Focused ultrasound-induced blood brain-barrier opening enhanced vascular permeability for GDNF delivery in Huntington's disease mouse model

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the gene encoding the huntingtin (Htt) protein, which results in a protein containing an abnormally expanded polyglutamine (polyQ) sequence. The expanded polyQ in the Htt protein is toxic to brain cells. No therapy exists to delay disease progression. This study describes a gene-liposome system that synergistically applied focused ultrasound (FUS)-blood-brain barrier (BBB) opening for rescuing motor and neuropathological impairments when administered from pre to post-symptomatic transgenic mouse models of HD. DPPC liposomes (LPs) are designed to carry glia cell line-derived neurotrophic factor (GDNF) plasmid DNA (GDNFp) to form a GDNFp-liposome (GDNFp-LPs) complex. Pulsed FUS exposure with microbubbles (MBs) was used to induce BBB opening for non-viral, non-invasive, and targeted gene delivery into the central nervous system (CNS) for therapeutic purposes. FUS-gene therapy significantly improved motor performance with GDNFp-LPs + FUS treated HD mice equilibrating longer periods in the animal behavior. Reflecting the improvements observed in motor function, GDNF overexpression results in significantly decreased formation of polyglutamine-expanded aggregates, reduced oxidative stress and apoptosis, promoted neurite outgrowth, and improved neuronal survival. Immunoblotting and histological staining further confirmed the neuroprotective effect from delivery of GDNF genes to neuronal cells. This study suggests that the GDNFp-LPs plus FUS sonication can provide an effective gene therapy to achieve local extravasation and triggered gene delivery for non-invasive in vivo treatment of CNS diseases. Schematic representation of FUS-mediated GDNFp-liposomes (GDNFp-LPs) delivery for treatment of HD transgenic mice. [Display omitted] •FUS-gene therapy can rescue and hinder the progression of motor deficits in HD mice.•FUS-gene therapy significantly improved motor performance in the HD animal behavior.•Neuroprotective effect from delivery of GDNF genes to neuronal cells.•The signaling pathways involved via FUS-GDNF therapy on mutant Htt protein aggregation.