J.B. Harford, S.S. Kim, M. Moghe, A.S. Rait, K.F. Pirollo, E.H. Chang
SynerGene Therapeutics, Inc.,
United States
Keywords: Blood-brain barrier, drug delivery, transferrin receptor, transcytosis, endocytosis
Summary:
We are developing several novel products based on a platform technology for drug delivery termed scL (for single chain Liposome) that has three components: a cationic liposome capable of encapsulating a variety of therapeutic entities; a targeting moiety that is a single chain monoclonal antibody fragment (scFv) recognizing the transferrin receptor (TfR); and the therapeutic payload itself. Cancer cells have elevated levels of cell surface TfRs compared to their normal cell counterparts, and TfR-mediated endocytosis has been recognized as having potential for targeting cancer cells in drug delivery. After intravenous administration, both primary and metastatic tumor cells take up payloads carried by scL nanocomplexes, whereas normal tissues adjacent to the tumors do not. For the brain to acquire iron, TfRs on the brain capillary endothelial cells are employed to shuttle transferrin across the blood-brain barrier (BBB). In this process, referred to as receptor-mediated transcytosis, TfRs bind their ligand on the blood side and release it on the brain side. When the cargo of the scL nanocomplex is a plasmid expression vector encoding green fluorescent protein (GFP), the expression of this reporter gene can be detected throughout the brain. Since only the final protein product is fluorescent, the fluorescence signal in the brain is dependent not only on the plasmid DNA being carried across the BBB by the scL nanocomplex, but it also requires uptake by neuronal cells, escape from the endosomal compartment, transcription of the GFP gene in the nucleus, and translation of GFP mRNA in the cytoplasm. In mice with intracranial brain tumors, TfR-mediated transcytosis is followed by TfR-mediated endocytosis by tumor cells resulting in accumulation of the payload in the tumors. The scL nanodelivery system has proven to be capable of encapsulating a wide variety of types of payloads including plasmid DNAs for gene therapy, antisense oligonucleotides or siRNAs for downmodulation of gene expression, and small molecule drugs. We have shown that the scL takes each kind of cargo into the brain and that the scL-encapsulated version of each payload outperforms its unencapsulated counterpart. Two investigational agents (SGT-94 and SGT-53) using the scL delivery vehicle have entered human trials as gene therapies for cancers, and one (SGT-53) is now in Phase II for patients with advanced pancreatic cancers with promising interim results and a very good safety profile. Our most recent application of the scL delivery system involves delivery of an oxime reactivator of acetylcholinesterase to reverse this enzyme's inhibition by a deadly organophosphate (OP). This new and improved OP countermeasure has not only been shown to improve survival in OP-exposed mice, but it also ameliorates OP-triggered neuroinflammation and brain damage. Because it excludes ~98% of all drugs, the BBB represents a challenging bottleneck in development of therapeutics to address various neurological diseases and conditions (Alzheimer's, Parkinson's, MS, ALS, etc.). We believe that the scL nanodelivery technology has the potential to open this bottleneck to allow diverse therapeutic agents to reach their intended targets in the brain.