Gene therapy in Alzheimer's disease - potential for disease modification.
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 beta-peptide (Abeta) 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, Abeta-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 beta-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.
Nilsson
Per
P
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
Iwata
Nobuhisa
N
Muramatsu
Shin-ichi
S
Tjernberg
Lars O
LO
Winblad
Bengt
B
Saido
Takaomi C
TC
D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D035843:Biomedical Research; D015536:Down-Regulation / Q000235:genetics; D015316:Genetic Therapy; D006801:Humans; D034741:RNA, Small Interfering / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D034741:RNA, Small Interfering