B6-hATP7B Mice

● Research on hepatolenticular degeneration (HLD);

● Preclinical evaluation of ATP7B-targeted drugs.

1. Detection of human ATP7B gene expression

Figure 2. Human ATP7B gene expression in the liver and lungs of wild-type mice (WT) and B6-hATP7B mice (hATP7B). RT-qPCR results show that there was the expression of the human ATP7B gene in the liver and lungs of B6-hATP7B mice, while there was no expression in the wild-type mice.
(ND: Not detected)

2. Detection of mouse Atp7b gene expression

Figure 3. Mouse Atp7b gene expression in the liver and lungs of wild-type mice (WT) and B6-hATP7B mice (hATP7B). RT-qPCR results show that there was the expression of the mouse Atp7b gene in the liver and lungs of wild-type mice, while there was no expression in the B6-hATP7B mice.

1. Basic information about the ATP7B gene

Hepatolenticular degeneration (HLD), also known as Wilson disease (WD), is an autosomal recessive copper transport disorder that can lead to liver failure. The incidence rate is about 1:30,000 [1]. The clinical manifestations of HLD mainly include chronic liver damage, and neurological and psychiatric symptoms, and can occasionally cause acute liver failure and hemolytic anemia. Its typical manifestation is the combination of liver disease and movement disorders in adolescence or early adulthood, but there is a large variation in phenotypic differences among patients, and up to 60% of patients have neurological or psychiatric symptoms [2]. Studies have shown that mutations in the ATP7B gene are associated with HLD. The characteristic feature is that with the loss of functional ATP7B protein, the clearance of excess copper is affected, leading to copper accumulation to toxic levels, damaging tissues and organs such as the liver and brain ^[1,3-4].

4. ATP7B gene and mutations

The copper ion transport ATPase β-peptide encoded by the ATP7B gene is a member of the P-type cation transport ATPase family. This family uses the energy stored in ATP to transport metals into and out of cells. The ATP7B protein consists of multiple transmembrane domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least two putative copper-binding sites ^[5]. This protein mainly exists in the liver, with small amounts found in the kidneys and brain. Its function as a copper transport ATPase plays a role in transporting copper from the liver to other parts of the body. More than 900 pathogenic mutations of the ATP7B gene have been reported, with the mutation types mainly concentrated in missense, nonsense, or frameshift mutations, and other mechanisms include exon skipping, large deletions, and intron variations. The most common mutation in patients from Northern and Eastern Europe is H1069Q, but its frequency varies greatly among different countries ^[2].

5. ATP7B-targeted gene therapy

With the continuous exploration of genetic pathogenesis, targeted gene therapy is expected to become the next “star therapy”. VTX-801 from Vivet Therapeutics has received U.S. FDA Fast Track Designation for the treatment of Wilson’s Disease. VTX-801 is a gene therapy vector based on rAAV, which is used to deliver small ATP7B transgenes. The functional protein encoded by the transgene can restore copper balance, reverse liver pathological changes, and reduce copper accumulation in the brain of Wilson’s disease mice models ^[6]. UX701 is a gene therapy drug based on AAV9 developed by Ultragenyx. It treats HLD by delivering modified ATP7B genes. Its preclinical studies have shown that UX701 can reduce copper accumulation in the liver, increase ceruloplasmin levels, and improve liver pathology ^[7].

In summary, the ATP7B gene is a significant pathogenic gene for hepatolenticular degeneration (HLD). ATP7B gene humanized mice from Cyagen can be used for preclinical research on HLD and customized services can also be provided for different point mutations.