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

Ségalat L - Orphanet J Rare Dis (2007)

Bottom Line: The biomedical world relies heavily on the definition of pharmaceutical targets as an essential step in the drug design process.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.For such diseases, the definition of a pharmaceutical target is less precise, and the identification of pharmaceutically-relevant targets may be difficult.

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Affiliation: CGMC, CNRS-UMR 5534, Université Lyon 1, France. segalat@cgmc.univ-lyon1.fr

ABSTRACT
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.

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Only a few specific loss-of-function genetic diseases match the concept of a pharmaceutical target. Although the concept of a pharmaceutical target does not fit most loss-of-function diseases, channelopathies and some metabolic diseases are exceptions to the rule. A) Schematic view of putative strategies to treat a partial loss-of-function affecting an ion channel. Agonists may stimulate the channel to increase its activity. Alternatively, antagonists of opposite-effect channels may restore the ion balance of the cell. B) Schematic view of putative strategies to treat a loss-of-function disease affecting an enzyme. In this example, the reduction of enzyme activity (blue cross) results in a deficit in a key metabolite A. This deficit may be compensated by inhibiting A-transforming enzymes (1), increasing the abundance of a precursor (2), and stimulating A-producing enzymes (3). (Supplementation of A, also a therapeutic possibility for some disorders, is not shown.)
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Figure 2: Only a few specific loss-of-function genetic diseases match the concept of a pharmaceutical target. Although the concept of a pharmaceutical target does not fit most loss-of-function diseases, channelopathies and some metabolic diseases are exceptions to the rule. A) Schematic view of putative strategies to treat a partial loss-of-function affecting an ion channel. Agonists may stimulate the channel to increase its activity. Alternatively, antagonists of opposite-effect channels may restore the ion balance of the cell. B) Schematic view of putative strategies to treat a loss-of-function disease affecting an enzyme. In this example, the reduction of enzyme activity (blue cross) results in a deficit in a key metabolite A. This deficit may be compensated by inhibiting A-transforming enzymes (1), increasing the abundance of a precursor (2), and stimulating A-producing enzymes (3). (Supplementation of A, also a therapeutic possibility for some disorders, is not shown.)

Mentions: A small proportion of loss-of-function (lof) genetic diseases are also well-suited to the concept of target-based drug design. These are mostly diseases with a simple and well-understood physiopathology, like channelopathies and some metabolic diseases. In such diseases, the reduction of a cellular function resulting from the mutation may be pharmacologically corrected by either stimulating this function or inhibiting an opposite function (Figure 2). For instance, in Myotonia congenita (a recessive disease caused by mutations in the chloride channel gene CLCN1), malfunction of the chloride channel impairs the skeletal muscle repolarization, the voltage-dependent sodium channels are improperly opened, and a subsequent myotonia ensues. Myotonia symptoms can be effectively reduced by a sodium channel antagonist, mexiletine, which decreases the muscle excitability, and thereby re-establishes the balance between excitation and relaxation [5] (Figure 2A). The concept of pharmaceutical targets (chloride channel and sodium channel in this case) makes perfect sense here because i) the physiology of muscle excitation is well-known and ii) channels are highly amenable to modulation by drugs.


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

Ségalat L - Orphanet J Rare Dis (2007)

Only a few specific loss-of-function genetic diseases match the concept of a pharmaceutical target. Although the concept of a pharmaceutical target does not fit most loss-of-function diseases, channelopathies and some metabolic diseases are exceptions to the rule. A) Schematic view of putative strategies to treat a partial loss-of-function affecting an ion channel. Agonists may stimulate the channel to increase its activity. Alternatively, antagonists of opposite-effect channels may restore the ion balance of the cell. B) Schematic view of putative strategies to treat a loss-of-function disease affecting an enzyme. In this example, the reduction of enzyme activity (blue cross) results in a deficit in a key metabolite A. This deficit may be compensated by inhibiting A-transforming enzymes (1), increasing the abundance of a precursor (2), and stimulating A-producing enzymes (3). (Supplementation of A, also a therapeutic possibility for some disorders, is not shown.)
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Related In: Results  -  Collection

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Figure 2: Only a few specific loss-of-function genetic diseases match the concept of a pharmaceutical target. Although the concept of a pharmaceutical target does not fit most loss-of-function diseases, channelopathies and some metabolic diseases are exceptions to the rule. A) Schematic view of putative strategies to treat a partial loss-of-function affecting an ion channel. Agonists may stimulate the channel to increase its activity. Alternatively, antagonists of opposite-effect channels may restore the ion balance of the cell. B) Schematic view of putative strategies to treat a loss-of-function disease affecting an enzyme. In this example, the reduction of enzyme activity (blue cross) results in a deficit in a key metabolite A. This deficit may be compensated by inhibiting A-transforming enzymes (1), increasing the abundance of a precursor (2), and stimulating A-producing enzymes (3). (Supplementation of A, also a therapeutic possibility for some disorders, is not shown.)
Mentions: A small proportion of loss-of-function (lof) genetic diseases are also well-suited to the concept of target-based drug design. These are mostly diseases with a simple and well-understood physiopathology, like channelopathies and some metabolic diseases. In such diseases, the reduction of a cellular function resulting from the mutation may be pharmacologically corrected by either stimulating this function or inhibiting an opposite function (Figure 2). For instance, in Myotonia congenita (a recessive disease caused by mutations in the chloride channel gene CLCN1), malfunction of the chloride channel impairs the skeletal muscle repolarization, the voltage-dependent sodium channels are improperly opened, and a subsequent myotonia ensues. Myotonia symptoms can be effectively reduced by a sodium channel antagonist, mexiletine, which decreases the muscle excitability, and thereby re-establishes the balance between excitation and relaxation [5] (Figure 2A). The concept of pharmaceutical targets (chloride channel and sodium channel in this case) makes perfect sense here because i) the physiology of muscle excitation is well-known and ii) channels are highly amenable to modulation by drugs.

Bottom Line: The biomedical world relies heavily on the definition of pharmaceutical targets as an essential step in the drug design process.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.For such diseases, the definition of a pharmaceutical target is less precise, and the identification of pharmaceutically-relevant targets may be difficult.

View Article: PubMed Central - HTML - PubMed

Affiliation: CGMC, CNRS-UMR 5534, Université Lyon 1, France. segalat@cgmc.univ-lyon1.fr

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus