Personalized Medicine

On September 21, 2006, in Personalized Medicine
Despite hundreds of false starts, hype, and disappointments, efforts to find genetic therapies for disease are finally starting to pay off. Signs of progress are evident in the success of two drugs that work on people with specific genetic variations.

These successes also suggest that routine collection of patient DNA during clinical trials of all new drugs would be a very good idea. Non-trial-related tissue banks will also help and are proliferating; for example, there is a new tissue bank of samples from bipolar patients that will help custom-tailor drugs to suit the genetic profile of the individual patient.

Progress toward personalized medicine is further evidenced by:

  • The discovery of a gene responsible for hearing lossin the elderly, which could lead to preventive therapies,
  • The curing of two patients with advanced melanoma, and
  • The identification of some 200 cancer-causing genes, which will also lead to therapies increasingly tailored to the specific patient within two to three years. Whose hype is this? — No less than the heads of the US National Institutes of Health and National Human Genome Research Institute.

But for some cancers, expensive tests to identify the presence of disease-causing genes in patients could be overkill. A simple formula, already posted on the Web, might suffice to show predisposition.

In other, related news:

  • Proteomicsunderstanding is leading to new understanding of, and potentially new therapies for, diabetes.
  • Genetic predisposition to bad behavior could become a courtroom defence. Genetic re-engineering to cure the predisposition might then become the punishment to fit the crime.

Phamacogenomics on Brink of Breaking Through

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Re-analysis of trial data for a “failed” experimental heart-failure drug — the beta blocker bucindolol — showed that it actually worked for patients who carried a particular version of a heart-related gene. Those patients turned out to be far more likely to be alive four years later if they took the drug than people with the other version of the gene. The study is notable, several doctors and researchers told Washington Post staff writer Rick Weiss, because it offers a definitive example of a drug whose potency depends on subtle genetic differences in patients and is a step towards “a revolution in health care: truly personalized medicine, with treatments customized to patients’ genomes.”

The hope is that there may be many more shelved drugs that will turn out to work for patients with a specific genetic makeup. But some experts caution that progress along the road to personalized medicine is likely to be slow. For one thing, the market for a targeted drug is inherently smaller than for a non-targeted drug, which has to be a “blockbuster” almost by definition in order to achieve regulatory approval. For another, our ability to test people for the all-important genetic difference is itself progressing slowly. Except for a few tests for genes on certain cancer cells, notes Gina Kolata in the New York Times, the genetics revolution “has not yet happened.” But “maybe, just maybe,” she writes, “the promised revolution is imminent,” citing bucindolol and breast cancer drug tamoxifen, which also works only in people with a specific genetic variation.

Progress might be much faster if patient DNA data were routinely collected during clinical trials of new drugs. More and more are in fact doing that, and there is increasing interest in looking for genetic variations that may determine whether a person responds to a particular drug.

Pharmacogenomics for Bipolar Disorder

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The University of Michigan Depression Center is combining hundreds of blood and cell samples it has collected from patients with bipolar disorder since the mid-1980s with 1,500 samples from Johns Hopkins University. The result will be the second-largest repository of bipolar patient samples in the nation. (Rutgers University has the largest.)

The samples will be used to find genetic markers for susceptibility to the disorder and help tailor treatments to suit different genetic profiles. Bipolar patients sometimes go through months-long trial periods before finding a medication that works for them, a researcher told Michelle Martinez of Crain’s Detroit Business.

Cancer: Pharmacogenomic Breakthrough

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“Instead of doing what we do now, which is to give the standard treatment for everybody, we will adjust the treatment for each patient and hopefully dramatically affect their cancer,” said US National Institutes of Health director Elias Zerhouni, in a glowing tribute to recently published “groundbreaking” and “truly remarkable” research that has succeeded in identifying a much greater number of genes that cause breast and colorectal cancers. “For the first time,” he said, “this tells us that you could identify what in cancer is the Achilles’ heel.”

Johns Hopkins University researchers discovered nearly 200 cancer-causing genes, with 69 genes driving colorectal cancer and 122 fueling breast tumors. Previously, only about 10 genes had been linked to those cancers. They were also surprised to find that each tumor they analyzed was different. Even tumors of the same organs had only about five genes in common, which could help explain why many chemotherapy drugs help only a fraction of patients.

US National Human Genome Research Institute director Francis Collins said it has been known for a number of years that cancer is not one disease but hundreds, and that the new research may help doctors focus on the handful of genes, or possibly even the single gene, that would stop or kill a cancer. The findings, he said, could help to better tailor therapies to patients within two or three years.

Simple Cancer Predictor

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After analyzing every case of colon cancer in Scotland from 1999 to mid-2003 involving people under 55, University of Edinburgh researchers have devised a simple way to screen cancer patients to find which ones fit the profiles of the four percent of patients with the genetic mutations that cause Lynch syndrome (an aggressive form of colon cancer) or are at risk for uterine, ovarian, and other forms of cancer.

The simple formula they devised combines such factors as the patient’s age and sex and cancer characteristics such as the tumor’s location, plus a relatively simple US$300 lab analysis. It produces a score for the likelihood that inherited mutations are responsible, and could replace $3,000 genetic tests as well as point to more effective chemotherapy approaches. It has been posted on the Web for any doctor to use.

Gene for Age-related Hearing Loss

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Mutations in a specific gene have been linked to hearing loss in the elderly. The Netherlands’ Royal National Institute for Deaf People said the finding offered “real hope for treatments.”

The researchers tested over 1,200 people’s hearing and studied their DNA. Three single-nucleotide polymorphisms (SNPs — single letter variations in the gene) were present only in people with hearing loss.

Further research could lead to preventive treatments. The researchers say they are “optimistic that in the future people will no longer face the prospect of losing their hearing as they age.”

Gene Therapy for Metastatic Cancer

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In what the US National Cancer Institute (NCI) has hailed as the first real success in cancer gene therapy, researchers have cured two patients — out of 17 — of advanced melanoma that had already spread through the body. Both patients have been cancer-free for two years since the therapy.

A patient’s immune system can be harnessed to fight cancer by extracting killer T-cells from his or her blood, cultivating the cells in the laboratory, and re-implanting them in much greater numbers into the patient’s bloodstream. But in some patients — melanoma patients in particular — killer T-cells are so diminished in number as to be hard to find. So the researchers took normal lymphocytes (which do not recognize cancer) out of the 17 advanced melanoma patients and infected those cells with a virus re-emgineered to carry genes that code for T-cell melanoma receptors.

The researchers don’t yet know why the therapy worked for only two of the 17, but one researcher said the riddle was solvable. The NCI plans to try the same gene therapy (but with genes coding for the appropriate receptors) in patients with common cancers such as breast or colon cancer.

Promising Proteomic Approach to Diabetes

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Stanford University scientists have shown in mice that the protein calcineurin, which regulates 10 genes associated with diabetes, is key to the health of insulin-producing pancreatic beta cells. The researchers bypassed calcineurin by activating another protein, called NFAT. Beta cells lacking calcineurin but with active NFAT behaved normally, leading the researchers to surmise that drugs that enhance the activity of calcineurin or NFAT could treat type-2 diabetes, and drugs that inhibit calcineurin or NFAT may treat diseases involving an excess of insulin, such as hypoglycaemia and some pancreatic tumors.

Treating isolated beta cells with drugs that enhance calcineurin could make those cells divide, producing more cells for transplantation. And activating calcineurin could potentially enable scientists to direct embryonic stem cells to become insulin-producing cells.

An American Diabetes Association official said the findings had “the potential to be big” and were “a major leap forward,” though human therapies based on the research are a long way from clinical trials.

Gene Therapy Starting to Work

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“Gene therapy is making a comeback,” writes Linda Marsa in an exceptionally thorough, comprehensive, and upbeat review in the Los Angeles Times of the state of gene therapy. European scientists have cured more than two dozen patients suffering from three rare immune disorders, new techniques are making therapy safer and more effective, and more than 300 gene therapy trials are underway around the world.

The most direct gene therapy approach replaces single, faulty genes with functional ones. It is being used to treat relatively rare genetic diseases such as muscular dystrophy, cystic fibrosis, sickle cell anemia, beta thalassemia, and hemophilia. An indirect approach, in which genes are introduced to support or inhibit a natural process, is being used against diseases not clearly and directly genetically inherited, such as cancer, hepatitis, AIDS, and heart disease.

“Today,” writes Marsa, “scientists are injecting genes into people to try to block the formation of deadly cancerous tumors. They’re implanting genes that stimulate cell growth in an attempt to regenerate heart muscle cells and grow blood vessels in patients with congestive heart failure; halt disease progression in people with macular degeneration; and slow the death of brain cells in Alzheimer’s as well as Parkinson’s patients.”

The chairman of the department of genetic medicine at Weill Medical College of Cornell University told her that “Gene therapy will evolve into a major therapeutic method.” While researchers are “very aware of the challenges,” as another put it, he did not think gene therapy was now being “over-hyped.”

Gene therapy trials:

  • In one human clinical trial against Parkinson’s, genetic material has been encased in a viral vector that is attracted to nerve cells in the brain and injected into a discrete region of the patient’s brain, that governs movement. 


  • A similar recently completed year-long trial to normalize the overactive nerve cells of 12 Parkinson’s patients resulted in a 27 percent improvement in stability and ability to walk, and less stiffness and tremors on the treated side of the body. 


  • Results are expected later this year of a trial targeting angina, in which the VEGF-2 gene was injected into the hearts of 400 patients to spark the growth of tiny blood vessels and increase blood flow to oxygen-starved cells. 


  • 300 patients are being given about 20 injections in each leg of the HIF-1 alpha gene, which controls the body’s response to low oxygen, to grow new blood vessels and improve blood flow in the legs of patients with peripheral arterial disease. 


  • A preliminary trial for arthritis showed a 20 to 30 percent reduction in swelling among 14 patients treated with a gene to interfere with an inflammation-causing chemical. 


  • Animal studies are underway for gene therapies to treat hearing loss and to clear clogged arteries. 

Psycho-social Genetics

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The discovery of a genetic predisposition for risk-taking in some mice suggests that some humans might also have such a predisposition, which would suggest in turn that we should re-visit the link between behavior and responsibility.

Some people would find the lifting of responsibility for their behavior liberating (paradoxically, for it would also mean they have no free will). Some would feel doomed by genetic fate, and some would feel depressed that their (and their children’s) accomplishments might not be the result of their intellectual efforts.

It could also encourage tolerance for, or breed bigotry against, genetic “types” — those with a genetic predisposition to obesity, for example — even though the newly discovered genes, and environmental factors that influence whether the genes become active or reman dormant, probably only influence rather than determine the “type.”

Such is the public’s faith in, but misperception of, science, that wrong conclusions are an ever-present danger.


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