Some recombinant adeno-associated viruses (rAAVs) can cross the neonatal blood-brain barrier (BBB) and efficiently transduce cells of the central nervous system (CNS). However, in the adult CNS, transduction levels by systemically delivered rAAVs are significantly reduced, limiting their potential for CNS gene therapy. Here, we characterized 12 different rAAVEGFPs in the adult mouse CNS following intravenous delivery. We show that the capability of crossing the adult BBB and achieving widespread CNS transduction is a common character of AAV serotypes tested. Of note, rAAVrh.8 is the leading vector for robust global transduction of glial and neuronal cell types in regions of clinical importance such as cortex, caudate-putamen, hippocampus, corpus callosum, and substantia nigra. It also displays reduced peripheral tissue tropism compared to other leading vectors. Additionally, we evaluated rAAVrh.10 with and without microRNA (miRNA)-regulated expressional detargeting from peripheral tissues for systemic gene delivery to the CNS in marmosets. Our results indicate that rAAVrh.8, along with rh.10 and 9, hold the best promise for developing novel therapeutic strategies to treat neurological diseases in the adult patient population. Additionally, systemically delivered rAAVrh.10 can transduce the CNS efficiently, and its transgene expression can be limited in the periphery by endogenous miRNAs in adult marmosets.

microRNAs (miRNAs) have been proposed to be key regulators of diverse biological processes such as transcriptional regulation, cell growth and tumorigenesis. Wnt signaling plays an important role in the regulation of tumorigenesis and cancer progression. However, little is known about whether miR‐144 regulates bladder cancer cell proliferation by controlling Wnt signaling. In this study, we found that the miR‐144 expression level is significantly decreased in bladder cancer cell lines as well as in clinical cancer tissues. miR‐144 inhibitor blocks the expression of endogenous miR‐144 and promotes cancer cell proliferation, whereas miR‐144 overexpression is sufficient to inhibit cell proliferation. We further demonstrated that enhancer of zeste homolog 2 (EZH2) is a target gene of miR‐144. miR‐144 downregulation relieves miR‐144‐mediated repression of EZH2, which results in activation of Wnt/β‐catenin signaling and subsequent cell proliferation. These data suggest miR‐144 is an essential mediator of bladder cancer cell proliferation, thus offering a new target for the development of therapeutic agents against bladder cancer.

No abstract