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From genomics to the drugs of tomorrow

To say that medicine expects a lot from genomics is to put it mildly. The more geneticists learn about the complex mechanics of genes involved in common or rare diseases, the better the treatment of those diseases will be. Researchers have already identified a multitude of genes involved in susceptibility to numerous ailments, such as certain cancers, arterial hypertension, diabetes, obesity, arterial sclerosis, infectious diseases, Alzheimer's, and psychiatric disorders. The list of disease genes gets longer every year. In the future, “other genes will undoubtedly be identified which will explain predispositions not usually considered pathological, such as longevity,” claims Axel Kahn,1 director of the Cochin Institute in Paris.
Rather than marking an end-point for biology, the completion of the human genome project has accelerated the deciphering of the book of life, many chapters of which directly concern the field of medicine. “This laborious effort, which has facilitated the identification of many disease genes and led to a greater diagnostic power, should help us understand the metabolic circuits leading from a DNA mutation to a disease,” says Pierre Sonigo, head of the Virus Genetics Laboratory at the Cochin Institute.2 The problem is that the link between a genetic modification and a clinical disorder only rarely obeys classical Mendelian genetics, where one mutation equals one disease. A rare example of such rigid determinism is phenylketonuria, which is the result of a mutation in the gene of a protein enzyme, phenylalanine hydroxylase. The disease is characterized by the accumulation of toxic amino acids in the blood, which disrupts the development of normal mental faculties. “Examples of such a direct link can be counted on one hand,” says Sonigo. “When a gene is out of order, it usually results in a slew of secondary problems. An analogy for this is oil leaking out of a car engine, which leads to a number of the engine's components eventually being affected. Genomics promises to be an invaluable tool for dissecting and reconstituting each step between the starting point of a disease to its ultimate manifestation.”

Progress in drug research has for a long time nurtured the ambition to find, with the help of genomics, the specific protein(s) involved in a disease, to determine its three-dimensional structure and to design a molecule capable of undoing the damage. In short, the goal is to find the key that fits the lock. This is an appealing strategy, on paper. “One of the rare successes of this approach, which focuses on finding a target to block, is the set of antiproteases directed against HIV-AIDS,” says Sonigo. “The sequencing of the HIV genes in 1985 made it possible to determine the structure of one of the virus's enzymes, the protease, and then to develop a drug to block it.”

The failure to find the magic key for most disease treatments has led researchers to concentrate on three other types of treatment: recombinant proteins, gene therapy, and genetic vaccines. The principle underlying the first type, which already represents some 30% of the pharmaceuticals utilized in hospitals (such as insulin and erythropoietin), consists in taking a gene corresponding to a protein, introducing it into a cell growing in a fermentor, and harvesting a large quantity of the protein which can then be administered to patients. “This method of manufacturing proteins using genetic engineering is a major biotechnological success,” states Sonigo. A whole series of these novel and promising therapeutic proteins will soon be leaving laboratories for pharmacies. Examples include adenosine deaminase and cytokines, molecular messengers that coordinate the activity of the immune system.

The other promising line of research concerns gene and cell therapy, with applications that are not limited to the treatment of genetic diseases. “Recourse to such a complicated and costly technique is still for now only possible in cases of serious diseases for which there are no available alternative treatments (such as Duchenne's muscular dystrophy) or for which available treatments prove ineffective either immediately or in the long term,” cautions Marc Piechaczyk, head of a laboratory at the Molecular Genetics Institute in Montpellier.3 Put more bluntly, gene therapy is not available for treating migraine headaches. Jean-Gérard Guillet, senior researcher at Inserm,4 Cochin Institute, emphasizes the point: “If there is a medical consensus that treatment is possible without replacing the defective gene, there is no reason to consider recourse to gene therapy, which is always the last resort.” Nevertheless, “many treatments that must be taken continuously have side effects that appear after long term use and can adversely affect the patient's quality of life. If we are able to correct a genetic defect once and for all, obviously there is no hesitation about doing so.”
How would this be done? “The idea consists of replacing a mutated gene by a normal gene which is vectored into the defective cell to express the desired protein,” explains Guillet. All of that depends on finding a biological taxi that knows its way around the human body and can deliver the gene to the right cells. Not only do viruses possess these very qualities, but scientists also know a lot about their genetics. Yet this process is quite problematic since viruses like nothing more than to multiply and wreak havoc. Guillet points out that “the viruses that we use as vectors are attenuated and therefore completely harmless.” Converting an adenovirus, a retrovirus or a virus derived from HIV, into a docile and compliant assistant requires an elaborate lab procedure. The goal is to remove all the genes used by the virus to multiply and proliferate while retaining the genes needed to deliver the goods. The next step is to rigorously select defective viruses that will never infect other human cells. The result is a tamed virus, ready to transport a new gene into the target cell.

Gene therapy can also be used to treat diseases that are not, strictly-speaking, genetic, like cancer. “In those cases, we can use oncolytic viruses for example, which have the property of exploding cancer cells and only those cells,” says Guillet. “In other words, we use a virus vector containing a gene that directs the virus specifically to the affected cell.” It is entirely possible to imagine “a virus equipped with a gene that codes for a therapeutic protein. It would target the tumor and the gene would induce the tumor cells to differentiate and transform themselves into normal tissue.”
Unfortunately, there is still a major problem with the use of viruses: As soon as they enter the body, the immune system starts trying to eliminate them. “Consequently, the immune response must be modified so that it doesn't disrupt the treatment. The procedure involves injecting a slightly modified virus that the immune system will not recognize,” says Guillet. The hope is that easily standardized and inexpensive vectors will eventually be available.

How many approved procedures have been used during the twelve years following the first clinical tests of gene therapy? Around 500, 60% of which have targeted cancer, while the remaining 40% have been applied to genetic and other non-cancerous diseases—a modest number, to say the least. “The technique is relatively new and still remains largely unproven,” explains Piechaczyk. “Let's not forget that a new medical treatment requires 10 to 15 years of trials before it is put on the market, and when it comes to a new conceptual approach…” The answer is obvious. But the success of Alain Fischer and Martina Cavazzana-Calvo at the end of the 1990s raised hopes. By acting directly on their DNA, the doctors from Necker hospital in Paris have improved the prospects of children afflicted with a rare immuno-deficiency syndrome that forced them to live in a sterile environment. “This was the first time, or almost the first time, that gene therapy was shown to be a valid concept,” says Guillet. This is true even if a few patients unfortunately developed leukemia, demonstrating that not all the mechanisms involved have been completely mastered. Another new development indicates a promising future for gene therapy: exon skipping (see glossary). This innovative technique was launched by Olivier Danos and Luis Garcia at the Center for Genetic Therapy in Evry.5 Exon skipping is a form of gene therapy that takes place at an intermediary step between gene transcription and protein synthesis, and results in the production of a truncated but functional protein. The technique has been successfully used to repair a defective gene responsible for the equivalent of Duchenne's muscular dystrophy in mice. As for vaccines containing genetic material (DNA or RNA), which were considered dangerous only a short time ago, some are already being tested. The first results are promising: malaria, AIDS, herpes and hepatitis C, fatal or debilitating diseases that have proven resistant to treatment or immunization, may one day be a thing of the past. The traditional means of vaccination, which saves countless millions from typhus, tetanus, measles and hepatitis A and B, involves “isolating the pathogen, killing it or attenuating it, and introducing it into the body. This tricks the immune system into protecting the body against the virulent form of the micro-organism,” says Guillet. Genetic vaccination follows the same principle but “instead of injecting the protein of the virus that will stimulate an immune reaction response, the DNA coding for the vaccinating antigen (the viral protein) is injected. Obviously, genes that could result in the assembly of complete viral particles and hence the development of the disease are avoided.”
Relying on a more global approach, pharmacogenomics is another concept raising a lot of interest in labs. The approach involves fine-tuning medical treatment to suit the individual genetics of the patient. Bio-markers of the patient are identified in order to gauge the potential toxicity and side effects of a treatment (such as antibiotics), which can then be adjusted according to the patients' susceptibility. Welcome to the world of customized drug treatment.

Philippe Testard-Vaillant


Notes :

1. “Génome humain et médecine,” Dossier pour la science, January-March 2005.
2. Laboratoire génétique des virus. INSERM / Institut Cochin.
3. Institut de génétique moléculaire. Joint lab: CNRS / Université Montpellier-II.
4. Joint lab: CNRS / Institut national scientifique pour la recherche médicale.
5. Centre de recherche et applications sur les thérapies géniques. Joint lab: CNRS / Université d'Évry / Généthon.

Contacts :

Jean-Gérard Guillet,

Marc Piechaczyk

Pierre Sonigo


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