Intranasal antisense therapy: preclinical models with a clinical future?

Recent progress in the development of two antisense strategies--DNA oligonucleotides and RNA interference for the treatment of respiratory diseases are discussed in this review. Appropriate formulations and chemical modifications for improved stability should foster the clinical application of antisense drugs, but the delivery of antisense drugs to their intended target tissue remains the biggest challenge for most therapeutic applications of these compounds. The nose provides a particularly attractive route for antisense drug delivery to the respiratory system; however, significant hurdles remain.

A zinc-binding dual-specificity YVH1 phosphatase in the malaria parasite, Plasmodium falciparum, and its interaction with the nuclear protein, pescadillo.

Biochemical evidence revealed protein tyrosine kinase and phosphatase activities in the human malarial parasite Plasmodium falciparum, a member of the Apicomplexa. A novel cDNA sequence of a dual-specificity phosphatase was identified in both sexual and asexual stages of P. falciparum, and named PfYVH1, since the predicted primary structure of the 278-amino acid polypeptide showed significant similarity to the human and yeast YVH1 phosphatases. The N-terminal half of PfYVH1 contained a conserved tyrosine phosphatase catalytic domain within a dual-specificity phosphatase domain. The C-terminal region, consisting of one histidine and eight cysteines, represented a zinc-binding domain with a potentially unconventional architecture. Recombinant PfYVH1 contained 2mol of zinc per mol protein and dephosphorylated both phosphoserine and phosphotyrosine residues. Mutation of specific Cys residues in the putative zinc finger region abolished zinc binding and drastically reduced phosphatase activity, suggesting an allosteric role of zinc in catalysis. PfYVH1 was expressed in essentially all erythrocytic stages of the parasite, and shuttled between the nucleus and the cytoplasm in a stage-specific manner. A Plasmodium ortholog of the nuclear pescadillo protein (PfPES) was also characterized and shown to interact with PfYVH1, thus implicating PfYVH1 in the regulation of parasitic development. PfYVH1 represents the first dual-specificity zinc-finger phosphatase characterized in the protozoan kingdom.