August 26, 2011 / 7:40 PM / 8 years ago

Separate paths lead to promising cholesterol drug

NEW YORK, Aug 26 (Reuters) - Discovery of one of the most promising cholesterol fighters in decades began in 1999 with Catherine Boileau, a Paris scientist who was seeking a genetic reason why 19 members of two French families she was studying had sky-high levels of “bad” LDL cholesterol.

Their LDL levels were in the 300 to 400 range, making them prone to early heart attack and death. Using gene-mapping, Boileau and colleagues at Paris-Ouest Medical School theorized that a gene in a specific area of Chromosome 1 was responsible.

She published her limited findings in the American Journal of Human Genetics the same year, an important step in what may pave the way for the next big breakthrough in treating heart disease. [ID:nN1E77L1IP]

For the following three years, Boileau and doctoral student Marianne Abifadel painstakingly analyzed about 50 genes in the chromosome, but none emerged as the likely culprit. With scores of other genes left to examine, her phone rang one day.

“I know you don’t know me, and I don’t know you, but we seem to be working on something similar,” said biochemist Nabil Seidah from the Clinical Research Institute of Montreal, who had read Boileau’s 1999 paper.

Seidah, in conducting unrelated research, had discovered a gene on Chromosome 1 which he quickly speculated might regulate cholesterol. He found the gene produced a protein highly present on the surface of liver cells, which are responsible for most of the body’s production of cholesterol.

“Catherine asked me, ‘How do you know this is the same gene I’m looking for?’ And I said, ‘I don’t, but I have a hint because it’s very rich in the liver.’”

Boileau then turned her full attention to the gene and its protein, an enzyme later named PCSK9. It was the ninth member of a family of enzymes Seidah had discovered, all of which were involved in activating hormones and cell-surface proteins.

“It was a very bewildering new protein, also found in the kidney and the brain, but we didn’t know what it does,” Boileau said.

Further analysis showed that all affected members of one French family had an identical mutation in the PCSK9 gene, while members of a smaller affected family shared a different mutation.

Although the mutations were different, they both appeared to have the same effect of creating LDL levels in the bloodstream five to 10 times higher than levels found in the general population. Some family members began showing signs of heart disease in their teenage years.

Boileau and Seidah published their joint findings in June 2003, but were still unaware of just how the gene functioned.

An answer came the following year from Rockefeller University in New York, where researcher Jan Breslow and his doctoral assistant Kara Maxwell had conducted mouse studies of the newly discovered gene and protein.

“We took the gene and put it into a virus, and then injected the virus into normal mice,” thereby elevating their PCSK9 beyond normal degrees, recalls Breslow. “Within just a day or two, the mice went from having very low levels of bad cholesterol to high levels that resemble what we see with familial hypercholesterolemia. It was a result that was so clear, and that doesn’t come along every day with research.”

Breslow’s studies showed that PCSK9 wipes out LDL receptors, proteins that bind to LDL cholesterol in the liver and remove the artery-clogging substance from the bloodstream.

The mechanism is just one of many ways the body regulates levels of LDL — to make sure there is enough of it to perform vital body functions, although not more than is necessary. By destroying LDL receptors, PCSK9 allows LDL to build in the bloodstream.

The specific mutations in PCSK9 found in the French families — called “gain-in-function” mutations — made the protein 10-fold more active than natural PCSK9 in destroying LDL receptors. It was doing its job far too well.

A separate discovery in Dallas, Texas, supplied remaining pieces of the PCSK9 puzzle in 2005.

It came from a laboratory at the University of Texas Southwestern Medical Center, where Michael Brown and Joseph Goldstein had won Nobel Prizes in 1985 for discovering the LDL receptor.

Helen Hobbs and Jonathan Cohen, colleagues of Brown and Goldstein, discovered that 2 percent of African-Americans in their study group had a far different inherited mutation in the PCSK9 gene.

Instead of elevating their LDL levels — as seen with the mutations in Boileau’s study — it led to LDL levels a third lower than those seen in the general population. And the mutation, by largely disabling PCSK9, had have greatly shielded the group from heart disease.

The surprise findings suggested that blocking PCSK9 with drugs might offer similar benefits.

“The therapeutic implications are immense,” Brown said after Hobbs’ and Cohen’s conclusions were published, calling them the most important work in cholesterol metabolism since his and Goldstein’s discoveries a generation earlier. (Reporting by Ransdell Pierson, editing by Matthew Lewis)

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