Development of lipoplexes as drug-delivery systems for oligonucleotides transport across blood brain barrier

The complexity of the blood brain barrier (BBB) and its high selective permeability pose a unique challenge for the application of brain gene therapy,1 a huge technological advance in the treatment of central nervous system (CNS) disorders. The entrapment of genetic material in nanocarriers seems to offer a promising solution to enhance BBB crossing capability of therapeutics. In this regard, cationic liposomes are ideal candidates due to their ability to complex nucleic acid drugs, resulting in systems known as lipoplexes.2 In this research work, we investigated the efficacy of cationic liposomes formulated with a cationic gemini amphiphile 3 (SS or MESO, Figure 1) in complexing and delivering a drug approved for the treatment of spinal muscular atrophy (SMA), Nusinersen (Spinraza®)4, which is currently administered by intrathecal injection due to its inability to cross the BBB. The best formulations in terms of size, polydispersity, ?-Potential and ability to complex Nusinersen were selected to evaluate their uptake on a monolayer of brain microvascular endothelial cells derived from human induced pluripotent stem cells (iBMECs). Interestingly, the different stereochemistry of the gemini amphiphile affected the therapeutic efficacy of lipoplexes, as revealed by the liposomes assay on human SMA type II fibroblasts (GM03813).