pubmed: alzheimer's and stem...
NCBI: db=pubmed; Term=alzheimer's and stem cell therapy
NCBI pubmed
  • Transcriptional dysregulation of inflammatory/immune pathways after active vaccination against Huntington's disease.
    Related Articles

    Transcriptional dysregulation of inflammatory/immune pathways after active vaccination against Huntington's disease.

    Hum Mol Genet. 2015 Aug 24;

    Authors: Ramsingh AI, Manley K, Rong Y, Reilly A, Messer A

    Abstract
    Immunotherapy, both active and passive, is increasingly recognized as a powerful approach to a wide range of diseases, including Alzheimer's and Parkinson's. Huntington's disease (HD), an autosomal dominant disorder triggered by misfolding of huntingtin (HTT) protein with an expanded polyglutamine tract, could also benefit from this approach. Individuals can be identified genetically at the earliest stages of disease, and there may be particular benefits to a therapy that can target peripheral tissues in addition to brain. In this active vaccination study, we first examined safety and immunogenicity for a broad series of peptide, protein, and DNA plasmid immunization protocols, using fragment (R6/1), and knock-in (zQ175) models. No safety issues were found. The strongest and most uniform immune response was to a combination of three non-overlapping HTT Exon1 coded peptides, conjugated to KLH, delivered with alum adjuvant. An N586-82Q plasmid, delivered via gene gun, also showed ELISA responses, mainly in the zQ175 strain, but with more variability, and less robust responses in HD compared to wild-type controls. Transcriptome profiling of spleens from the triple peptide-immunized cohort showed substantial HD-specific differences including differential activation of genes associated with innate immune responses, absence of negative feedback control of gene expression by regulators, a temporal dysregulation of innate immune responses, and transcriptional repression of genes associated with memory T cell responses. These studies highlight critical issues for immunotherapy and HD disease management in general.

    PMID: 26307082 [PubMed - as supplied by publisher]

  • Degradation of amyloid beta by human induced pluripotent stem cell-derived macrophages expressing Neprilysin-2.
    Related Articles

    Degradation of amyloid beta by human induced pluripotent stem cell-derived macrophages expressing Neprilysin-2.

    Stem Cell Res. 2014 Nov;13(3 Pt A):442-53

    Authors: Takamatsu K, Ikeda T, Haruta M, Matsumura K, Ogi Y, Nakagata N, Uchino M, Ando Y, Nishimura Y, Senju S

    Abstract
    The purpose of this study was to evaluate the therapeutic potential of human induced pluripotent stem (iPS) cell-derived macrophage-like cells for Alzheimer's disease (AD). In previous studies, we established the technology to generate macrophage-like myeloid lineage cells with proliferating capacity from human iPS cells, and we designated the cells iPS-ML. iPS-ML reduced the level of Aβ added into the culture medium, and the culture supernatant of iPS-ML alleviated the neurotoxicity of Aβ. We generated iPS-ML expressing the Fc-receptor-fused form of a single chain antibody specific to Aβ. In addition, we made iPS-ML expressing Neprilysin-2 (NEP2), which is a protease with Aβ-degrading activity. In vitro, expression of NEP2 but not anti-Aβ scFv enhanced the effect to reduce the level of soluble Aβ oligomer in the culture medium and to alleviate the neurotoxicity of Aβ. To analyze the effect of iPS-ML expressing NEP2 (iPS-ML/NEP2) in vivo, we intracerebrally administered the iPS-ML/NEP2 to 5XFAD mice, which is a mouse model of AD. We observed significant reduction in the level of Aβ in the brain interstitial fluid following administration of iPS-ML/NEP2. These results suggested that iPS-ML/NEP2 may be a potential therapeutic agent in the treatment of AD.

    PMID: 25460605 [PubMed - indexed for MEDLINE]

pubmed: alzheimer's and stem...
NCBI: db=pubmed; Term=alzheimer's and stem cell treatment
NCBI pubmed
  • Transcriptional dysregulation of inflammatory/immune pathways after active vaccination against Huntington's disease.
    Related Articles

    Transcriptional dysregulation of inflammatory/immune pathways after active vaccination against Huntington's disease.

    Hum Mol Genet. 2015 Aug 24;

    Authors: Ramsingh AI, Manley K, Rong Y, Reilly A, Messer A

    Abstract
    Immunotherapy, both active and passive, is increasingly recognized as a powerful approach to a wide range of diseases, including Alzheimer's and Parkinson's. Huntington's disease (HD), an autosomal dominant disorder triggered by misfolding of huntingtin (HTT) protein with an expanded polyglutamine tract, could also benefit from this approach. Individuals can be identified genetically at the earliest stages of disease, and there may be particular benefits to a therapy that can target peripheral tissues in addition to brain. In this active vaccination study, we first examined safety and immunogenicity for a broad series of peptide, protein, and DNA plasmid immunization protocols, using fragment (R6/1), and knock-in (zQ175) models. No safety issues were found. The strongest and most uniform immune response was to a combination of three non-overlapping HTT Exon1 coded peptides, conjugated to KLH, delivered with alum adjuvant. An N586-82Q plasmid, delivered via gene gun, also showed ELISA responses, mainly in the zQ175 strain, but with more variability, and less robust responses in HD compared to wild-type controls. Transcriptome profiling of spleens from the triple peptide-immunized cohort showed substantial HD-specific differences including differential activation of genes associated with innate immune responses, absence of negative feedback control of gene expression by regulators, a temporal dysregulation of innate immune responses, and transcriptional repression of genes associated with memory T cell responses. These studies highlight critical issues for immunotherapy and HD disease management in general.

    PMID: 26307082 [PubMed - as supplied by publisher]