April 04, 2005
PCSK9 Gene New Target For Cholesterol Lowering Drugs

The gene for the protein PCSK9 is a promising new target for the development of a new class of cholesterol lowering drugs.

DALLAS March 29, 2005 Mice lacking a key protein involved in cholesterol regulation have low-density lipoprotein, or "bad" cholesterol, levels more than 50 percent lower than normal mice, and researchers suggest that inhibiting the same protein in humans could lead to new cholesterol-lowering drugs.

In a study to be published in the Proceedings of the National Academy of Sciences and available online this week, researchers at UT Southwestern Medical Center deleted the Pcsk9 gene in mice. The gene, present in both mice and humans, makes the PCSK9 protein, which normally gets rid of receptors that latch onto LDL cholesterol in the liver. Without this degrading protein, the mice had more LDL receptors and were thus able to take up more LDL cholesterol from their blood.

"The expression of LDL receptors is the primary mechanism by which humans lower LDL cholesterol in the blood," said Dr. Jay Horton, associate professor of internal medicine and molecular genetics and senior author of the study. "This research shows that in mice, deleting the PCSK9 protein results in an increase in LDL receptors and a significant lowering of LDL cholesterol."

The results of this study illustrate how new drug development begins. When a protein is found to play a key role in regulating some part of metabolism that can contribute to disease development or disease prevention then suddenly the pharmaceutical companies have a new target for for drug development. Pharmaceutical firms may well react to this report by screening tens of thousands of chemical compounds to look for compounds that bind to the protein PCSK9. Or (and more expensively), the pharma companies could grow cells that express PCSK9 in culture and then introduce compounds to see if the compounds increase or decrease the amount of PCSK9 found in those cells.

Another important thing to note about this study: The investigation relied on the ability to produce a mouse strain which has the PCSK9 gene deleted or disabled. The techniques used to knock out genes and produce special strains of mice are incredibly valuable and have sped up the process of identifying what functional purposes are served by the tens of thousands of genes shared by humans and mice.

It is not hard to imagine other ways that genes could be modified in mice to study gene function. For example, every gene has a promoter region which controls when a gene is expressed. Special promoter sequences can be placed in front of each gene to change when it will be turned on. One can place a special promoter on a gene that will turn it on only in the presence of a particular drug. Or multiple copies of a gene could be inserted to increase the level of expression of the gene.

In the future the process of producing gene knock-out mice will become more automated. Also, implantable miniature blood sensors will allow automated and cheap checking of blood hormones, gasses, proteins, and other compounds. Work like the research done PCSK9 gene knock-out study will some day be done in a much more automated way that will allow many effects of many genes to be checked in parallel.

Humans have been identified who have low levels of PCSK9 gene and low LDL cholesterol.

On average, mice lacking the Pcsk9 gene, called knockout mice, had blood LDL cholesterol levels of 46 milligrams per deciliter, while wild-type mice had levels around 96 mg/dl, a difference of 52 percent.

Dr. Horton's research is consistent with findings from another recent UT Southwestern study showing that humans with mutations in their PCSK9 gene, which prevented them from making normal levels of PCSK9 protein, had LDL cholesterol levels 40 percent lower than individuals without the mutation. That study, based on data gathered from nearly 6,000 participants in the Dallas Heart Study, was published in February in Nature Genetics. The research was led by Dr. Helen Hobbs, director of the Dallas Heart Study and of the Eugene McDermott Center for Growth and Development, and Dr. Jonathan Cohen, associate professor of internal medicine.

"The lower cholesterol levels of humans with mutations in PCSK9, combined with the results of our studies in mice, suggest that variations in the levels of the PCSK9 protein significantly affect blood cholesterol levels, and compounds that inhibit this protein may be useful for the treatment of high cholesterol," Dr. Horton said.

The latter study on humans illustrates another way that proteins and genes will be identified for drug development: Genetically compare humans who have a condition or a disease with humans who do not have that condition or disease. See if there are any consistent genetic difference between the groups. Advances that lower the cost of DNA sequencing and other genotyping technologies (e.g. single nucleotide polymorphism testing using gene chips) will eventually lower the cost of doing human genetic comparison studies by orders of magnitude. This too will accelerate the identification of targets for drug development.

Advances that accelerate the rate of identification of functions of genes will produce larger numbers of targets for drug development. Further into the future the identification of the purposes of various genes will provide targets for the development of gene therapies as well. Why take a drug for decades to keep your cholesterol low when you will be able to get a gene therapy that will modify your PCSK9 gene to lower your LDL cholesterol to a range optimal for long term vascular health?

Share |      Randall Parker, 2005 April 04 03:23 PM  Biotech Advance Rates

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