Megan and Devin have the rapid-aging disorder progeria. (Photo courtesy of the Progeria Research Foundation)
Surely progeria is among the saddest of genetic diseases, and one of the rarest. The recent finding that a shelved cancer drug (lonafarnib) may provide a treatment is good news – for all of us.
An infant with progeria looks normal, but when he or she is between the ages of one and two, parents notice changes – or absence of them. Weight gain slows. Hair thins. The gums remain smooth, bereft of erupting teeth. Joints stiffen and bones weaken. Skin wrinkles as the child’s chubbiness melts away too quickly, and a cherubic toddler becomes increasingly bird-like in appearance.
Beneath the child’s toughening skin, blood vessels stiffen with premature atherosclerosis, fat pockets shrink, and connective tissue hardens. Inside cells, chromosome tips whittle down at a frightening rate, marking time too quickly. But some organs remain healthy, and intellect is spared.
The child with Hutchinson-Gilford progeria syndrome is hurtling towards old age. The end comes, typically during adolescence, from a heart attack or stroke.
The strange illness has been recognized for a very long time, and ignored until relatively recently. The first reported case was a 3½-year-old boy, described by Sir Jonathan Hutchinson, a surgeon and pathologist, in 1886. Another British surgeon, Hastings Gilford, followed up on the boy and added another, in 1897. Dr. Gilford named the condition "progeria," from the Greek for “old age.”
Now there’s wonderful news for the dozens of children known to have progeria, and possibly also for the many millions of people who have atherosclerosis. And it doesn’t involve complex technologies, such as gene therapy or stem cells, but repurposing of a drug originally intended to treat childhood brain cancer. It’s all thanks to understanding how a disease happens – basic research.
The journey towards a twice-daily pill that seems to slow or even reverse some of the ravages of progeria has followed an accelerated pace, just like the disease. It began with a chance meeting between the father of an affected child and Francis Collins, M.D., Ph.D., the director of the National Institutes of Health. Dr. Collins recently shared his memories of the occasion.
The scene: A farewell reception for Health and Human Services secretary Donna Shalala, on her exit from the Clinton administration in 2000.
A young man came up to Dr. Collins and introduced himself as Scott Berns, a White House fellow and emergency medical physician.
"I have a son with a rare disease, maybe one you’ve never heard of," he said to Dr. Collins.
"Try me."
"My son Sam has progeria," Dr. Berns answered.
"Actually, that is a disease I know something about. Tell me more," said Dr. Collins.
Flashback to the early 1980s. Dr. Collins was starting a fellowship in clinical genetics at Yale, when he was assigned a very unusual patient, 20-year-old Meg Casey, who was on the high end of the age scale for progeria.
"She was one feisty, remarkable young woman who never let her physical impairment get in the way. I felt very much like I wanted to do everything possible to help her, but there was very little anyone could do and very little known about this disease," Dr. Collins said.
He never forgot Meg, who died a few years later. Meanwhile, Dr. Collins had gone to the University of Michigan, where he led a team that identified several key disease-causing genes throughout the 1990s. But progeria was a much tougher nut to crack.
"It seemed pretty hopeless, because progeria never recurs in families. So the tools we were used to being available for cystic fibrosis, Huntington’s disease, neurofibromatosis, weren’t available," Dr. Collins said. The disease is too severe for anyone to survive to have kids, and so cases arise spontaneously – in sperm. And the mutation is dominant, one impaired copy of the gene enough to cause disease.
Dr. Collins invited 3-year-old Sam and his parents, Dr. Berns and his wife Leslie Gordon, M.D., Ph.D., to visit him and his wife Diane, who is a genetic counselor. There, they decided to set up a foundation to stimulate and coordinate research into identifying the mutation responsible for progeria – the first step in seeking a treatment. Dr. Collins was becoming convinced that something could indeed be done about the disease.
They were starting from scratch, although it helped to have the then-head of the National Human Genome Research Institute on board.
"When Sam was diagnosed, we didn’t have the mutation. There was no research, no treatments, and physicians had no place to go for information. That’s why we started the Progeria Research Foundation [PRF]. There was absolutely nothing going on and no hope of a future for this 100% fatal disease. So we wanted to find out what people needed to jumpstart the field and do it," said Dr. Gordon, who is lead author on the September 27, 2012 report in the Proceedings of the National Academy of Sciences announcing the exciting preliminary results using the drug lonafarnib. She is affiliated with Boston Children’s Hospital and Hasbro Children’s Hospital in Rhode Island.
The PRF formed in 1999, less than a year after Sam’s diagnosis. The patient advocacy research organization established a cell and tissue bank, assembled a research team, and raised enough funds, some from the NIH, to get started.
Dr. Collins’ team got involved. "I had a new post-doc, Maria Eriksson. We sat down to talk about what she’d be working on. I said, 'if you’re interested in something high risk, try progeria and see if we can get the answer.'" Just four years later, Dr. Eriksson would be lead author on the Nature paper unveiling the progeria gene.
The clinicians and scientists who formed the PRF’s genetics consortium discovered the gene in record time. What "helped hugely," Dr. Collins told me, was that fibroblasts (connective tissue cells) were already available from the Coriell Cell Repository in Camden, NJ. Physicians had sent them in over the years whenever they’d examine a patient who seemed to be rapidly aging, and "without those cells, the gene discovery would have taken us a very long time." A few patients with abnormal chromosomes led the researchers to a site on chromosome 1 that includes a gene called LMNA, which encodes the protein lamin A. And the gene was already known to cause several diseases.
PRF had set up a genetics consortium to hunt down the gene in 2002, and Dr. Gordon, with her three qualifications -- physician, scientist, and parent -- served as something of a catalyst. But she’s quick to credit Dr. Collins. "He was busy sequencing the human genome, but he took on the smallest and most rare disease on earth."
Dr. Collins still sounds excited when discussing the discovery. "We found the answer, and it took just about a year. It was one nucleotide in codon 608 in the lamin A gene." That little glitch activated a splice site in the gene, and as a result, 50 of its 656 amino acids were snipped out of the corresponding protein, like removing a clause from a sentence in a way that destroys the meaning. The shortened version of lamin A was named progerin -- and we all have it. The errant protein builds up as we age.
Five of the 25 samples that the PRF team worked with to find the progeria gene had different mutations, not the splice site error. One patient's cells were especially intriguing, because the mutation came as a double dose from one parent, a phenomenon called uniparental disomy. "When I read the report it looked familiar. It was Meg Casey! I’d forgotten I’d sent her sample to Coriell, hoping someone would work on her cells, never dreaming 20 years later that it would be me!" Dr. Collins recalled.
And then the best of all possible things happened. The change in the lamin A protein in most of the patients – the missing 50 amino acids -- suggested precisely how the pace of life is so tragically sped up.
The deletion removes a site from one end of the protein that normally binds an organic molecule called farnesyl. Eighteen amino acids at the end plus the farnesyl must be jettisoned for the protein to nestle smoothly in the nuclear membrane and interact with the chromosomes within. Instead, the nuclear membranes bulge as they dip near the genetic material. When progerin tenaciously hangs onto its farnesyl, the altered activity somehow causes the accelerated aspects of aging, which seem to center on connective tissues.
Amazingly, a class of experimental drugs already existed that block farnesyl binding, accomplishing what’s supposed to happen by an alternate route -- theoretically.
Drug discovery is at its best when what’s predicted to counter a disease actually does, and that’s what’s apparently happening in the continuing saga of progeria. I’ll finish the latest chapter in this ongoing genetic success story next week!
(This post first appeared at PLoS Blogs and I wrote a more technical article for Medscape Medical News)
An infant with progeria looks normal, but when he or she is between the ages of one and two, parents notice changes – or absence of them. Weight gain slows. Hair thins. The gums remain smooth, bereft of erupting teeth. Joints stiffen and bones weaken. Skin wrinkles as the child’s chubbiness melts away too quickly, and a cherubic toddler becomes increasingly bird-like in appearance.
Beneath the child’s toughening skin, blood vessels stiffen with premature atherosclerosis, fat pockets shrink, and connective tissue hardens. Inside cells, chromosome tips whittle down at a frightening rate, marking time too quickly. But some organs remain healthy, and intellect is spared.
The child with Hutchinson-Gilford progeria syndrome is hurtling towards old age. The end comes, typically during adolescence, from a heart attack or stroke.
The strange illness has been recognized for a very long time, and ignored until relatively recently. The first reported case was a 3½-year-old boy, described by Sir Jonathan Hutchinson, a surgeon and pathologist, in 1886. Another British surgeon, Hastings Gilford, followed up on the boy and added another, in 1897. Dr. Gilford named the condition "progeria," from the Greek for “old age.”
Now there’s wonderful news for the dozens of children known to have progeria, and possibly also for the many millions of people who have atherosclerosis. And it doesn’t involve complex technologies, such as gene therapy or stem cells, but repurposing of a drug originally intended to treat childhood brain cancer. It’s all thanks to understanding how a disease happens – basic research.
The journey towards a twice-daily pill that seems to slow or even reverse some of the ravages of progeria has followed an accelerated pace, just like the disease. It began with a chance meeting between the father of an affected child and Francis Collins, M.D., Ph.D., the director of the National Institutes of Health. Dr. Collins recently shared his memories of the occasion.
The scene: A farewell reception for Health and Human Services secretary Donna Shalala, on her exit from the Clinton administration in 2000.
A young man came up to Dr. Collins and introduced himself as Scott Berns, a White House fellow and emergency medical physician.
"I have a son with a rare disease, maybe one you’ve never heard of," he said to Dr. Collins.
"Try me."
"My son Sam has progeria," Dr. Berns answered.
"Actually, that is a disease I know something about. Tell me more," said Dr. Collins.
Flashback to the early 1980s. Dr. Collins was starting a fellowship in clinical genetics at Yale, when he was assigned a very unusual patient, 20-year-old Meg Casey, who was on the high end of the age scale for progeria.
"She was one feisty, remarkable young woman who never let her physical impairment get in the way. I felt very much like I wanted to do everything possible to help her, but there was very little anyone could do and very little known about this disease," Dr. Collins said.
He never forgot Meg, who died a few years later. Meanwhile, Dr. Collins had gone to the University of Michigan, where he led a team that identified several key disease-causing genes throughout the 1990s. But progeria was a much tougher nut to crack.
"It seemed pretty hopeless, because progeria never recurs in families. So the tools we were used to being available for cystic fibrosis, Huntington’s disease, neurofibromatosis, weren’t available," Dr. Collins said. The disease is too severe for anyone to survive to have kids, and so cases arise spontaneously – in sperm. And the mutation is dominant, one impaired copy of the gene enough to cause disease.
Dr. Collins invited 3-year-old Sam and his parents, Dr. Berns and his wife Leslie Gordon, M.D., Ph.D., to visit him and his wife Diane, who is a genetic counselor. There, they decided to set up a foundation to stimulate and coordinate research into identifying the mutation responsible for progeria – the first step in seeking a treatment. Dr. Collins was becoming convinced that something could indeed be done about the disease.
They were starting from scratch, although it helped to have the then-head of the National Human Genome Research Institute on board.
"When Sam was diagnosed, we didn’t have the mutation. There was no research, no treatments, and physicians had no place to go for information. That’s why we started the Progeria Research Foundation [PRF]. There was absolutely nothing going on and no hope of a future for this 100% fatal disease. So we wanted to find out what people needed to jumpstart the field and do it," said Dr. Gordon, who is lead author on the September 27, 2012 report in the Proceedings of the National Academy of Sciences announcing the exciting preliminary results using the drug lonafarnib. She is affiliated with Boston Children’s Hospital and Hasbro Children’s Hospital in Rhode Island.
The PRF formed in 1999, less than a year after Sam’s diagnosis. The patient advocacy research organization established a cell and tissue bank, assembled a research team, and raised enough funds, some from the NIH, to get started.
Dr. Collins’ team got involved. "I had a new post-doc, Maria Eriksson. We sat down to talk about what she’d be working on. I said, 'if you’re interested in something high risk, try progeria and see if we can get the answer.'" Just four years later, Dr. Eriksson would be lead author on the Nature paper unveiling the progeria gene.
The clinicians and scientists who formed the PRF’s genetics consortium discovered the gene in record time. What "helped hugely," Dr. Collins told me, was that fibroblasts (connective tissue cells) were already available from the Coriell Cell Repository in Camden, NJ. Physicians had sent them in over the years whenever they’d examine a patient who seemed to be rapidly aging, and "without those cells, the gene discovery would have taken us a very long time." A few patients with abnormal chromosomes led the researchers to a site on chromosome 1 that includes a gene called LMNA, which encodes the protein lamin A. And the gene was already known to cause several diseases.
PRF had set up a genetics consortium to hunt down the gene in 2002, and Dr. Gordon, with her three qualifications -- physician, scientist, and parent -- served as something of a catalyst. But she’s quick to credit Dr. Collins. "He was busy sequencing the human genome, but he took on the smallest and most rare disease on earth."
Dr. Collins still sounds excited when discussing the discovery. "We found the answer, and it took just about a year. It was one nucleotide in codon 608 in the lamin A gene." That little glitch activated a splice site in the gene, and as a result, 50 of its 656 amino acids were snipped out of the corresponding protein, like removing a clause from a sentence in a way that destroys the meaning. The shortened version of lamin A was named progerin -- and we all have it. The errant protein builds up as we age.
Five of the 25 samples that the PRF team worked with to find the progeria gene had different mutations, not the splice site error. One patient's cells were especially intriguing, because the mutation came as a double dose from one parent, a phenomenon called uniparental disomy. "When I read the report it looked familiar. It was Meg Casey! I’d forgotten I’d sent her sample to Coriell, hoping someone would work on her cells, never dreaming 20 years later that it would be me!" Dr. Collins recalled.
And then the best of all possible things happened. The change in the lamin A protein in most of the patients – the missing 50 amino acids -- suggested precisely how the pace of life is so tragically sped up.
The deletion removes a site from one end of the protein that normally binds an organic molecule called farnesyl. Eighteen amino acids at the end plus the farnesyl must be jettisoned for the protein to nestle smoothly in the nuclear membrane and interact with the chromosomes within. Instead, the nuclear membranes bulge as they dip near the genetic material. When progerin tenaciously hangs onto its farnesyl, the altered activity somehow causes the accelerated aspects of aging, which seem to center on connective tissues.
Amazingly, a class of experimental drugs already existed that block farnesyl binding, accomplishing what’s supposed to happen by an alternate route -- theoretically.
Drug discovery is at its best when what’s predicted to counter a disease actually does, and that’s what’s apparently happening in the continuing saga of progeria. I’ll finish the latest chapter in this ongoing genetic success story next week!
(This post first appeared at PLoS Blogs and I wrote a more technical article for Medscape Medical News)