A microRNA-dependent oncolytic virus
Creation of oncolytic viruses (OVs) suitable for the clinic requires strategies in virus design that spare normal tissues. Altered expression of microRNAs is a common hallmark of cancer cells. In this issue, Edge et al. show that altered microRNA expression in cancer cells can be exploited to achieve tumor-specific replication of an engineered oncolytic vesicular stomatitis virus (VSV). Incorporation of let-7 microRNA complementary sequences within VSV eliminated replication and toxicity in normal cells but permitted growth in cancer cells in vitro and in vivo. The results provide proof of concept that the use of viruses designed to exploit the differential microRNA expression in cancer cells is a potential approach to enhancing OV safety. See page 1437.
Form and function of drug delivery carriers
Endothelial cells (ECs) lining the vascular lumen are important for delivery of therapeutics by nanoscale and microscale carriers. Muro et al. show that carrier geometry influences endothelial targeting and the rate of endocytosis and lysosomal transport within ECs. Disks had longer half-lives in circulation and higher targeting specificity in mice, whereas spheres were endocytosed more rapidly. Micron-size carriers had prolonged residency in prelysosomal compartments, beneficial for endothelial antioxidant protection by delivered catalase. Submicron carriers trafficked to lysosomes more readily, optimizing effects of acid sphingomyelinase enzyme replacement in a model of lysosomal storage disease. Therefore, rational design of carrier geometry should help optimize endothelium-targeted therapeutics. See page 1450.
Gene therapy reconstitutes lymphoid cells in Artemis-deficient mice
Patients with mutations in the Artemis gene display a complete absence of T and B lymphocytes and increased cellular radiosensitivity, leading to a radiosensitive severe combined immunodeficiency. Benjelloun et al. used a self-inactivated lentiviral vector to express Artemis in Artemis knockout (Art–/–) mice. Transplantation of Artemis-transduced hematopoietic stem cells (HSCs) into irradiated Art–/– mice restored a stable and functional T- and B-cell repertoire that was comparable to that of control mice. The success of secondary transplantations demonstrated that the HSCs had been transduced. See page 1490.
HIV takes a double hit with an aptamer-siRNA chimera
The successful use of small interfering RNAs (siRNAs) for therapeutic purposes requires safe and efficient delivery to specific cells and tissues. Zhou et al. demonstrated cell type–specific delivery of anti-HIV siRNAs through fusion to an anti-gp120 aptamer. They show that the anti-gp120 aptamer–siRNA chimera is specifically taken up by cells expressing HIV-1 gp120, and that the appended siRNA is processed by Dicer, releasing an anti-tat/rev siRNA that inhibits HIV replication. The chimera represents a dual-functioning aptamer-siRNA therapeutic in which both the aptamer and the siRNA portions have potent anti-HIV activities. See pages 1481 and 1356.
Lentivectors get retargeted
Retargeting lentiviral vector entry to cell types of interest is a key step in improving gene transfer safety and efficacy. In this issue, Funke et al. show that the retargetable envelope glycoproteins of measles virus (MV)—the hemagglutinin (H) responsible for receptor recognition and the fusion protein—can pseudotype HIV-1 vectors upon truncation of their cytoplasmic tails. They then pseudotyped HIV-1 vectors with MV glycoproteins that displayed on H either the epidermal growth factor or a single-chain antibody directed against CD20 but were unable to recognize their native receptors. Gene transfer into cells expressing the targeted receptor was several orders of magnitude more efficient than into cells not expressing it. See pages 1427 and 1349.
