Targeting mutant huntingtin for the development of disease-modifying therapy

• Published in: Drug discovery today Vol. 17; no. 21-22; pp. 1217 - 1223
• Main Authors: Appl, Thomas, Kaltenbach, Linda, Lo, Donald C., Terstappen, Georg C.
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.11.2012; Elsevier
• Subjects: Animals; Biological and medical sciences; Brain; Brain - physiopathology; Cognition Disorders - drug therapy; Cognition Disorders - etiology; Drug Design; General pharmacology; Humans; Huntingtin Protein; Huntington Disease - drug therapy; Huntington Disease - genetics; Huntington Disease - physiopathology; Medical sciences; Molecular Targeted Therapy; Mutation; Nerve Tissue Proteins - genetics; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Protein Folding; Target; Pharmaceutical technology; Treatment; Targeting
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/j.drudis.2012.06.017

► No disease-modifying therapy is available for Huntington's disease. ► Disease-modifying therapy might be achieved through reduction of mHTT protein levels. ► Disease-modification might be achieved through modulation of PTMs of mHTT. Huntington's disease (HD) is a progressive and fatal neurodegenerative disease, and the most common inherited CAG repeat disorder. A polyglutamine expansion in the N-terminus of the huntingtin protein (HTT) leads to protein misfolding and downstream pathogenic processes culminating in widespread functional impairment and neurodegeneration in the striatum, cortex and other brain areas. To date, only symptomatic treatments are available that address motor, psychiatric and cognitive deficits. Here we review recent strategies for developing disease-modifying therapies designed to limit or abolish the pathogenic activities of the primary molecular target in HD, the mutant HTT protein itself.