arguably the most important with respect to the use of designer zinc-finger proteins for therapeutic gene modulation. if a methylase domain is bound to the designer zinc-finger protein, when the zinc-finger protein binds to the target dna sequence an increase in methylation state of dna in that region will subsequently result. transcription rates of genes so-affected will be reduced. many of the effector domains function to modulate either the dna directly - e.g. via methylation, cleaving, or recombination of the target dna sequence - or by modulating its transcription rate - e.g. inhibiting transcription via repressor domains that block transcriptional machinery, promoting transcription with activation domains that recruit transcriptional machinery to the site, or histone- or other epigenetic-modification domains that affect chromatin state and the ability of transcriptional machinery to access the affected genes. epigenetic modification is a major theme in determining varying expression levels for genes, as explained by the idea that how tightly-wound the dna strand is - from histones at the local level up to chromatin at the chromosomal level - can influence the accessibility of sequences of dna to transcription machinery, thereby influencing the rate at which it can be transcribed. if, instead of impacting the dna strand directly, as described above, a designer zinc-finger protein instead affects epigenetic modification state for a target dna region, modulation of gene expression could similarly be accomplished. in the first case to successfully demonstrate the use of designer zinc-finger proteins to modulate gene expression in vivo, choo et al designed a protein consisting of three zinc-finger domains that targeted a specific sequence on a bcr-abl fusion oncogene. this specific oncogene is implicated in acute lymphoblastic leukemia. the oncogene typically enables leukemia cells to proliferate in the absence of specific growth factors, a hallmark of cancer. by including a nuclear localization signal with the tri-domain zinc-finger protein in order to facilitate binding of the protein to genomic dna in the nucleus, choo et al were able to demonstrate that their engineered protein could block transcription of the oncogene in vivo. leukemia cells became dependent on regular growth factors, bringing the cell cycle back under the control of normal regulation. post-transcriptional gene modulation the major approach to post-transcriptional gene modulation is via rna interference (rnai). the primary problem with using rnai in gene modulation is drug delivery to target cells. rnai gene modulation has been successfully applied to mice toward the treatment of a mouse model for inflammatory bowel disease. this treatment utilized liposome-based beta-7 integrin-targeted, stabilized nanoparticles entrapping short interfering rnas (sirnas). there are several other forms of rnai delivery, including: polyplex delivery, ligand-sirna conjugates, naked delivery, inorganic particle deliver using gold nanoparticles, and site specific local delivery. clinical significance designer zinc-finger proteins, on the other hand, have undergone some trials in the clinical arena. the efficacy and safety of ew-a-401, an engineered zinc-finger transcription factor, as a pharmacologic agent for treating claudication, a cardiovascular ailment, has been investigated in clinical trials. the protein consists of an engineered plasmid dna that prompts the patient to produce an engineered transcription factor, the target of which is the vascular endothelial growth factor-a (vegf-a) gene, which positively influences blood vessel development. although not yet approved by the u.s. food and drug administration (fda), two phase i clinical studies have been completed which identify this zinc-finger protein as a promising and safe potential therapeutic agent for treatment of peripheral arterial disease in humans.