Menkes Disease
Menkes disease is a fatal X-linked recessive disorder caused by mutations in the ATP7A copper transporter gene. At Protheragen, we focus on developing novel therapeutics and building accurate animal models to accelerate preclinical studies of potential therapies for Menkes disease. Our expertise ensures that client's research receives the most reliable and relevant support, accelerating their drug development journey.
Introduction to Menkes Disease
Menkes disease is a rare, X-linked recessive neurometabolic disorder caused by mutations in the ATP7A gene, leading to severe systemic copper deficiency. The disease primarily affects male infants, with an estimated incidence of 1 in 100,000 to 1 in 250,000 live births. Clinical manifestations typically appear within the first few months of life and include progressive neurodegeneration, connective tissue abnormalities, and distinctive "kinky hair" due to defective keratin cross-linking.
Fig.1 Schematic representation of the role of ATP7A and ATP7B proteins in response to Cu exposure in enterocytes (A) and in hepatocytes (B). (El Nachef L, et al., 2023)
Pathogenesis of Menkes Disease
Menkes disease is caused by mutations in the ATP7A gene, disrupting copper transport and leading to systemic copper deficiency. This impairs critical copper-dependent enzymes like cytochrome c oxidase and lysyl oxidase, resulting in severe neurological degeneration and connective tissue abnormalities. The defective copper metabolism primarily affects the nervous system and vascular integrity, driving the disease's devastating clinical manifestations.
Fig.2 ATP7A has six copper binding sites (Cu), eight transmembrane domains, an activation domain (A), a phosphorylation domain (P), and a nucleotide domain (N) (B). (Mauri A, et al., 2023)
Therapeutic Development for Menkes Disease
| Drug Names | Mechanism of Action | Targets | Research Phase |
| Copper Histidinate | Bypasses defective intestinal copper absorption by providing bioavailable copper (Cu2+) in a chelated form. Restores systemic copper levels and supports copper-dependent enzyme function. | ATP7A-dependent copper transport system (indirectly); cuproenzymes (e.g., cytochrome c oxidase, lysyl oxidase) | Approved |
| Levetiracetam | Modulates synaptic neurotransmitter release by binding to synaptic vesicle protein SV2A, reducing neuronal hyperexcitability. | SV2A (synaptic vesicle glycoprotein 2A) | Approved |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
As a professional preclinical research service provider, Protheragen is dedicated to accelerating breakthroughs in the field of Menkes disease. We offer end-to-end solutions encompassing diagnostic development, novel therapeutic development, precise disease modeling, and rigorous preclinical validation. Our blood-brain barrier model enables critical assessments of drug permeability in the central nervous system (CNS), ensuring optimal brain exposure while minimizing systemic toxicity, thus expediting the development of effective therapies.
Therapeutic Development Services
By Mechanism of Action
Disease Model Development Services
In Vitro Model Development
- ATP7A Mutant Mice: Genetically engineered mice with targeted disruptions in the ATP7A gene, recapitulating the systemic copper deficiency and neurological defects seen in human Menkes disease.
- Other Models
At Protheragen, we are committed to validating and optimizing therapies for Menkes disease through preclinical studies including pharmacodynamics (PD), pharmacokinetics (PK) and toxicology to ensure their successful regulatory approval. If you are interested in our services, please feel free to contact us for more details and quotation information of related services.
References
- El Nachef L, Al-Choboq J, Bourguignon M, et al. Response of fibroblasts from Menkes' and Wilson's copper metabolism-related disorders to ionizing radiation: influence of the nucleo-shuttling of the ATM protein kinase[J]. Biomolecules, 2023, 13(12): 1746.
- Mauri A, Saielli L A, Alfei E, et al. Menkes disease complicated by concurrent ACY1 deficiency: A case report[J]. Frontiers in Genetics, 2023, 14: 1077625.