Washington:
Researchers, led by an Indian-origin scientist, have developed a "genome-editing" approach for permanently reducing cholesterol levels in mice through a single injection, a development that could reduce the risk of heart attacks in humans by 40 to 90 per cent.
"For the first iteration of an experiment, this was pretty remarkable," said Kiran Musunuru of Harvard Stem Cell Institute (HSCI), an assistant professor in Harvard's Department of Stem Cell and Regenerative Biology (SCRB).
Mr Musunuru, however, cautioned that it could take a decade of concerted effort to get this approach for fighting heart disease from the laboratory to phase I clinical trials in humans.
Mr Musunuru and colleagues at the University of Pennsylvania focused on altering the function of a liver gene called PCSK9. In 2003, researchers in France studying families with very high cholesterol levels and very early heart attacks found that PCSK9 was a cholesterol regulator, because they found that mutations in this gene seemed to be responsible for the high cholesterol levels and the heart attacks.
But a research group in Texas discovered that about 3 per cent of the population have mutations in PCSK9 that have the opposite effect.
Those with the mutations have low-density lipoprotein (LDL, or bad) cholesterol levels about 15 to 28 per cent lower than the average level. And the people with that "good" defect have heart attack risks that range from about 47 to 88 per cent below average.
Mr Musunuru and colleagues' project to turn normal PCSK9 genes into those with the "good" defect came at an inflection point in genome editing, the refinement early last year of a technology called CRISPR/Cas9, first discovered in 2007.
"What we were thinking was that, with this genome-editing technology, we can do something we couldn't do before: make permanent changes in the genome at the level of the DNA. We can actually go to the source," said Mr Musunuru.
"So the question was whether we can use genome editing to make normal people like people born with the 'good' mutations. The answer, in mice, was yes," Mr Musunuru said.
"The first question was whether we could get CRISPR/Cas9 into the liver, and once we got it into the liver, would it function properly?" Mr Musunuru asked. "And it did. It could have had no effect, but it turned out to have a dramatic effect. Within three to four days of delivering the system into the liver, the majority of the PCSK9 gene copies in all of the liver cells were disrupted, knocked out. And what we hoped to see was much less of the protein product in the bloodstream, which is what we saw.
"The other consequence that we saw was a 35 to 40 per cent reduction in cholesterol levels in these mice, which would translate in humans to a heart attack risk-reduction of as high as 90 per cent," Mr Musunuru said.
The research was published in Circulation Research, a journal of the American Heart Association.
"For the first iteration of an experiment, this was pretty remarkable," said Kiran Musunuru of Harvard Stem Cell Institute (HSCI), an assistant professor in Harvard's Department of Stem Cell and Regenerative Biology (SCRB).
Mr Musunuru, however, cautioned that it could take a decade of concerted effort to get this approach for fighting heart disease from the laboratory to phase I clinical trials in humans.
Mr Musunuru and colleagues at the University of Pennsylvania focused on altering the function of a liver gene called PCSK9. In 2003, researchers in France studying families with very high cholesterol levels and very early heart attacks found that PCSK9 was a cholesterol regulator, because they found that mutations in this gene seemed to be responsible for the high cholesterol levels and the heart attacks.
But a research group in Texas discovered that about 3 per cent of the population have mutations in PCSK9 that have the opposite effect.
Those with the mutations have low-density lipoprotein (LDL, or bad) cholesterol levels about 15 to 28 per cent lower than the average level. And the people with that "good" defect have heart attack risks that range from about 47 to 88 per cent below average.
Mr Musunuru and colleagues' project to turn normal PCSK9 genes into those with the "good" defect came at an inflection point in genome editing, the refinement early last year of a technology called CRISPR/Cas9, first discovered in 2007.
"What we were thinking was that, with this genome-editing technology, we can do something we couldn't do before: make permanent changes in the genome at the level of the DNA. We can actually go to the source," said Mr Musunuru.
"So the question was whether we can use genome editing to make normal people like people born with the 'good' mutations. The answer, in mice, was yes," Mr Musunuru said.
"The first question was whether we could get CRISPR/Cas9 into the liver, and once we got it into the liver, would it function properly?" Mr Musunuru asked. "And it did. It could have had no effect, but it turned out to have a dramatic effect. Within three to four days of delivering the system into the liver, the majority of the PCSK9 gene copies in all of the liver cells were disrupted, knocked out. And what we hoped to see was much less of the protein product in the bloodstream, which is what we saw.
"The other consequence that we saw was a 35 to 40 per cent reduction in cholesterol levels in these mice, which would translate in humans to a heart attack risk-reduction of as high as 90 per cent," Mr Musunuru said.
The research was published in Circulation Research, a journal of the American Heart Association.
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