group of academic and government scientists, including Dr. Francis Collins, former director of the National Institutes of Health, are working on an innovative technique to stop progeria.
Gene editing could be effective in slowing or stopping progeria, researchers say, but the method could also help treat other rare genetic diseases that have no treatments or cures and, like progeria, have attracted little interest from pharmaceutical companies.
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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 of progeria gene editing.
The project “has benefits, but it also has 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 edit worked well in mice, there’s no guarantee it will work in human patients.
Collins first became interested in progeria while he was training as a medical geneticist at Yale University in 1982, nearly three decades before he was appointed to direct the NIH. One day, he saw a new patient, Meg Casey. She was less than four feet tall, hairless under her wig, and wrinkled like an older woman. She was only in her 20s.
She had progeria.
Collins was sad and moved. 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. Although Casey and others have reached 20, people with the disease often only live to be 14 or 15, and many die of heart attacks or strokes.
“I thought, ‘Gee, somebody should work on this,'” Collins recalls. “Then I moved on to other things.”
Nineteen years later, Collins, then leading a federal project to sequence the human genome, was approached at a party by Dr. Scott Berns, a pediatric emergency room physician, who told Collins that his toddler, Sam, had a terminal illness.
“I don’t know if you’ve heard of it,” Berns said. “It’s called progeria.”
“I know a little bit about it,” Collins replied.
He remembered Casey.
Collins invited Berns, his wife, Dr. Leslie Gordon, a pediatrician in training, and 4-year-old Sam to his home. Collins talked to Sam’s parents about the disease and played Frisbee with the boy. Sam lived to be 17 years old.
Gordon told Collins she was under no illusions: The disease was a curiosity, but not a research priority because of its rarity. So she, Berns and her sister Audrey, a lawyer, set up the Progeria Research Foundation to support promising studies.
“There was nothing else,” she said.
Collins was inspired. Although he was an administrator at the NIH, he also had a small lab and was free to do whatever he wanted. He decided to tackle progeria.
But it took years, and the advent of a new era of molecular medicine with advances in gene editing, before the prospect of a cure for progeria seemed possible.
The new types of gene editing are “potentially the answer to a dream that we all want to realize,” Collins said. “There are about 7,000 genetic diseases for which we know the mutation.”
Of these genetic diseases, 85% are extremely rare, affecting less than 1 in 1 million people.
And of those, Collins said, “only a few hundred have received treatment.”
The easy part
Collins began by giving an assignment to a new postdoctoral researcher in his lab: find the cause of progeria.
“Let’s try it for a year,” he told her.
That turned out to be the easy part. It took Maria Eriksson, the fellow, just a few months. A single letter in the string of 3 billion individual letters—each a G, A, C, and T—that make up human DNA was changed. At a certain spot in a gene known as lamin A, one of those letters is replaced by another. The result is the production of a toxic protein, progerin, which disrupts the scaffolding that holds a cell’s nucleus in its proper shape.
Eriksson, Collins and colleagues published a paper in 2003 explaining the finding.
The mutation in lamin A occurs in a sperm or egg cell before fertilization. It’s just a random, horrible bit of luck.
With the abnormal progerin, cells begin to deteriorate after a few divisions, looking more and more unusual. Eventually, the deterioration signals the cells to self-destruct.
The next step in the research was to stop the lamin A mutation in mice. Just like people with the disease, the animals aged rapidly, developed heart disease, wrinkled skin, and lost their hair. And they died young.
But it wasn’t until 2012, when CRISPR, a DNA-cutting technology, came onto the market, that the small research group thought they could come up with a bold new treatment. CRISPR could cut DNA and knock out a gene. But that was far from ideal — what they really needed was something that could fix a gene.
The solution emerged in 2017 from the lab of David Liu, a Harvard professor who is director of the Merkin Institute for Transformative Technologies in Healthcare. His group devised a gene-editing system that acts like a pencil at the site of a mutation, with an enzyme erasing one of the DNA letters — adenine, or A — and writing in a guanine, or G. That’s exactly what’s needed to correct the progeria mutation.
That gene-editing enzyme is never seen in nature. Nicole Gaudelli, then a postdoctoral researcher in Liu’s lab, produced one anyway in a survival-of-the-fittest experiment: Gaudelli forced bacteria to make the enzyme or die. (Liu has co-founded several gene-editing companies focused on treating more common diseases.)
Liu called the system his group invented “base editing” because it directly edits the letters, or bases, that make up DNA.
In one test, Luke Koblan, a graduate student working in Liu’s lab, attempted to fix the progeria mutation in patients’ cells growing in petri dishes. His experiment was successful.
Liu was elated. He had watched documentaries about progeria and the patients had touched his heart.
In 2018, Liu was invited to give a seminar at the NIH. He knew Collins would be in the audience, so he added a few slides about base editing cells from progeria patients.
Collins was fascinated. He called Gordon to tell her what he had heard.
“It was like a bolt of lightning,” Gordon said.
Here at last was real hope.
“I thought then, ‘Oh my God, let’s go,’” Collins recalls.
The hard part
NIH researchers first tried to improve the health of mice with progeria. They started with a preliminary single infusion of the base editor.
The results, reported in a 2021 paper, far exceeded their cautious expectations. Nearly all damage to the large heart arteries, a hallmark of the disease, was reversed. The mice looked healthy. They kept their hair. And they lived to the onset of senescence in mice — about 510 days — instead of dying after 215 days with progeria.
To streamline production 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. That was a tall order, because even nature’s original DNA-cutting CRISPR scissors system doesn’t fit into a single delivery mechanism.
Once they had achieved the shrinkage, the researchers had to test the new gene-editing enzyme on mice and see if the edit still worked. It did.
Now they are conducting a longer-term experiment to see if the mice grow old.
While they wait, the researchers are plotting the next steps to use their innovations to cure children with progeria. The team meets every Monday at 4 p.m. on Zoom.
Their goal is to get approval from the Food and Drug Administration to start a clinical trial.
An important step is finding a production partner who can create the basic editor for human use.
“We want to start this trial within two years or sooner,” Collins said.
And if it works? What if Progeria base editing helps point the way for thousands of other genetic diseases that can’t be treated?
“Then wow,” Collins said.
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