Polynucleic acid-based drugs (DNA, RNA, oligonucleotides) require cell- specific intracellular delivery as a conditio sine qua non to be efficacious. However, this has proved to be an elusive goal. We have proposed that mimicry of the pathophysiologic pathway of viral infection using synthetic constructs may provide a means to overcome natural barriers of cell entry. Based on this hypothesis, we have designed artificial viral envelopes (AVE) replicating the structure and mimicking the function of enveloped viruses. An HIV-1-mimicking AVE facilitated efficient and selective intracellular transfer of macromolecules to CD4+ target cells, while a respiratory syncytial virus-mimicking AVE facilitated entry into tracheobronchial target cells. The long-term objective of this proposal is to expand this delivery strategy toward "chimeric" carriers by insertion or attachment of non-viral targeting moieties, e.g. carbohydrates, peptides, or small molecules. One important organ target for numerous metabolic, neoplastic and infectious diseases is the liver. A pathophysiologic process that utilizes targeting to liver hepatocytes with superior selectivity and efficiency is the infection with malaria sporozoites. It is known that a specific region (region II+ sequence) of the major surface protein of the parasite is responsible for this targeting effect. Hence, the specific aim of this Phase I study is to explore the feasibility of delivering (marker) gene products selectively and efficiently to hepatocytes in vitro and in vivo in mice using a chimeric AVE-region II+ carrier for a great variety of liver diseases including neoplastic diseases, viral (e.g. hepatitis B) and parasitic infections, and metabolic diseases (enzyme deficiencies, e.g. alpha1- antitrypsin, glucocerebroside beta-glucosidase deficiency). In Phase II, the delivery and efficacy of pharmacologically active compounds including at least one gene encoding for a metabolic enzyme (alpha1-antitrypsin) and at least one antiviral oligonucleotide construct will be tested in appropriate animal models.Proposed commercial application:The research project proposed here will generate a platform technology which will be applicable for therapy of a wide variety of severe and currently incurable hepatic diseases with novel pharmacologically active entities, specifically gene and oligonucleotide constructs. This will create not only opportunities for improvement of existing therapies, but will facilitate the introduction of new therapeutic regimens in several large medical arenas, specifically the cancer and infectious disease area.National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
