ABSTRACT
In children with MPNs, clots are most common in those with JAK2 mutations and those with polycythemia vera.
Subject(s)
Myeloproliferative Disorders , Polycythemia Vera , Thrombosis , Child , Humans , Janus Kinase 2/genetics , Mutation , Myeloproliferative Disorders/complications , Myeloproliferative Disorders/genetics , Polycythemia Vera/complications , Polycythemia Vera/genetics , Thrombosis/complicationsABSTRACT
Promoting hope was identified in our prior work as the top priority research question among patients and caregivers with diverse childhood-onset chronic conditions. Here, we aimed to construct a conceptual model to guide future research studies of interventions to improve hope. We conducted eight monthly virtual focus groups and one virtual workshop with patients, caregivers, and researchers to explore key constructs to inform the model. Discussions were facilitated by Patient Co-Investigators. Participants developed a definition of hope and identified promotors and inhibitors that influence the experience of hope. We utilized qualitative methods to analyze findings and organize the promotors and inhibitors of hope within three strata of the socio-ecologic framework: structural, interpersonal, and intrapersonal. Participants identified three types of interventions to promote hope: resources, navigation, and activities to promote social connection. The hope conceptual model can be used to inform the selection of interventions to assess in future research studies aimed at improving hope and the specification of outcome measures to include in hope research studies. Inclusion of the health care system in the model provides direction for identifying strategies for improving the system and places responsibility on the system to do better to promote hope among young patients with chronic illness and their caregivers.
ABSTRACT
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the world, and intracellular neurofibrillary tangles and extracellular amyloid-beta protein deposits represent the major pathological hallmarks of the disease. Currently available treatments provide some symptomatic relief but fail to modify primary pathological processes that underlie the disease. Erythropoietin (EPO), a hematopoietic growth factor, acts primarily to stimulate erythroid cell production, and is clinically used to treat anemia. EPO has evolved as a therapeutic agent for neurodegeneration and has improved neurological outcomes and AD pathology in rodents. However, penetration of the blood-brain barrier (BBB) and negative hematopoietic effects are the two major challenges for the therapeutic development of EPO for chronic neurodegenerative diseases like AD. The transferrin receptors at the BBB, which are responsible for transporting transferrin-bound iron from the blood into the brain parenchyma, can be used to shuttle therapeutic molecules across the BBB. In this review, we discuss the role of EPO as a potential neurotherapeutic for AD, challenges associated with EPO development for AD, and targeting the BBB transferrin receptor for EPO brain delivery.
Subject(s)
Alzheimer Disease/drug therapy , Erythropoietin/therapeutic use , Neuroprotective Agents/therapeutic use , Alzheimer Disease/etiology , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Animals , Blood-Brain Barrier , Cognition/drug effects , Cognition/physiology , Erythropoietin/biosynthesis , Erythropoietin/genetics , Erythropoietin/pharmacology , Gene Expression Regulation , Genetic Predisposition to Disease , Humans , Inflammation , Mice , Microglia/physiology , Mitochondria/physiology , Models, Neurological , Neuroprotective Agents/adverse effects , Neuroprotective Agents/pharmacology , Neurotransmitter Agents/metabolism , Oxidative Stress , Protein Transport , Rats , Receptors, Erythropoietin/genetics , Receptors, Erythropoietin/metabolism , Receptors, Transferrin , TranscytosisABSTRACT
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 Aß 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 Aß peptide number ( p < 0.05) and immune-positive area ( p < 0.05), a decrease in hippocampal synaptic loss ( p < 0.05) and cortical microglial activation ( p < 0.001), and improved spatial memory ( p < 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 (Aß load, synaptic loss, microglial activation) and improving spatial memory in the APP/PS1 mouse model of AD.
