• Open Access

Gene therapy in Alzheimer’s disease – potential for disease modification

Authors

  • Per Nilsson,

    1. Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan
    2. KI-Alzheimer’s Disease Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Novum, Huddinge, Sweden
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  • Nobuhisa Iwata,

    1. Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan
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  • Shin-ichi Muramatsu,

    1. Division of Neurology, Department of Medicine, Jichi Medical School, Shimotsuke, Tochigi, Japan
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  • Lars O. Tjernberg,

    1. KI-Alzheimer’s Disease Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Novum, Huddinge, Sweden
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  • Bengt Winblad,

    1. KI-Alzheimer’s Disease Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Novum, Huddinge, Sweden
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  • Takaomi C. Saido

    Corresponding author
    1. Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan
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Correspondence to: Takaomi C. SAIDO, Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2–1 Hirosawa, Wako-shi, Saitama 351–0198, Japan.
Tel.: +81-48-467-9715
Fax: +81-48-467-9716
E-mail: saido@brain.riken.jp

Abstract

  • • Introduction
  • • Targets and ongoing research
    • - NGF
      • - Neurotrophic function of NGF
      • - Levels of NGF in AD
      • - Role of NGF in AD
      • - NGF as a therapeutic agent
      • - Development of NGF gene therapy
      • - In vivo gene delivery of NGF
    • - BDNF
      • - Neurotrophic function of BDNF
      • - BDNF levels in AD
      • - BDNF function in AD
      • • Towards BDNF gene therapy
    • - Neprilysin
      • - Role of neprilysin in AD
      • - Neprilysin levels in AD
      • - Gene delivery of neprilysin in AD animal models
  • • Potential gene therapy target candidates
    • - APOE
    • - ECE
    • - Cathepsin B
    • - Other Aβ degrading enzymes
  • • Down-regulation of AD-associated proteins by siRNA
    • - BACE1
    • - APP
  • • Concluding remarks

Alzheimer’s disease (AD) is the major cause of dementia in the elderly, leading to memory loss and cognitive decline. The mechanism underlying onset of the disease has not been fully elucidated. However, characteristic pathological manifestations include extracellular accumulation and aggregation of the amyloid β-peptide (Aβ) into plaques and intracellular accumulation and aggregation of hyperphosphorylated tau, forming neurofibrillary tangles. Despite extensive research worldwide, no disease modifying treatment is yet available. In this review, we focus on gene therapy as a potential treatment for AD, and summarize recent work in the field, ranging from proof-of-concept studies in animal models to clinical trials. The multifactorial causes of AD offer a variety of possible targets for gene therapy, including two neurotrophic growth factors, nerve growth factor and brain-derived neurotrophic factor, Aβ-degrading enzymes, such as neprilysin, endothelin-converting enzyme and cathepsin B, and AD associated apolipoprotein E. This review also discusses advantages and drawbacks of various rapidly developing virus-mediated gene delivery techniques for gene therapy. Finally, approaches aiming at down-regulating amyloid precursor protein (APP) and β-site APP cleaving enzyme 1 levels by means of siRNA-mediated knockdown are briefly summarized. Overall, the prospects appear hopeful that gene therapy has the potential to be a disease modifying treatment for AD.

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