Brain Penetrating Bifunctional Erythropoietin-Transferrin Receptor Antibody Fusion Protein for Alzheimer\u27s Disease

Erythropoietin (EPO), a glycoprotein cytokine essential to hematopoiesis, has neuroprotective effects in rodent models of Alzheimer’s disease (AD). However, high therapeutic doses or invasive routes of administration of EPO are required to achieve effective brain concentrations due to low blood–brain barrier (BBB) penetrability, and high EPO doses result in hematopoietic side effects. These obstacles can be overcome by engineering a BBB-penetrable analog of EPO, which is rapidly cleared from the blood, by fusing EPO to a chimeric monoclonal antibody targeting the transferrin receptor (cTfRMAb), which acts as a molecular Trojan horse to ferry the EPO into the brain via the transvascular route. In the current study, we investigated the effects of the BBB-penetrable analog of EPO on AD pathology in a double transgenic mouse model of AD. Five and a half month old male APPswe/PSEN1dE9 (APP/PS1) transgenic mice were treated with saline (n = 10) or the BBB-penetrable EPO (n = 10) 3 days/week intraperitoneally for 8 weeks, compared to same-aged C57BL/6J wild-type mice treated with saline (n = 8) with identical regiment. At 9 weeks following treatment initiation, exploration and spatial memory were assessed with the open-field and Y-maze test, mice were sacrificed, and brains were evaluated for Aβ peptide load, synaptic loss, BBB disruption, microglial activation, and microhemorrhages. APP/PS1 mice treated with the BBB-penetrable cTfRMAb-EPO fusion protein had significantly lower cortical and hippocampal Aβ peptide number (p \u3c 0.05) and immune-positive area (p \u3c 0.05), a decrease in hippocampal synaptic loss (p \u3c 0.05) and cortical microglial activation (p \u3c 0.001), and improved spatial memory (p \u3c 0.05) compared with APP/PS1 saline controls. BBB-penetrating EPO was not associated with microhemorrhage development. The cTfRMAb-EPO fusion protein offers therapeutic benefits by targeting multiple targets of AD pathogenesis and progression (Aβ load, synaptic loss, microglial activation) and improving spatial memory in the APP/PS1 mouse model of AD

Disorders of sexual development in a cultural context

BACKGROUND: Disorders of sexual development (DSD) are congenital conditions in which the development of the chromosomal, gonadal or anatomical sex can be deemed atypical. The external genitalia should appear ‘normal’ in size and shape from birth, with no question of abnormality, and the individual must receive appropriate social-environmental feedback in the course of the sexual maturation process. METHODS: We review regional differences in the variables considered important for gender assignment in individuals with DSD. Various approaches to certain forms of DSD are analysed within their cultural context. RESULTS: The decision to leave the sex of rearing undisturbed or to change it is difficult. It depends on the patient’s age and the extent to which the gender identity has been established with parental gender preference, social, cultural and religious factors. Severe forms of genetically female congenital adrenal hyperplasia, androgen insensitivity syndrome, 17β-hydroxysteroid dehydrogenase-3, 5α-reductase and cytochrome P450 oxidoreductase deficiencies are found to be the most difficult cases to diagnose and/or manage. CONCLUSION: Gender assignment in children with DSD is a subject of intense debate. Each case of DSD must be evaluated individually and on its merits and potentials. Although early admission and appropriate diagnostic facilities could provide the correct diagnosis, this is not the case in some cultures. It is seen that ‘gender panic’, social and religious concepts affect the decision-making process in gender assignment, especially in delayed cases

Brain Penetrating Bifunctional Erythropoietin–Transferrin Receptor Antibody Fusion Protein for Alzheimer’s Disease

Erythropoietin (EPO), a glycoprotein cytokine essential to hematopoiesis, has neuroprotective effects in rodent models of Alzheimer’s disease (AD). However, high therapeutic doses or invasive routes of administration of EPO are required to achieve effective brain concentrations due to low blood–brain barrier (BBB) penetrability, and high EPO doses result in hematopoietic side effects. These obstacles can be overcome by engineering a BBB-penetrable analog of EPO, which is rapidly cleared from the blood, by fusing EPO to a chimeric monoclonal antibody targeting the transferrin receptor (cTfRMAb), which acts as a molecular Trojan horse to ferry the EPO into the brain via the transvascular route. In the current study, we investigated the effects of the BBB-penetrable analog of EPO on AD pathology in a double transgenic mouse model of AD. Five and a half month old male APPswe/PSEN1dE9 (APP/PS1) transgenic mice were treated with saline (n = 10) or the BBB-penetrable EPO (n = 10) 3 days/week intraperitoneally for 8 weeks, compared to same-aged C57BL/6J wild-type mice treated with saline (n = 8) with identical regiment. At 9 weeks following treatment initiation, exploration and spatial memory were assessed with the open-field and Y-maze test, mice were sacrificed, and brains were evaluated for Aβ peptide load, synaptic loss, BBB disruption, microglial activation, and microhemorrhages. APP/PS1 mice treated with the BBB-penetrable cTfRMAb-EPO fusion protein had significantly lower cortical and hippocampal Aβ peptide number (p \u3c 0.05) and immune-positive area (p \u3c 0.05), a decrease in hippocampal synaptic loss (p \u3c 0.05) and cortical microglial activation (p \u3c 0.001), and improved spatial memory (p \u3c 0.05) compared with APP/PS1 saline controls. BBB-penetrating EPO was not associated with microhemorrhage development. The cTfRMAb-EPO fusion protein offers therapeutic benefits by targeting multiple targets of AD pathogenesis and progression (Aβ load, synaptic loss, microglial activation) and improving spatial memory in the APP/PS1 mouse model of AD