ATP7B knockout mouse model for Wilson disease

This technology is an ATP7B knockout mouse capable of recapitulating the pathophysiology of Wilson disease.

Unmet Need: In vivo models of Wilson disease pathophysiology

Very few in vivo models exist for the study of Wilson disease, an autosomal dominant disease caused by mutations in the ATP7B gene that results in copper accumulation in the liver. Wilson disease is associated with a number of hepatic, neurological, psychiatric, hematological, renal, and endocrine disorders. However, existing ATP7B mutant mouse models do not fully recapitulate these human phenotypes and may have off-target effects on the expression of nearby genes.

The Technology: ATP7B knockout mice for Wilson disease research and therapeutic screening

This technology describes an ATP7B knockout mouse line for in vivo modeling of Wilson disease. The mouse line was generated by inserting a premature stop codon into the second exon of ATP7B, leading to no detectable ATP7B mRNA or protein expression. The mice exhibit reduced hepatic copper at birth and a 60-fold increase in copper levels after 5 months, with similar trends in the kidney, brain, placenta, and lactating mammary glands. Importantly, these mice go on to develop a cirrhosis-like liver and complex neurological abnormalities, similarly to Wilson disease in human patients. As such, this technology provides an improved model for Wilson disease modeling and therapeutic screening.

Applications:

• Drug development and screening for Wilson disease
• Research tool for Wilson disease pathophysiology
• Research tool for studying copper homeostasis across different organs

Advantages:

• More accurately represents the different stages of human Wilson disease development
• Genetic design is less likely to impact expression of other genes
• Robustly models the complexity of Wilson disease neurological pathophysiology
• Models the effect of systemic high copper in various organs and tissues

Lead Inventor:

Thomas Conrad Gilliam, Ph.D.

Related Publications:

• Buiakova OI, Xu J, Lutsenko S, Zeitlin S, Das K, Das S, Ross BM, Mekios C, Scheinberg IH, Gilliam TC. “Null mutation of the murine ATP7B (Wilson disease) gene results in intracellular copper accumulation and late-onset hepatic nodular transformation” Hum Mol Genet. 1999 Sept; 8(9): 1665-71.

• Shah AB, Chernov I, Zhang HT, Ross BM, Das K, Lutsenko S, Parano E, Pavone L, Evgrafov O, Ivanova-Smolenskaya IA, Annerén G, Westermark K, Urrutia FH, Penchaszadeh GK, Sternlieb I, Scheinberg IH, Gilliam TC, Petrukhin K. “Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses” Am J Hum Genet. 1997 Aug; 61(2): 317-28.

Tech Ventures Reference:

• IR CU18413

• Licensing Contact: Sara Gusik