AIRWAY-TO-BIOPHASE TRANSFER OF INHALED OLIGONUCLEOTIDES

Because systemic delivery of proteins and peptides proceeds via the lu ng, and oligonucleotides (ONs) possess some similar molecular characte ristics, it is tempting to propose that inhalation may solve some of t he systemic delivery problems being experienced by scientists in the O N industry. It is also likely that a variety of ON targets exist withi n the lung itself. Although the lungs and respiratory tract (RT) may o ffer their own metabolic challenges, this route offers an enormous abs orptive surface area, quite capable of slowly delivering 5-7 kDa compo unds to the circulation. Moreover, the presentation of-formulated ONs appears capable of suppressing the local (lung) expression of gene pro ducts involved in inflammation and other disease processes. In this re view we describe the current state of the art surrounding the cell bio logy of ONs and then critically analyze those factors which determine the feasibility of their delivery by aerosol inhalation. At present, s ystemic dosing requirements for the majority of ONs are a little too l arge to envisage their routine delivery via inhalation. ON molecular d esign to increase potency and decrease susceptibility to nuclease enzy mes may or may not change this situation in the near future. On the ot her hand, ON delivery for the purposes of inhibiting expression of pro teins involved with lung pathology at a local level is advocated becau se it appears to be within easy reach of current aerosol delivery tech nology.