ABSTRACT
The accumulation and deposition of the 40-42-amino acid peptide amyloid beta (Abeta) is thought to be a critical event in the pathology of Alzheimer's disease (AD). Both passive and active immunizations against Abeta in amyloid-depositing transgenic mice have reduced Abeta pathology and improved memory-related behavior. Peripheral treatments with other amyloid-binding agents have also reduced Abeta pathology. The present study demonstrates that peripheral delivery of plasmid DNA coding for the amyloid-binding protein plasma gelsolin reduces brain Abeta in two separate amyloid-depositing transgenic mouse models of AD when inter-litter variability is accounted for. The reduction in Abeta pathology observed is accompanied by an apparent increase in activated and reactive microglia and soluble oligomeric forms of amyloid. These findings demonstrate that peripheral expression of plasma gelsolin may be a suitable gene-therapeutic approach for the prevention or treatment of AD.
Subject(s)
Alzheimer Disease/therapy , Amyloid/metabolism , Gelsolin/genetics , Genetic Therapy/methods , Alzheimer Disease/pathology , Animals , Blotting, Western , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Gelsolin/blood , Gelsolin/physiology , Humans , Immunoprecipitation , Mice , Mice, Transgenic , Microglia/metabolism , Microglia/pathology , Plasmids/genetics , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Over the past decade, significant research has been done in the area of polymer-mediated gene delivery. Synthesis of new polymers and modifications to existing polymers has resulted in polyplexes with improved in vitro and in vivo transfection efficiencies. Targeting has been an important aspect of this research, and various strategies for obtaining selective and enhanced gene delivery to the target site have been evaluated. This review covers the different aspects involved in polyplex targeting. Development of targeted polyplexes involves a careful consideration of the target site, the targeting ligand and the physicochemical properties of the polyplex itself. The need to redirect the polyplexes by using the 'shield and target' approach by reducing nonspecific interactions with negatively charged components, while conferring specificity by incorporating targeting ligands, is discussed. Basic chemistry involved in modifying polymers is covered and examples of targeting strategies used for tissue-specific gene delivery are discussed. Targeting is also discussed in the broader context of developing safe and effective polymeric vectors for in vivo gene delivery. Maximum benefit of targeting can be obtained when it is used as part of a multi-functional complex containing elements designed to improve gene delivery and reduce overall toxicity of the polyplex.
