Kritz, Angelika; (2003) Peptides from phage display libraries for targeted gene delivery via the p75NTR neurotrophic receptor. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

An upregulation of neurotrophic receptor (p75NTR) expression has been associated with a number of neurodegenerative disorders, cancers and atherosclerosis, and often directly contributes to disease progression. Hence p75-targeted gene delivery vectors should prove useful for the treatment of these diseases, either by expression of relevant therapeutic genes or by blocking expression of p75NTR in affected cells. Three phage display libraries were screened on cells over-expressing human p75NTR to isolate peptides with high affinity for this receptor. Two 7-mer peptides - VNLQNPY and VYARSMN - were identified as strong and highly specific binders to cells expressing p75NTR when displayed on bacteriophage M13. The p75-specificity of these peptides was further confirmed by phage immunostaining and confocal microscopy. Both peptides were subsequently synthesised with a DNA-targeting polylysine tail (K16) and incorporated into a liposome vector harbouring the luciferase reporter gene. Compared with un targeted control vectors, transfection efficiencies to p75-positive cells were between 5-10 fold higher, in particular with the VYARSMN peptide. Gene delivery to p75-negative cells was generally reduced by 50%. The identified peptide may thus be useful for designing synthetic and viral vectors for targeted gene transfer to degenerating neurons, vascular plaques or cancer cells in patients with AD, atherosclerosis and cancer respectively.

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