DPM-1001 decreased copper levels and ameliorated deficits in a mouse model of Wilson's disease

Krishnan, N., Felice, C., Rivera, K., Pappin, D. J., Tonks, N. K. (2018) DPM-1001 decreased copper levels and ameliorated deficits in a mouse model of Wilson's disease. Genes Dev, 32 (13-14). pp. 944-952. ISSN 0890-9369

URL: https://www.ncbi.nlm.nih.gov/pubmed/29945887
DOI: 10.1101/gad.314658.118

Abstract

The levels of copper, which is an essential element in living organisms, are under tight homeostatic control. Inactivating mutations in ATP7B, a P-type Cu-ATPase that functions in copper excretion, promote aberrant accumulation of the metal, primarily the in liver and brain. This condition underlies Wilson's disease, a severe autosomal recessive disorder characterized by profound hepatic and neurological deficits. Current treatment regimens rely on the use of broad specificity metal chelators as "decoppering" agents; however, there are side effects that limit their effectiveness. Here, we present the characterization of DPM-1001 {methyl 4-[7-hydroxy-10,13-dimethyl-3-({4-[(pyridin-2-ylmethyl)amino]butyl}amino)hexadeca hydro-1H-cyclopenta[a]phenanthren-17-yl] pentanoate} as a potent and highly selective chelator of copper that is orally bioavailable. Treatment of cell models, including fibroblasts derived from Wilson's disease patients, eliminated adverse effects associated with copper accumulation. Furthermore, treatment of the toxic milk mouse model of Wilson's disease with DPM-1001 lowered the levels of copper in the liver and brain, removing excess copper by excretion in the feces while ameliorating symptoms associated with the disease. These data suggest that it may be worthwhile to investigate DPM-1001 further as a new therapeutic agent for the treatment of Wilson's disease, with potential for application in other indications associated with elevated copper, including cancer and neurodegenerative diseases.

Item Type: Paper
Uncontrolled Keywords: Wilson's chelator copper toxic milk
Subjects: diseases & disorders > congenital hereditary genetic diseases > Wilson's disease
CSHL Authors:
Communities: CSHL labs > Pappin lab
CSHL labs > Tonks lab
Depositing User: Matt Covey
Date Deposited: 23 Jul 2018 16:58
Last Modified: 23 Jul 2018 16:58
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36978

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