What is Hepatolenticular Degeneration?
 

Hepatolenticular Degeneration, also known as Wilson Disease (WD), is a rare autosomal recessive genetic disorder caused by mutations in the ATP7B gene, leading to abnormal copper accumulation in organs such as the liver, brain, and corneas. Clinically, most WD patients are young individuals, presenting with characteristic features including extrapyramidal symptoms, liver cirrhosis, Kayser-Fleischer rings in the cornea, low serum ceruloplasmin levels (<50 mg/L), and high urinary copper excretion (>100 μg/24h). The prevalence of WD is estimated to be between 1 in 30,000 and 1 in 50,000 individuals. In China, the prevalence is higher than in Western countries, with the age of onset ranging from 1 to 72 years.
 

Pathogenesis
 

WD is caused by mutations in the ATP7B gene, which encodes the ATP7B copper-transporting P-type ATPase protein located on the long arm of chromosome 13. The ATP7B protein, expressed in hepatocytes, plays a dual role in copper homeostasis. When intracellular copper levels are low, it localizes to the Golgi apparatus and assists in the synthesis of holoceruloplasmin. When hepatic copper content rises, the ATP7B protein relocates to carry copper ions for biliary excretion. It also binds excess copper, transporting it via vesicles to the plasma membrane for release into the extracellular space, thereby facilitating copper elimination.

 

(Image: Structural Diagram of the ATP7B Copper Transporter Protein - PubMed)

Mutations in the ATP7B gene impair the function of the ATP7B protein, leading to defective ceruloplasmin synthesis and reduced biliary copper excretion, resulting in copper accumulation within the liver. Once hepatic copper storage capacity is saturated, copper ions are released into the bloodstream and deposit in extrahepatic organs like the brain, corneas, and kidneys, causing oxidative damage and organ dysfunction.

(Image: Copper Toxicity in WD Pathogenesis - PubMed)

ATP7B gene mutations exhibit significant racial and geographical variation. Over 800 different mutations have been reported, including missense, nonsense, insertion/deletion, and splice-site mutations.

Caucasian Populations: The most common mutation is p.H1069Q (c.3207C>A), accounting for 37%-63% of European alleles.

Asian Populations: Common mutations include p.R778L (c.2333G>T), p.P992L (c.2975C>T), and p.T935M, with reported allele frequencies of 28.7%, 9.3%, and undetermined frequency, respectively.
 

Gene Therapy
 

Gene Editing Technology: Aims to repair ATP7B gene mutations and restore copper transport function. Preliminary progress has been achieved in animal models.

AAV Vector-Mediated Gene Therapy: Uses adeno-associated virus (AAV) to deliver a functional ATP7B gene to the liver. Preclinical studies have shown restoration of copper metabolism. In December 2024, the MWAV201 study, initiated by Professor Fan Jianguo, Director of the Department of Gastroenterology at Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, administered the first dose to a Wilson Disease subject, with the process proceeding smoothly and no adverse reactions observed. On February 6, 2025, Beijing Genecradle Pharmaceutical Technology Co., Ltd.'s self-developed gene therapy drug, GC310 adeno-associated virus injection, received implicit approval from the National Medical Products Administration (NMPA) for clinical trial registration.
 

Mouse Models
 

ATP7B-/- Mice: Generated by gene knockout technology to inactivate the ATP7B gene, leading to significant hepatic copper accumulation and modeling the copper metabolism disorder seen in human WD.

TX-J Mice: Carry a point mutation (c.2135G>A) in the ATP7B gene, causing a p.G712D amino acid substitution. This model exhibits hepatic copper accumulation, mitochondrial abnormalities, and an inflammatory response.

R778L Point Mutation Mice: Carry the p.R778L (c.2333G>T) mutation. These mice exhibit neurological deficits in motor coordination and cognitive function, accompanied by increased expression of inflammatory cytokines in the central nervous system.

H1069Q Point Mutation Mice: Carry the p.H1069Q (c.3207C>A) mutation. Used for studying the mechanism of this common European WD mutation and developing targeted therapies.
 

MingCeler Biotech Facilitates Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has developed multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target gene locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various WD mouse models according to client needs, such as ATP7B-/- mice, TX-J mice, R778L point mutation mice, and H1069Q point mutation mice. We welcome inquiries!

 

References:

[1] Immergluck J, Grant LM, Anilkumar AC. Wilson Disease. [Updated 2025 Apr 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-.

[2] Xiong X, Gao C, Meng X, Liu A, Gong X, Sun Y. Research progress in stem cell therapy for Wilson disease. Regen Ther. 2024 Mar 15;27:73-82. doi: 10.1016/j.reth.2024.03.005. PMID: 38525238; PMCID: PMC10959646.

[3] Kucinskas L, Jeroch J, Vitkauskiene A, Sakalauskas R, Petrenkiene V, Kucinskas V, Naginiene R, Schmidt H, Kupcinskas L. High frequency of the c.3207C>A (p.H1069Q) mutation in ATP7B gene of Lithuanian patients with hepatic presentation of Wilson's disease. World J Gastroenterol. 2008 Oct 14;14(38):5876-9. doi: 10.3748/wjg.14.5876. PMID: 18855987; PMCID: PMC2751898.

[4] Malipati, A., Kaidiriya, K., Xu, L., & Sun, X. (n.d.). Research advances in the pathogenesis, phenotype-genotype relationship, and pharmacotherapy of hepatolenticular degeneration. Department of Infectious Diseases, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830000, China.

[5] Beijing Genecradle Pharmaceutical Technology Co., Ltd. News.

[6] Penning LC, Berenguer M, Czlonkowska A, Double KL, Dusek P, Espinós C, Lutsenko S, Medici V, Papenthin W, Stremmel W, Willemse J, Weiskirchen R. A Century of Progress on Wilson Disease and the Enduring Challenges of Genetics, Diagnosis, and Treatment. Biomedicines. 2023 Feb 1;11(2):420. doi: 10.3390/biomedicines11020420. PMID: 36830958; PMCID: PMC9953205.

[7] Yang Yulong, Wei Taohua, Yang Wenming, et al. Research Progress on Animal Models of Hepatolenticular Degeneration. Journal of Clinical Hepatology, 2022, 38(5): 1169-1174. DOI: 10.3969/j.issn.1001-5256.2022.05.041.

[8] Dong, J., Xiang, G., Xia, X. et al. Aberrant copper metabolism and hepatic inflammation cause neurological manifestations in a mouse model of Wilson’s disease. J Neuroinflammation 21, 235 (2024). https://doi.org/10.1186/s12974-024-03178-5

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