Abstract
Viral vectors are rapidly being developed for a range of applications in research and gene therapy. Prototype foamy virus (PFV) vectors have been described for gene therapy, although their use has mainly been restricted to ex vivo stem cell modification. Here we report direct in vivo transgene delivery with PFV vectors carrying reporter gene constructs. In our investigations, systemic PFV vector delivery to neonatal mice gave transgene expression in the heart, xiphisternum, liver, pancreas, and gut, whereas intracranial administration produced brain expression until animals were euthanized 49 days post-transduction. Immunostaining and confocal microscopy analysis of injected brains showed that transgene expression was highly localized to hippocampal architecture despite vector delivery being administered to the lateral ventricle. This was compared with intracranial biodistribution of lentiviral vectors and adeno-associated virus vectors, which gave a broad, non-specific spread through the neonatal mouse brain without regional localization, even when administered at lower copy numbers. Our work demonstrates that PFV can be used for neonatal gene delivery with an intracranial expression profile that localizes to hippocampal neurons, potentially because of the mitotic status of the targeted cells, which could be of use for research applications and gene therapy of neurological disorders.
Highlights
Intravenous injection was poorly tolerated; three of the four Prototypic FV (PFV)-luciferase cohorts died before the first imaging time point
We have shown that PFV vectors are capable tools for direct in vivo gene delivery, in the developing neonatal hippocampus, which adds a new dimension to their role in the growing field of gene therapy
The ability of PFV vectors to integrate into the host genome makes them an appropriate choice for ex vivo gene therapy
Summary
626 Molecular Therapy: Nucleic Acids Vol 12 September 2018 a 2018 The Authors. Subcutaneous therapy.[22,23,24] like all retroviruses, LV vectors are confounded by the risk of insertional mutagenesis, which is a concern in clinical translation.[25] In a recent clinical trial for b-thalassemia stem cell therapy, LV vector integration into the HMGA2 proto-oncogene led to transcription of a truncated mRNA and benign clonal dominance.[26]. Foamy virus (FV) vectors are derived from a subfamily of retroviruses known as Spumaretroviridae, possessing several distinguishing properties that show potential for gene therapy.
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