Treatment for Neuropathic MPS

Transgene / Protein Delivery across the BBB into the CNS

The problems of gene therapy for diseases involving the CNS are well known. In addition to the general concerns of efficient gene transfer and effective and sustained transgene expression, there is the problem of transgene / vector access to the CNS due to the existence of the blood-brain-barrier (BBB). The BBB excludes from the brain more than 98 percent of all small-molecule drugs and ~100 percent of large-molecule therapeutics, including peptides, proteins, antibodies, RNA interference (RNAi)-based drugs and gene vectors. To overcome the hurdles of accessibility to CNS by therapeutics, researchers around the globe have investigated several strategies with promising development, such as intrathecal injection, direct in vivo gene therapy (intracranial or systemic vector delivery), small molecule therapies (substrate reduction and chaperone therapy) and cell-based therapies. Regardless of variations in therapeutic strategies, the main questions still remain, i.e., if and how a therapeutic enzyme can reach the brain, and if the quantity and distribution within brain parenchyma are sufficient to make a significant impact on the clinical progression of the diseases. The lentivirus vectors were proven to be capable of transducing nondividing cells such as brain neuronal cells, and the BBB also possesses specific receptors allowing selective delivery of several large proteins. The Pan Lab is interested in 1) the potential application of lentiviral vectors with the choice of targeted cells and the route of administration, 2) protein engineering to identify the “hidden password” for delivery across the BBB, and 3) the neurological pathogenesis and / or BBB remodeling in MPS diseases.