Changing trends in the development of AAV-based gene therapies: a meta-analysis of past and present therapies.

Gene therapy has seen a transformation from a proof-of-concept approach to a clinical reality over the past several decades, with adeno-associated virus (AAV)-mediated gene therapy emerging as the leading platform for in vivo gene transfer. A systematic review of AAV-based gene therapies in clinical development was conducted herein to determine why only a handful of AAV-based gene therapy products have achieved market approval. The indication to be treated, route of administration and vector design were investigated as critical factors and assessed for their impact on clinical safety and efficacy. A shift in recent years towards high-dose systemic administration for the treatment of metabolic, neurological and haematological diseases was identified, with intravenous administration demonstrating the highest efficacy and safety risks in clinical trials. Recent years have seen a decline in favour of traditional AAV serotypes and promoters, accompanied by an increase in favour and higher clinical success rate for novel capsids and tissue-specific promoters. Furthermore, a meta-analysis was performed to identify factors that may inhibit the translation of therapeutic efficacy from preclinical large animal studies to first-in-human clinical trials and a detrimental effect on clinical efficacy was associated with alterations to administration routes.

Comparative study using spheres, rods and spindle-shaped nanoplatelets on dispersion stability, dissolution and toxicity of CuO nanomaterials.

Copper oxide nanoparticles with different shapes were used to examine the effect of shape on the various physicochemical properties (reactivity, aggregation, suspension stability) and to examine the behaviour by which CuO nanoparticles exhibit their biological response towards alveolar type-I cells. The different shapes examined in this study include spherical-, rod- and spindle-shaped platelet particles. In vitro dissolution studies (7 days) in 1 mM NaNO3 matrix showed a marked difference in dissolved Cu release between the nanoparticles. However, in serum-free cell-culture media (exposure media to cells), the particles' dissolution was found to be significantly enhanced with close to complete dissolution reported for all particle types. Biological studies showed both shape and size of the CuO nanoparticles tested to have a significant effect on TT-1 cell viability and release of pro-inflammatory cytokines IL-6 and IL-8. This study shows a complex interplay between particulate and dissolved species triggering the biological response. Upon immediate exposure of CuO nanoparticles of different shapes, the particulate form contributes towards the toxicity. However, for any biological response observed over and beyond a period of 24 h, the dissolved fraction becomes significant.