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Therapeutic approaches in neurodegeneration
Chamsy Sarkis, Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus, Neurodégénératifs (LGN) Centre National de la Recherche Scientifique UMR 7091, Hôpital Pitié-Salpétrière (Bâtiment CERVI), Paris, France,
Jacques Mallet, Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus, Neurodégénératifs (LGN) Centre National de la Recherche Scientifique UMR 7091, Hôpital Pitié-Salpétrière (Bâtiment CERVI), Paris, France
In the past 20 years, the development of molecular biology and genetic engineering has led to new horizons in therapy. Introducing therapeutic nucleic sequences into the organism for curing a disease is a very attractive approach for treating both inherited and acquired diseases for which classical drug therapy is not satisfactory. Although the idea is simple, many hurdles have to be overcome before clinical applications can be envisaged. The transfer vector and the therapeutic gene are the major determinants for successful therapy. An ideal vector would be easy to produce, and safe for the patient and the environment. Ideally, it must transduce only the target cells and do so efficiently. It should be possible to readminister the vector to the patients without triggering a deleterious immune reaction from the host, and the transgene has to be expressed at an appropriate level for the desired duration. The optimal characteristics of the gene depend on the disease. For a recessive monogenic disease, a wild-type allele of the mutated gene is generally required. For a dominant monogenic disease, sequences that inhibit the expression of the mutated allele, or that counter its physiological effect may be used. For many complex diseases, whether inherited or acquired, there are several potentially therapeutic genes. A therapeutic gene must be effective, but have minimal side effects. In particular, it should not lead to an immune response from the host organism, and this can be a major problem for recessive monogenic diseases, where the patient had never been in contact with the wild-type gene product.
There is compelling evidence for the existence of susceptibility genes for bipolar disorder. Association studies using functional DNA variations are an important approach for identifying these genes. The enzyme catechol-O-methyltransferase (COMT) plays a key role in the degradation of catecholamine neurotransmitters and is a candidate for involvement in bipolar disorder. Recently a common functional genetic polymorphism that underlies population variation in COM Tactivity has been elucidated and a simple assay developed.
In a collaboration involving seven European centres, we have undertaken an association study of this functional polymorphism in 412 unrelated West European caucasian DSM - III-R bipolar patients and 368 ethnically matched controls.
We found no evidence of allelic or genotypic association.
We can conclude that variation at this functional polymorphism does not make an important contribution to bipolar disorder in the Western European population. Future studies using this powerful experimental approach can be expected to contribute to identification of bipolar susceptibility genes.
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