Malignant progression in cancer requires populations of tumor-initiating cells (TICs

The encapsulation of mRNA in nanosystems as gene vaccines for immunotherapy purposes has experienced an exponential increase in recent years. Despite the many advantages envisaged within these approaches, their application in clinical treatments is still limited due to safety issues. These issues can be attributed, in part, to liver accumulation of most of the designed nanosystems and to the inability to transfect immune cells after an intravenous administration. In this context, this study takes advantage of the known versatile properties of the oligopeptide end-modified poly (β-amino esters) (OM-PBAEs) to complex mRNA and form discrete nanoparticles. Importantly, it is demonstrated that the selection of the appropriate end-oligopeptide modifications enables the specific targeting and major transfection of antigen-presenting cells (APC) in vivo, after intravenous administration, thus enabling their use for immunotherapy strategies. Therefore, with this study, it can be confirmed that OM-PBAE are appropriate systems for the design of mRNA-based immunotherapy approaches aimed to in vivo transfect APCs and trigger immune responses to fight either tumors or infectious diseases.

Cultivated murine bone marrow mesenchymal stem cells (MSCs) frequently accumulate chromosome abnormalities, become oncogenically transformed, and generate sarcomas when transplanted in mice. Although human MSCs appear to be more resistant, oncogenic transformation has also been observed in MSCs cultivated past the senescence phase. Cell therapy for tissue regeneration using human autologous MSCs requires transplantation of cells previously expanded in vitro. Thus, an important concern is to determine if oncogenic transformation is a necessary outcome of the expansion procedures. We have analyzed the proliferation capacity, organ colonization, and oncogenicity of enhanced green fluorescent protein and luciferase-labeled human adipose tissue-derived mesenchymal stem cells (hAMSCs), implanted in immunocompromised mice during a prolonged time period (8 months) using a non-invasive bioluminescence imaging procedure. Our data indicates that the liver was the preferred target organ for colonization by intramuscular or intravenous implantation of hAMSCs. The implanted cells tended to maintain a steady state, population did not proliferate rapidly after implantation, and no detectable chromosomal abnormalities nor tumors formed during the 8 months of residence in the host's tissues. It would appear that hAMSCs, contrary to their murine correlatives, could be safe candidates for autologous cell therapy procedures since in our experiments they show undetectable predisposition to oncogenic transformation after cultivation in vitro and implantation in mice.

Brain-derived neurotrophic factor (BDNF) is the main candidate for neuroprotective therapeutic strategies for Huntington's disease. However, the administration system and the control over the dosage are still important problems to be solved. Here we generated transgenic mice overexpressing BDNF under the promoter of the glial fibrillary acidic protein (GFAP) (pGFAP-BDNF mice). These mice are viable and have a normal phenotype. However, intrastriatal administration of quinolinate increased the number of reactive astrocytes and enhanced the release of BDNF in pGFAP-BDNF mice compared with wild-type mice. Coincidentally, pGFAP-BDNF mice are more resistant to quinolinate than wild-type mice, suggesting a protective effect of astrocyte-derived BDNF. To verify this, we next cultured astrocytes from pGFAP-BDNF and wild-type mice for grafting. Wild-type and pGFAP-BDNF-derived astrocytes behave similarly in nonlesioned mice. However, pGFAP-BDNF-derived astrocytes showed higher levels of BDNF and larger neuroprotective effects than the wild-type ones when quinolinate was injected 30 days after grafting. Interestingly, mice grafted with pGFAP-BDNF astrocytes showed important and sustained behavioral improvements over time after quinolinate administration as compared with mice grafted with wild-type astrocytes. These findings show that astrocytes engineered to release BDNF can constitute a therapeutic approach for Huntington's disease.

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