Ceruloplasmin administration in the preclinical mouse model of aceruloplasminemia reveals a sex-related variation in biodistribution.

Mutations in the ceruloplasmin (CP) gene are responsible for the rare genetic disease aceruloplasminemia characterized by iron accumulation in different organs, including the brain. We previously reported that administration of purified CP in the CP-deficient (cpKO) mouse model of the disease, was therapeutically effective. Here we evaluated the bioavailability of the therapeutic protein in different organs of the cpKO mouse. The distribution of administered radiolabelled-[(64)Cu]-CP was assessed in brain and peripheral tissues in vivo and ex vivo. The uptake of [(64)Cu]-CP in cpKO mice varied according to animal sex and age, with a higher accumulation in the cerebellum and liver of males at 6 months of age, while higher levels were observed in the same organs in females at 10 months. Sex-specific variations in the uptake of radiolabelled-CP were genotype-associated, by comparison with wild type mice. Based on these findings, we assessed sex effects on the therapeutic efficacy of the CP-replacement therapy previously performed. Multivariate analysis confirmed that the therapeutic effect was present for both sexes, and this was more pronounced in males than females. Therefore, sex-related variation in CP tissue bioavailability point to the possibility of sex-specific therapeutic regimens in the design of future CP-replacement therapies for aceruloplasminemia.