Lentiviral Vectors for Gene Delivery to the Nervous System

Eleftheriadou, Ioanna; Mazarakis, Nicholas D.

doi:10.1007/978-1-4939-2306-9_2

Cited by 5 publications

(3 citation statements)

References 165 publications

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“…Therefore, in this study, we tested the hypothesis whether SOCS3 played an important role in CIP and its possible interaction with TLR4 in DRG tissues of rats with bone cancer (BC). Using replication-deficient and self-inactivating lentiviral (LV) vectors, 23 , 24 we developed a feasible approach to induce SOCS3 overexpression in the DRG tissues. We showed that tumor cell injection significantly reduced the expression of SOCS3 in DRG tissues and that overexpression of SOCS3 attenuated the hyperalgesia, reversed the hyperexcitability of DRG neurons innervating the tibia, and reduced the expression of TLR4.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of suppressor of cytokine signaling 3 in dorsal root ganglion attenuates cancer-induced pain in rats

Wei

Wang

et al. 2017

Mol Pain

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BackgroundCancer-induced pain (CIP) is one of the most severe types of chronic pain with which clinical treatment remains challenging and the involved mechanisms are largely unknown. Suppressor of cytokine signaling 3 (SOCS3) is an important intracellular protein and provides a classical negative feedback loop, thus involving in a wide variety of processes including inflammation and nociception. However, the role of SOCS3 pathway in CIP is poorly understood. The present study was designed to investigate the role of SOCS3 in dorsal root ganglion (DRG) in the development of CIP.MethodCIP was established by injection of Walker 256 mammary gland tumor cells into the rat tibia canal. Whole-cell patch clamping and Western blotting were performed.ResultsFollowing the development of bone cancer, SOCS3 expression was significantly downregulated in rat DRGs at L2–L5 segments. Overexpression of SOCS3, using lentiviral-mediated production of SOCS3 at spinal cord level, drastically attenuated mechanical allodynia and body weight-bearing difference, but not thermal hyperalgesia in bone cancer rats. In addition, overexpression of SOCS3 reversed the hyperexcitability of DRG neurons innervating the tibia, and reduced abnormal expression of toll-like receptors 4 in the DRGs.ConclusionsThese results suggest that SOCS3 might be a key molecular involved in the development of complicated cancer pain and that overexpression of SOCS3 might be an important strategy for treatment for mechanical allodynia associated with bone cancer.

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Section: Introductionmentioning

confidence: 99%

Overexpression of suppressor of cytokine signaling 3 in dorsal root ganglion attenuates cancer-induced pain in rats

Wei

Wang

et al. 2017

Mol Pain

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“…Hence, novel treatment modalities are desperately needed. Gene therapy could hold the promise of therapeutic progress (Blömer et al 1996 ; Wong et al 2006 ; Eleftheriadou and Mazarakis 2015 ). As many neurodegenerative diseases develop with progressive, incurable degeneration of neuronal cells, gene therapy approaches for the treatment of such disorders require vector systems that can efficiently transduce non-dividing neurons.…”

Section: Introductionmentioning

confidence: 99%

“…Lentiviral vectors have been shown to do so and by integrating their genome into the genome of the transduced cells they supposedly provide permanent expression of the transferred therapeutic gene in these cells and also in the progeny of transduced dividing neuronal precursors (Lundberg et al 2008 ). In addition to these therapeutic approaches, lentiviral vectors can be used for modelling of neurodegenerative disorders in different experimental settings (Déglon and Hantraye 2005 ; Eleftheriadou and Mazarakis 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Tropism, intracerebral distribution, and transduction efficiency of HIV- and SIV-based lentiviral vectors after injection into the mouse brain: a qualitative and quantitative in vivo study

Hlavatý

Tonar

Renner

et al. 2017

Histochem Cell Biol

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Lentiviruses are suitable to transfer potential therapeutic genes into non-replicating cells such as neurons, but systematic in vivo studies on transduction of neural cells within the complete brain are missing. We analysed the distribution of transduced cells with respect to brain structure, virus tropism, numbers of transduced neurons per brain, and influence of the Vpx or Vpr accessory proteins after injection of vectors based on SIVsmmPBj, HIV-2, and HIV-1 lentiviruses into the right striatum of the mouse brain. Transduced cells were found ipsilaterally around the injection canal, in corpus striatum and along corpus callosum, irrespective of the vector type. All vectors except HIV-2SEW transduced also single cells in the olfactory bulb, hippocampus, and cerebellum. Vector HIV-2SEW was the most neuron specific. However, vectors PBjSEW and HIV-1SEW transduced more neurons per brain (means 41,299 and 32,309) than HIV-2SEW (16,102). In the presence of Vpx/Vpr proteins, HIV-2SEW(Vpx) and HIV-1SEW(Vpr) showed higher overall transduction efficiencies (30,696 and 27,947 neurons per brain) than PBjSEW(Vpx) (6636). The distances of transduced cells from the injection canal did not differ among the viruses but correlated positively with the numbers of transduced neurons. The presence of Vpx/Vpr did not increase the numbers of transduced neurons. Parental virus type and the vector equipment seem to influence cellular tropism and transduction efficiency. Thus, precision of injection and choice of virus pseudotype are not sufficient when targeted lentiviral vector transduction of a defined brain cell population is required.Electronic supplementary materialThe online version of this article (doi:10.1007/s00418-017-1569-1) contains supplementary material, which is available to authorized users.

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MiR-505-3p is a Repressor of the Puberty Onset in Female Mice miR-505-3p and the puberty onset

Zhou

Wang

et al. 2018

Preprint

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24Puberty onset is a complex trait regulated by multiple genetic and environmental factors. In this 25 study, we narrowed a puberty related QTL down to a 1.7 Mb region on chromosome X in female mice 26 and inferred miR-505-3p as the functional gene. 27We conducted ectopic expression of miR-505-3p in the hypothalamus of prepubertal female mice 28 through lentivirus-mediated orthotopic injection. The impact of miR-505-3p on female puberty was 29 evaluated by the measurement of pubertal events and histological analysis. The results showed that 30 female mice with overexpression of miR-505-3p in the hypothalamus manifested later puberty onset 31 timing both in vaginal opening and ovary maturation, followed by weaker fertility lying in the longer 32 interval time between mating and delivery, higher abortion rate and smaller litter size. We also 33 constructed miR-505-3p knockout mice by CRISPR/Cas9 technology. MiR-505-3p knockout female 34 mice showed earlier vaginal opening timing, higher serum gonadotrophin and higher expression of 35 puberty-related gene, as well as its target gene Srsf1 in the hypothalamus than their wild type 36 littermates. 37Srsf1 was proved to be the target gene of miR-505-3p that played the major role in this process. 38The results of RIP-seq (RNA Immunoprecipitation-sequencing) showed that SF2, the protein product 39 of Srsf1 gene, mainly bound to ribosome protein (RP) mRNAs in GT1-7 cells. The collective evidence 40 implied that miR-505-3p/SRSF1/RP could play a role in the sexual maturation regulation of mammals. 41 Author summary 42 The puberty onset in mammals is a vital biological process that signals the acquisition of 43 reproductive capacity. The initiation of puberty is triggered by the activation of hypothalamic pulsatile 44 GnRH surge. The dysregulation of pubertal development shows relevance to later health risks of type 2 3 45 diabetes, cardiovascular disease, breast cancer and other health disorders. Recent progress indicates 46 that a lot of genes play a role in the excitatory or inhibitory regulation of GnRH release. However, the 47 detailed pathway of pubertal timing remains unclear. Our previous studies isolated an X-linked QTL 48that was associated with the timing of puberty in mice. In this study, we proved that miR-505-3p was a 49 female puberty onset regulator based on data from positional cloning, ectopic expression and knockout 50 mouse models. We also assigned Srsf1 as the functional target gene of miR-505-3p underlying this 51 process. The results of RIP-seq showed that SF2, the protein of Srsf1 gene, preferential bound to 52 ribosome protein (RP) mRNAs in GT1-7 cells. We propose that miR-505-3p/SF2/RP could play a role 53 in the sexual maturation regulation of mammals. 54

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Lentiviral Vectors for Gene Delivery to the Nervous System

Cited by 5 publications

References 165 publications

Overexpression of suppressor of cytokine signaling 3 in dorsal root ganglion attenuates cancer-induced pain in rats

Overexpression of suppressor of cytokine signaling 3 in dorsal root ganglion attenuates cancer-induced pain in rats

Tropism, intracerebral distribution, and transduction efficiency of HIV- and SIV-based lentiviral vectors after injection into the mouse brain: a qualitative and quantitative in vivo study

MiR-505-3p is a Repressor of the Puberty Onset in Female Mice miR-505-3p and the puberty onset

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