A next step in adeno‐associated virus‐mediated gene therapy for neurological diseases: regulation and targeting

摘要: Recombinant adeno-associated virus (rAAV) vectors mediating long term transgene expression are excellent gene therapy tools for chronic neurological diseases. While rAAV2 was the first serotype tested in clinics, more efficient derived from rh10 currently being evaluated and other serotypes likely to be near future. In addition, aside used stereotaxy-guided intraparenchymal delivery, new techniques global brain transduction (by intravenous or intra-cerebrospinal injections) very promising. Various strategies therapeutic delivery central nervous system have been explored human clinical trials past decade. Canavan disease, a genetic disease caused by an enzymatic deficiency, approved. Three transfer paradigms Parkinson's explored: converting L-dopa into dopamine through AADC putamen; synthesizing GABA GAD overactive subthalamic nucleus providing neurotrophic support neurturin nigro-striatal pathway. These pioneer demonstrated safety tolerability of rAAV at moderate doses. Therapeutic effects however, were modest, emphasizing need higher doses product which could achieved using cassettes. This will require re-addressing pharmacological aspects, with attention cases either localized cell-type specific brain-wide expression, when it is necessary modulate terminate administration product. The ongoing development targeted regulated described.