TARGETED DRUG DELIVERY SYSTEM FOR RSV

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Recurrent infections with respiratory syncytial virus (RSV) occur at all ages. However, they are of particular concern in infants and young children where RSV is the most common cause of severe, acute lower respiratory tract infections. RSV is the major cause of bronchiolitis during infancy and one of the major causes of pneumonia in childhood. The recommended treatment of severe RSV infection, aerosolized ribavirin, has only minimal clinical efficacy. We propose a novel concept for the therapy of RSV infections. Artificial viral envelopes (virosomes) containing an antiviral drug will be formulated in such a manner as to target for respiratory cell uptake. Virosomes will be constructed with RSV G (attachment) and F (fusion) surface glycoproteins. The objective is to mimic the molecular strategy adopted by RSV to attach and penetrate epithelial cells in the lung (active targeting) as well as to provide a strong stimulus for alveolar macrophages to phagocytize the drug-containing vesicle (passive targeting). The goal is to accumulate therapeutic concentrations of antiviral drug selectively within the two major host cells for RSV, the respiratory epithelial cell and the alveolar macrophage. The specific aims are: 1. To determine the optimal composition of RSV virosomes for maximum and rapid fusion with host cells. 2. To measure the ability of ribavirin- loaded virosomes to inhibit RSV replication in HEp-2 cells and alveolar macrophages compared to free ribavirin. 3. To assess the stability of these virosomes upon nebulization and lyophylization. 4. To assess toxicity of ribavirin-loaded virosomes in terms of: a) alterations in alveolar macrophage viability and phagocytic function; b) alterations in epithelial cell morphology and ciliary function; c) alterations in airway function in the lamb; d) induction of airway sensitization to RSV F or G glycoprotein in the lamb; and e) alterations in airway function in healthy adult volunteers. 5. To compare the efficacy of ribavirin- loaded virosomes with free ribavirin for the treatment of lower respiratory tract disease induced by RSV infection in young lambs and to evaluate the effects of this therapeutic intervention on reexposure to the virus.