In our previous studies, proline analogues such as cis-4-hydroxy-L-proline (cHyp, a potent inhibitor of collagen synthesis) have been attached to a class of water soluble polymers which were found to sustain release, reduce toxicity, and increase antifibrotic potency. The water soluble polymer consists of an alternating copolymer of low molecular wt polyethylene glycol (PEG) and the amino acid lysine (Lys), which provides an attachment site for cHyp, making a poly [PEG-Lys-cHyp] conjugate. cHyp is one of a series of proline analogues which have been shown to be a potent inhibitor of synthesis of collagen, and thus has been considered as a potential antifibrotic agent. Because of the size of the polymer (MW = 21,000 d) liposomes are required for cellular uptake. It was found that uptake by endothelial cells, and subsequently uptake in vivo, was enhanced by using a polysaccharide-coated liposome construct. Using a series of cell culture and in vivo studies, the Phase l results showed that the liposomal encapsulated poly[PEG-Lys-cHyp] was effective in decreasing into the right ventricular pressure and pulmonary artery collagen deposition that resulted from experimentally induced pulmonary hypertension. The goal of these proposed Phase Il studies is to further develop the compound formulation and to begin pre-clinical efficacy, toxicity, and safety studies. As in Phase I, the formulation and any modifications will be tested using cell culture and in vivo assays to determine the potential safety and bioactivity of this compound.
Currently, there are no effective treatments for pulmonary hypertension. Supplemental oxygen therapy increases longevity, but does not reverse the disease. General vasodilators such as hydralazine and the prostacyclin analogue epoprostenol have been used, but are only marginally effective. Although there are a number of companies which are developing antifibrotic agents, there is no competition, to the management's knowledge, for a site-directed therapeutic agent to combat pulmonary hypertension.
