The Milano Gene and Other Gene Therapy

The Milano Gene

Heredity has long been recognized as a factor in heart disease, so much so that coping with heart disease has been likened to a game of bridge or poker: you don't get to choose the cards—what counts is how you play the game. If scientists at Cedars-Sinai Medical Center in California are right, the Milano gene may change this. Using gene therapy, doctors may be able to change your genetic makeup just enough to heal the wounded arteries that put you at risk of heart attack.

In the late 1970s, scientists from Milan, Italy, found a family in a town on the south shore of Lake Garda whose members had very low HDL cholesterol levels, but no clinical signs of the coronary artery disease that causes heart attacks. Study of the family's history showed that many ancestors enjoyed long life. Further study isolated the APO A-I Milano gene, which protects its carriers from the otherwise risky effect of low HDL ("Healthy" cholesterol). In 1994, Dr Prediman Shah and his team at Cedars-Sinai showed that injection of a genetically engineered protein similar to the one made by the Milano gene reduced plaque buildup in the arteries of animals on a high cholesterol diet.

By 2005, work on the Milano gene progressed to human trials, "Based on the results of Shah’s studies, a clinical trial was conducted in humans with similar results. After five weeks of once-a-week injections, apo A-I Milano significantly shrank plaque in coronary arteries. The protein appeared to actually remove bad cholesterol, even from sites on arteries where plaque had accumulated."

In November 2005, Dr Shah looked to the future when the Milano gene itself may be used to cure wounds in coronary arteries:
“The initial studies and treatments were based on injection of the apo A-I Milano protein. Now we are using not the protein, but the Milano gene itself. We are putting the Milano gene inside an innocuous virus and injecting the virus so that the body can produce its own supply of apo A-I Milano. One single injection of the Milano gene, carried by the virus, markedly reduces plaque buildup in mice. Advantages of this approach are that we would not need to produce the protein in the laboratory and there would be no need for repeated injections, as there is with the protein. With the animal studies confirming the effectiveness of the gene therapy approach, it may be possible that human trials could begin within several years.” Milano gene, Cedars-Sinai.

Other Gene Therapies for Heart Disease

A related study presented at the American Heart Association meetings in November 2005 showed how a vaccine might be used to reduce LDL ("Lousy" cholesterol). Cedars-Sinai researchers, collaborating with researchers from University of Lund in Sweden, described an immunization technique in which antibodies were injected that specifically targeted oxidized LDL. An earlier study found that the antibody therapy could prevent plaque buildup, but this work documented that pre-existing plaque could be reduced by up to 50 percent in the animal model.
“The present study suggests that antibody treatment has the ability to rapidly and significantly reduce the extent of already present, advanced atherosclerotic lesions.... Positive immunization with antibodies directed against oxidized LDL isotopes might constitute a future fast-acting therapy for patients at high risk for acute cardiovascular events.”

Genes Can Be Switched On or Off

Late in 2004, Weill Cornell Medical College and Rockefeller University announced that scientists have shown how the activity of a gene can be switched on or off, modifying not the DNA code of a gene, but instead the spool-like histone proteins around which DNA tightly wraps itself in the nucleus of cells in the body. Epigenetics, Weill Cornell Medical College.

Our genes, the cards we are dealt at birth, are not equally powerful. Just as in a game of bridge where some cards are "trump" and some are not, some genes are switched on—they are "expressed"—while others are silent. Welcome to the science of epigenetics, a new form of gene therapy.

Epigenetics tells us how the environment of a gene affects its functioning. A smoker provides a different environment for his genes than does a non-smoker. Someone who eats broccoli and other cabbage-family vegetables provides a different environment for genes than someone who does not eat vegetables. Epigenetics, now in its infancy, may eventually reveal to us how lifestyle determines what chronic diseases we suffer.

Identical twins have the same genes, but may differ in the expression of their genes. Manel Esteller of the Spanish National Cancer Center in Madrid and colleagues found that 35% of twin pairs had significant differences in gene expression. Older twin pairs were more epigenetically different than were younger twins. Twins who reported having spent less time together during their lives, or who had different medical histories, had the greatest epigenetic differences. Gene expression analysis revealed that two twin pairs (3-year olds and 50-year olds) showed four times as many differences in the older pair compared to the younger pair. Epigenetic differences in twins, PNAS.

It's Not All in the Cards

The genes you receive at birth do not completely determine the quality of your life. Just as in cards, how you play the game may be just as important as what you start with. Epigenetics is gradually revealing the role of gene expression in chronic disease.

At present, there is no way of knowing if a specific person should take vitamin B supplements to improve heart health. That's too specific. We don't know if the person has genes that predispose to deficiency in B12, B6 or folate and we don't know how the genes interact with the vitamins. Today, we deal in probabilities and averages based on studies of large groups. What we can say is this: Adequate nutrition and exercise is needed to avoid chronic diseases of aging. If the person does not eat red meat, then a B12 supplement is probably needed. If the person is over 50, B12 should be taken in the form of its co-enzyme because aging usually reduces the ability to convert B12 to its biologically active form, methylcobalamin.

The science of epigenetics gives hope because it shows that we are not trapped by our genes. Lifestyle change is a form of gene therapy that we can manage ourselves. Unfortunately, the health and supplements industry could turn that hope into frustration by confusion. There are so many vitamins, minerals, and anti-oxidants! How many should I take? Which ones? Should I take all of them just to be on the safe side. My suggestion is this:

Pick as few supplements as you can without feeling anxiety, but don't sweat the small stuff. Instead, strive to succeed with the big stuff:

  • quit smoking
  • reduce alcohol
  • stop eating crap
  • eat more fruit and vegetables
  • get more exercise
Some day epigenetics may become precise enough to prescribe custom combinations of ingredients to combat aging, but that day is still far off.