May 23, 2003
Enzyme Makes HDL Cholesterol More Beneficial

A recent report about the benefits of the higher level of an enzyme provides a candidate for the use of gene therapy to reduce the risk of heart disease and of other illnesses associated with old age. Activity of an enzyme called paraoxonase can reduce the risk of heart attacks.

DALLAS, May 20 – An oxidation-fighting enzyme called paraoxonase (PON1) can significantly reduce the risk of heart attacks, according to research reported in today’s rapid access issue of Circulation: Journal of the American Heart Association. The enzyme attaches itself to high-density lipoprotein (HDL), which is known as “good” cholesterol. When PON1 is highly active, the risk for heart attack is cut by 43 percent, says study author Michael Mackness, Ph.D., of the University Department of Medicine, Manchester Royal Infirmary, Manchester, United Kingdom.

Postprandial peaks in plasma concentration of lipid hydroperoxides (in laymans terms: a boost in free radicals in fats in the blood after meals caused by the generation of fat free radicals in the gut during digestion) are theorized to contribute to the development of atherosclerosis and to the risks of heart disease and stroke. It is even possible that the boost in blood free radicals after each meal contributes to the general aging of the body. Peroxonase is probably working by breaking down lipid hydroperoxide free radicals into compounds that are less harmful to the body. More peroxonase attached to HDL cholesterol in blood serum probably causes the more rapid breakdown of lipid hydroperoxides after meals and therefore reduces the amount of cumulative damage that they cause.

The authors of this research paper state that if a dietary change or drug could boost PON1 activity then it is likely this would reduce the risk of heart disease and stroke. But a more permanent solution would be to do gene therapy to increase the blood levels of PON1. Researchers at University of Texas Southwestern Medical Center have already developed an experimental gene therapy for boosting paraoxonase levels.

Those veterans who have suffered brain damage from OP exposure during the war express significantly lower levels of PON, type Q, than those soldiers who remained well after the war. Other research has shown that these polymorphisms may also be involved in the development of Parkinson's Disease, amyotropic lateral sclerosis, and atherosclerosis. The inventors have developed gene therapy vectors that can be introduced into humans to boost their levels of PON and may lead to effective treatments to combat or prevent the aforementioned conditions.

There has been a lot of previous research into the role paraoxonase plays as an antioxidant in the blood.

The data are consistent with the hypothesis that lower expression of this anti-oxidant enzyme increases risk of coronary disease. Ageing has also been identified as an independent determinant of serum paraoxonase levels. Ageing is correlated with reduced serum paraoxonase levels, which may compromise the protective influence of enzyme. The results are consistent with the contention that the protective, anti-oxidant capacity of high density lipoproteins is at least in part genetically determined.

Gene therapy to raise paraoxonase might be useful for those younger people who have genetically low levels of paraoxonase. But note that since paraoxonase declines with age even people who have high levels of paraoxonase in their youth and middle age might benefit from gene therapy to boost paraoxonase as they age.

The reason for this post is to make a larger point: it may seem depressing to know that you probably have genetic variations that increase your risk for a variety of illnesses and that cause you to grow older faster. But a more optimistic way to see all the genetic risk factors that are being discovered is that future candidates for gene therapy are being identified. As more details are filled in about how different genetic variations contribute to development of diseases many potential benefits of future gene therapies are becoming better understood.

Is it realistic to expect that the effects of the deleterious genetic variations can be dealt with using gene therapies? Well, one reason to have that more optimistic view is that many genes are expressed only in a single organ or their role in the development of particular diseases is due to their effects in a single organ. Therefore gene therapy doesn't have to be able to reach every cell in the body (which would be incredibly hard to do) in order to be beneficial. In the case of paraoxonase the concentration of it in the blood is probably coming from synthesis in the liver followed by excretion into the blood. Therefore a gene therapy aimed at boosting blood paraoxonase only has to reach some cells in the liver. Another possibility would be to do gene therapy to stem cells that are capable of becoming liver cells. But the point is that gene therapy has to reach only a fairly small fraction of the body's cells in order to reverse the effects of an unfortunate inherited predisposition to disease. Your genetic inheritance does not have to dictate your health destiny.

Share |      Randall Parker, 2003 May 23 02:32 AM  Biotech Therapies


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