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17.6.14


A single injection may soon permanently lower cholesterol levels in humans reducing their risk of heart attack by 90%.


Harvard Stem Cell Institute (HSCI) scientists collaborating with researchers at the University of Pennsylvania have developed a "genome-editing" approach for permanently reducing cholesterol levels in mice through a single injection.

The work focused on altering the function of a liver gene called PCSK9. In 2003, a group of researchers in France studying families with very high cholesterol levels and very early heart attacks discovered 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.

A research group in Texas discovered that about 3% of the population has 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% lower than the average level.

And the people with that good defect have heart attack risks that range from about 47 to 88% below average.The project to turn normal PCSK9 genes into those with the good defect started last year after a technology called CRISPR/Cas9, was discovered.

"Cas9 is a protein that will create a break in DNA and the CRISPR is an RNA component that will bind to a matching sequence. It directs the Cas9 to that sequence in the DNA in which we are interested. This creates a break where you want it. The cell can then repair itself though often with errors which is useful if you want to disrupt a gene," said Kiran Musunuru of HSCI.

"Our reasoning was that nature has already done the experiment; you have people who have won the genetic lottery," said Musunuru. "They are protected from heart attack, and there are no known adverse consequences. So that led us to reason that if we could find a way to replicate this, we could significantly protect people from heart attack," the scientist added.

"The PCSK9 gene is expressed primarily in the liver producing a protein that is active in the bloodstream and prevents the removal of cholesterol from the blood. Several drug companies have been developing antibodies to it but the problem with antibody-based drugs is they don't last forever; you'd need an injection every few weeks. The main option for reducing cholesterol is statin drugs such as Lipitor but many people taking statin drugs every day still have heart attacks. So there is still a great need for other approaches," Musunuru said.

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