Systemic immune-checkpoint blockade with anti-PD1 antibodies does not alter cerebral amyloid-β burden in several amyloid transgenic mouse models.

Chronic inflammation represents a central component in the pathogenesis of Alzheimer's disease (AD). Recent work suggests that breaking immune tolerance by Programmed cell Death-1 (PD1) checkpoint inhibition produces an IFN-γ-dependent systemic immune response, with infiltration of the brain by peripheral myeloid cells and neuropathological as well as functional improvements even in mice with advanced amyloid pathology (Baruch et al., (): Nature Medicine, 22:135-137).

Genetic manipulations of adenovirus type 5 fiber resulting in liver tropism attenuation.

The development of genetically modified adenoviral vectors capable of specifically transducing a given cell population requires the addition and functional presentation of particular tropism determinants within the virus capsid, together with the abrogation of the molecular determinants that dictate their natural tropism in vivo. The human adenovirus serotype 5 (Ad5) first attaches to the cell surface following high-affinity binding of the C-terminal knob of the fiber capsid protein to the coxsackie and adenovirus receptor (CAR). Here we have assessed whether genetic shortening of the fiber shaft (virus BS1), or replacing the Ad5 fiber shaft and knob with their Ad3 counterparts (virus DB6), could cripple this interaction in vitro and in vivo.

Controlled transgene expression by E1-E4-defective adenovirus vectors harbouring a "tet-on" switch system.

Background: The "tet switch system" was originally described under the tet-off configuration with its components encoded by two separate plasmids. Since then, many virus vectors harbouring tet-off components have been designed and their regulation by tetracycline is widely reported. On the contrary, tet-on regulation by viral vectors is poorly documented.

Gene transfer of a chimeric trans-activator is immunogenic and results in short-lived transgene expression.

Pharmacologic gene regulation is a key technology, necessary to achieve safe, long-term gene transfer. The approaches described in the scientific literature all share in common the creation of artificial transcription factors by fusing a DNA-binding domain, a drug-binding domain and a transcription activation domain. These transcription factors activate the transgene expression upon binding of the pharmacologic agent (antibiotics of the tetracycline family, insect hormone, progesterone antagonist, or immunosuppressor drug) to the drug-binding domain.

Efficient gene regulation by PPAR gamma and thiazolidinediones in skeletal muscle and heart.

We have developed a new gene regulation system for gene therapy. This system consists of two expression cassettes; one expresses the human peroxisome proliferator-activated receptor gamma(PPAR gamma), and the other expresses the therapeutic gene under the control of multiple peroxisome proliferator-activated receptor (PPAR) response elements (PPREs) linked to a basal promoter. Using direct injection of plasmid DNA into skeletal muscle or myocardium of rodents and oral administration of clinically approved PPAR gamma activators, we demonstrate that reporter gene expression can be induced more than 25-fold.

A novel method using baculovirus-mediated gene transfer for production of recombinant adeno-associated virus vectors.

The baculovirus Autographa californica multiple nucleopolyhedrosis virus causes non-productive infection in mammalian cells. Recombinant baculovirus therefore has the capability to transfer and express heterologous genes in these cells if a mammalian promoter governs the gene of interest. We have investigated the possibility of using baculovirus as a tool to produce recombinant adeno-associated virus (rAAV).

Potential gene therapy for lecithin-cholesterol acyltransferase (LCAT)-deficient and hypoalphalipoproteinemic patients with adenovirus-mediated transfer of human LCAT gene.

Background: Overexpression of human lecithin-cholesterol acyltransferase (LCAT) in transgenic mice results in an increase of the antiatherogenic HDLs.

Methods And Results: To investigate the potential use of LCAT for gene therapy, a recombinant adenovirus was constructed in which the human LCAT cDNA was expressed under the control of the human cytomegalovirus immediate/early promoter followed by a chimeric intron (AdCMV human LCAT). Human apolipoprotein (apo) A-I transgenic mice infected with AdCMV human LCAT by intravenous injection accumulated reactive LCAT in the plasma.