Tag Archive | mice

Therapeutic virus-like particle- based vaccines against cervical cancer

Cervical cancer represents the second most frequent gynecological malignancy in the world. It is caused by a persistent virus infection by the high-risk human papillomavirus (HR-HPV) but no cervical cancer vaccine has been marketed to date. In a paper published in PLoS, Juan Martin Caballero, director of the PRBB animal facility, together with colleagues from a pharmaceutical company have generated a virus-like particle (VLP)-based vaccine to treat this cancer and have tested it in humanized transgenic mice.

The researchers took a long C-terminal fragment of the HPV-16 E7 protein – one of the two viral proteins necessary for induction and maintenance of malignant transformation – and introduced it into the infectious bursal disease virus (IBDV) VLP. The combination of tumor antigens and IBDV-VLPs has been shown as a good strategy to boost the immune response and direct it against different types of cancer.

The authors tested the therapeutic potential of their new vaccine, VLP-E7, in HLA-A2 humanized transgenic mice grafted with TC1/A2 tumor cells. They performed a series of tumour challenge experiments demonstrating a strong immune response against already formed tumors, including its complete eradication. Remarkably, therapeutic efficacy was obtained with a single dose without adjuvant and it persisted when the mice were re-challenged with a second tumor cell inoculation. As the authors state, this indicates a high immunogenic potential and in vivo efficacy of  their cervical cancer candidate vaccine, VLP-E7, although further studies will be necessary to investigate the potential of the IBDV VLP carrier and its applications to other human diseases.

Reference:

Martin Caballero J, Garzón A, González-Cintado L, Kowalczyk W, Jimenez Torres I, Calderita G, Rodriguez M, Gondar V, Bernal JJ, Ardavín C, Andreu D, Zürcher T, von Kobbe C. Chimeric Infectious Bursal Disease Virus-Like Particles as Potent Vaccines for Eradication of Established HPV-16 E7-Dependent Tumors. PLoS One. 2012;7(12):e52976

Understanding cannabis

Cannabis has a long history of use as medicine, with historical evidence dating back more than 4000 years.  The potential therapeutic benefits of cannabinoid compounds are huge, but this substance can also have negative effects. A recent paper by Andrés Ozaita and colleagues at the Neurophar laboratory of Rafael Maldonado (CEXS-UPF) has given new insights into the molecular mechanisms that underlie cannabinoid-mediated effects.

Using mice as a model system, the authors had previously shown that blocking the mTOR pathway prevented the amnesic-like effects of THC (a synthetic form of cannabinoid). In the present study, published in the journal Neuropsychopharmacology, they have gone further, proving that the inhibition of the mTOR pathway by the rapamycin derivative temsirolimus, prevents both the anxiogenic- and the amnesic-like effects produced by acute THC, but has no effect on THC-induced anxiolysis, hypothermia, hypolocomotion, and antinociception (lack of pain perception).

Therefore, treatment with temsirolimus could segregate the potentially beneficial effects of cannabinoid agonists, such as the decrease of pain and anxiety, from the negative effects, such as amnesia and an increase of anxiety. As the authors say, these results could help targeting the endocannabinoid system in order to prevent possible side effects.

Reference:

Puighermanal E, Busquets-Garcia A, Gomis-González M, Marsicano G, Maldonado R, Ozaita A. Dissociation of the Pharmacological Effects of THC by mTOR Blockade. Neuropsychopharmacology. 2013 Jan 28;

Down syndrome hippocampal defects improved in a mouse model

In a recent work published in Neurobiology of disease, the research groups lead by Mara Dierssen at the CRG and Cristina Fillat, now at the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) have joined efforts to find a potential therapeutic target for Down Syndrome (mice).

mice

Down Syndrome (DS), caused by the trisomy of human chromosome 21 (HSA21), is the most common chromosome abnormality in humans. It is typically associated with a delay in cognitive ability, with an average IQ of around 50 in young adults compared with 100 in adults without the condition, as well as with physical growth and a particular set of facial characteristics.

The Ts65Dn mouse is a genetic model for DS with a trisomy of the homologous chromosome in mice. In this model, overexpression of HSA21 homologous genes has been associated with strong visuo-spatial cognitive alterations, ascribed to hippocampal dysfunction. One of these genes is Dyrk1A (Dual specificity tyrosine-phosphorylation-regulated kinase 1A), a candidate gene for DS which seems to play a significant role in a signaling pathway regulating cell proliferation and which may be involved in brain development.

Dierssen, Fillat and colleagues decided to study whether the normalization of the expression levels of Dyrk1A – that is, reducing its expression, which in these mice is double than normal – might correct hippocampal defects in Ts65Dn mice.

They injected adeno-associated viruses containing a short hairpin RNA against Dyrk1A and a Luciferase reporter gene in the hippocampus of 2 months-old Ts65Dn mice. After checking that the injected hippocampi were efficiently transduced (via bioluminescence in vivo imaging, luciferase activity quantification and immunohistochemical analysis) and that the Dyrk1A expression had indeed been normalized at the molecular level, the researchers compared electrophysiological recordings of hippocampal slices from the Ts65Dn injected mice with those from mice injected with an AAV2/1 control virus.

The mice with normalized Dyrk1A levels displayed attenuation of the synaptic plasticity defects of trisomic mice. They also showed partial improvement in their hippocampal-dependent search strategy, as seen in the Morris water maze task – although long-term consolidation of the task was not achieved.

As the authors conclude, these results show Dyrk1A as a critical player in the pathophysiology of DS and define Dyrk1A as a therapeutic target in adult trisomic mice.

Reference:

Altafaj X, Martín E, Ortiz-Abalia J, Valderrama A, Lao-Peregrin C, Dierssen M, Fillat C. Normalization of Dyrk1A expression by AAV2/1-shDyrk1A attenuates hippocampal-dependent defects in the Ts65Dn mouse model of Down syndrome. Neurobiol Dis. 2012 Dec 4;

Coffee can be good for your brain

Several studies have suggested that daily caffeine administration can protect against brain injury in some cases, for example in animal models of neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases, as well as in ischemic and traumatic brain injury, or allergic encephalitis. Olga Valverde’s group at the CEXS-UPF decided to check if it could also have a positive effect on MDMA-induced neuroinflammation.

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The recreational drug MDMA, or ecstasy, induces astrocytic and microglial activation in mice striatum, which leads to inflammation and neurotoxicity. They injected caffeine (10, 20, or 30 mg/kg, i.p) for 21 consecutive days into mice, and then on day 22, mice pretreated with caffeine or saline (controls) received a neurotoxic regimen of MDMA (3 × 20 mg/kg, i.p., 2-h interval) or saline. Changes in body temperature were evaluated. Forty-eight hours after the last MDMA or saline injection, behavioral parameters such as locomotor activity, sensorimotor reflexes, and anxiety were investigated and microglia and astroglia activation to MDMA treatment was examined in the mouse striatum.

The results, published in the journal Psychopharmacology, show that consuming regularly low doses of caffeine (10 mg/kg) completely prevented MDMA-induced glial activation without inducing physiological or behavioral alterations in any of the assays performed. Therefore, caffeine can have anti-inflammatory effects on ecstasy-induced neuroinflammation in mice.

Reference:

Ruiz-Medina J, Pinto-Xavier A, Rodríguez-Arias M, Miñarro J, Valverde O. Influence of chronic caffeine on MDMA-induced behavioral and neuroinflammatory response in mice. Psychopharmacology (Berl). 2012 Nov 29;

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