Abstract
Traumatic brain injury (TBI) is a complex and progressive brain injury with no approved treatments that needs both short- and long-term therapeutic strategies to cope with the variety of physiopathological mechanisms involved. In particular, neuroinflammation is a key process modulating TBI outcome, and the potentiation of these mechanisms by pro-inflammatory gene therapy vectors could contribute to the injury progression. Here, we evaluate in the controlled cortical impact model of TBI, the safety of integrative-deficient lentiviral vectors (IDLVs) or the non-viral HNRK recombinant modular protein/DNA nanovector. These two promising vectors display different tropisms, transduction efficiencies, short- or long-term transduction or inflammatory activation profile. We show that the brain intraparenchymal injection of these vectors overexpressing green fluorescent protein after a CCI is not neurotoxic, and interestingly, can decrease the short-term sensory neurological deficits, and diminish the brain tissue loss at 90 days post lesion (dpl). Moreover, only IDLVs were able to mitigate the memory deficits elicited by a CCI. These vectors did not alter the microglial or astroglial reactivity at 90 dpl, suggesting that they do not potentiate the on-going neuroinflammation. Taken together, these data suggest that both types of vectors could be interesting tools for the design of gene therapy strategies targeting immediate or long-term neuropathological mechanisms of TBI.
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Acknowledgements
We thank Fundació Marató TV3 (110533), Catalunya, Spain; Comisión Sectorial de Investigación Científica (CSIC-UDELAR), Uruguay; Agencia Nacional de Investigación e Innovación (ANII), Uruguay; PEDECIBA, Uruguay; FOCEM (MERCOSUR Structural Convergence Fund), COF 03/1111; and Banco de Seguros del Estado (BSE), Uruguay.
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Blanco-Ocampo, D., Cawen, F.A., Álamo-Pindado, L.A. et al. Safe and neuroprotective vectors for long-term traumatic brain injury gene therapy. Gene Ther 27, 96–103 (2020). https://doi.org/10.1038/s41434-019-0073-8
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DOI: https://doi.org/10.1038/s41434-019-0073-8
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