Loss-of-function genetic diseases and the concept of pharmaceutical targets

The biomedical world relies heavily on the definition of pharmaceutical targets as an essential step in the drug design process. It is therefore tempting to apply this model to genetic diseases as well. However, whereas the model applies well to gain-of-function genetic diseases, it is less suited to most loss-of-function genetic diseases. Most common diseases, as well as gain-of-function genetic diseases, are characterized by the activation of specific pathways or the ectopic activity of proteins, which make well identified targets. By contrast, loss-of-function genetic diseases are caused by the impairment of one protein, with potentially distributed consequences. For such diseases, the definition of a pharmaceutical target is less precise, and the identification of pharmaceutically-relevant targets may be difficult. This critical but largely ignored aspect of loss-of-function genetic diseases should be taken into consideration to avoid the commitment of resources to inappropriate strategies in the search for treatments

A Genome-Wide Collection of Mos1 Transposon Insertion Mutants for the C. elegans Research Community

Methods that use homologous recombination to engineer the genome of C. elegans commonly use strains carrying specific insertions of the heterologous transposon Mos1. A large collection of known Mos1 insertion alleles would therefore be of general interest to the C. elegans research community. We describe here the optimization of a semi-automated methodology for the construction of a substantial collection of Mos1 insertion mutant strains. At peak production, more than 5,000 strains were generated per month. These strains were then subject to molecular analysis, and more than 13,300 Mos1 insertions characterized. In addition to targeting directly more than 4,700 genes, these alleles represent the potential starting point for the engineered deletion of essentially all C. elegans genes and the modification of more than 40% of them. This collection of mutants, generated under the auspices of the European NEMAGENETAG consortium, is publicly available and represents an important research resource

L'Intelligence Artificielle

Ségalat Laurent. L'Intelligence Artificielle. In: Raison présente, n°76, 4e trimestre 1985. Esprit, es-tu là ? pp. 83-97

Loss-of-function genetic diseases and the concept of pharmaceutical targets-0

<p><b>Copyright information:</b></p><p>Taken from "Loss-of-function genetic diseases and the concept of pharmaceutical targets"</p><p>http://www.OJRD.com/content/2/1/30</p><p>Orphanet Journal of Rare Diseases 2007;2():30-30.</p><p>Published online 2 Jul 2007</p><p>PMCID:PMC1936415.</p><p></p>ls of biological information. Once treatments are available for a few diseases, taking advantage of the connections will facilitate the identification of treatments for other diseases

Loss-of-function genetic diseases and the concept of pharmaceutical targets-1

<p><b>Copyright information:</b></p><p>Taken from "Loss-of-function genetic diseases and the concept of pharmaceutical targets"</p><p>http://www.OJRD.com/content/2/1/30</p><p>Orphanet Journal of Rare Diseases 2007;2():30-30.</p><p>Published online 2 Jul 2007</p><p>PMCID:PMC1936415.</p><p></p>ls of biological information. Once treatments are available for a few diseases, taking advantage of the connections will facilitate the identification of treatments for other diseases

C. elegans comme modèle pour les maladies dégénératives héréditaires humaines

La génétique du nématode C. elegans, modèle majeur en biologie du développement, trouve un champ d’application d’importance croissante pour l’étude de la physiopathologie des maladies humaines. Les modèles obtenus par mutation de gènes conservés chez ce nématode, ou d’animaux transgéniques exprimant des protéines de maladies humaines dont C. elegans est dépourvu, présentent des anomalies retrouvées dans les modèles mammifères. Ces observations suggèrent que les analyses génétiques dans C. elegans permettront d’éclairer la nature des mécanismes cellulaires affectés dans les maladies humaines. Ces modèles sont de plus utiles pour rechercher et caractériser des molécules présentant un potentiel thérapeutique. Cet article illustre ces aspects en prenant pour exemples deux maladies héréditaires, la myopathie de Duchenne et la chorée de Huntington.The nematode C. elegans is an established model for developmental biology. Since the early 90’s, this simple model organism has been increasingly used for studying human disease pathogenesis. C. elegans models based either on the mutagenesis of human disease genes conserved in this nematode or transgenesis with disease genes not conserved in C. elegans show several features that are observed in mammalian models. These observations suggest that the genetic dissection and pharmacological manipulation of disease-like phenotypes in C. elegans will shed light on the cellular mechanisms that are altered in human diseases, and the compounds that may be used as drugs. This review illustrates these aspects by commenting on two inherited degenerative diseases, Duchenne’s muscular dystrophy and Huntington’s neurodegenerative disease