A cure for an ultrarare disease, progeria, could be on the horizon. The disease accelerates aging in children and greatly shortens their lives. But, until recently, there was no path towards a very effective treatment.
Now, a small group of academics and government scientists, including Dr. Francis Collinsformer director of the National Institutes of Health, working with no expectation of financial gain to stop progeria in its tracks with an innovative gene editing technique.
If gene editing is effective in slowing or stopping progeria, researchers say, the method could also help treat other rare genetic diseases that have no treatment or cure and, like progeria, receive little attention from companies. drugs.
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After a quarter of a century of research, the group is approaching manufacturers and planning to seek regulatory approval for a clinical trial of progeria gene editing.
“The project has value, but also risk,” 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 is no guarantee it will work in human patients.
Collins first 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 4 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. Little was known about the disease, which affects 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 have lived into their 20s, people with the disease often live only 14 or 15 years, and many die of heart attacks or strokes.
“I thought, ‘Gosh, somebody should work on this,'” Collins said. “Then I went on to other things.”
Nineteen years later, Collins, then in charge of a federal project to map the human genome, was at a party when Dr. Scott Berns, a pediatric emergency room physician, contacted him. He 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 about it,” Collins replied.
He remembered Casey.
Collins invited Berns; his wife, Dr. Leslie Gordon, pediatric resident; 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 until he was 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, founded the Progeria Research Foundation to support promising studies.
“There was nothing else,” she said.
Collins was motivated. 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 take on progeria.
But it took years, as a new era of molecular medicine emerged with advances in gene editing, for progeria to appear to be curable.
The new types of gene editing “could be the answer to a dream we all want to come true,” 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 among them, Collins said, “only a few hundred have treatments.”
The Easy Part
Collins began giving a new postdoc in his lab an assignment: Find the cause of progeria.
“We’d give it a year,” he told her.
That was the easy part. It only took Maria Eriksson, the man, a few months. A single letter was changed among the string of 3 billion individual letters — each G, A, C and T — that make up human DNA. 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, which disrupts the scaffolding that keeps the cell’s nucleus in its proper shape.
Eriksson, Collins and colleagues published a paper explaining the finding in 2003.
The mutation in lamin A occurs in a sperm or egg cell before fertilization. It’s just a random bit of terrible luck.
With the aberrant progerin, cells begin to decline after several divisions, looking larger and more abnormal. Eventually, the degeneration sends out a signal in the cells to destroy themselves.
The next step in the research was to introduce the lamin A mutation into mice. As in humans with the disease, the animals grew old quickly, heart disease, wrinkled skin and lost their hair. And they died young.
But it wasn’t until the advent of CRISPR, a DNA-cutting technology, in 2012 that the small research group thought a bold new treatment could be devised. CRISPR can slice DNA and disable a gene. That, however, was far from ideal – what was really needed was something that could repair a gene.
The solution emerged in 2017 from the laboratory of David Liu, a Harvard professor who is 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 delete one of the DNA letters – adenine, or A – and write in guanine, or G. That’s exactly what is needed. to correct the progeria mutation.
That gene editing enzyme is never seen in nature. Nicole Gaudelli, who was a postdoctoral researcher in Liu’s lab at the time, produced one anyway with an excellent survival experiment: Gaudelli forced bacteria to make the enzyme or die. (Liu is a 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 edits the letters, or bases, that make up DNA.
In one test, Luke Koblan, a graduate student working in Liu’s lab, tried to correct the progeria mutation in patient cells grown in petri dishes. His experiment was a success.
Liu was delighted. He watched documentaries on progeria, and the patients 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 put up a few slides of edited stem cells from progeria patients.
Collins had rivets. 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’m like, ‘Oh, my god, let’s go,'” Collins said.
The hard part
NIH researchers first tried to improve the health of mice with progeria. They started with a single trial infusion of the original.
The results, documented in a 2021 paper, exceeded their cautious hopes. Almost all the damage to large heart arteries, the hallmark of the disease, was reversed. The mice looked healthy. They kept their hair. And they lived until the beginning of old age in mice – about 510 days – instead of dying at 215 days with progeria.
To streamline manufacturing 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 deliver to cells in a single molecular carrier. It was a tall order because even the original DNA-cutting CRISPR scissor system by nature does not fit into one such delivery mechanism.
Once they achieved the contraction, the researchers had to test the new gene editing enzyme in mice and see if the editing still worked. He was.
Now, they are running a longer experiment to see if the mice live to old age.
While they wait, the researchers are figuring out the next steps to use their innovations to cure children with progeria. The team meets on Zoom every Monday at 4 pm
Their goal is to get approval from the Food and Drug Administration to start a clinical trial.
A key step will be to find a manufacturing partner to make an original editor for use in humans.
“We want to start this trial in two years or less,” Collins said.
And if it works? If editing the base of progeria helps show the way to thousands of other genetic diseases without any treatment?
“Wow there,” Collins said.
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