The use of an optimized chimeric envelope glycoprotein enhances the efficiency of retrograde gene transfer of a pseudotyped lentiviral vector in the primate brain

Tanabe, Soshi; Inoue, Ken; Tsuge, Hitomi; Uezono, Shiori; Nagaya, Kiyomi; Fujiwara, Maki; Kato, Shigeki; Kobayashi, Kazuto

doi:10.1016/j.neures.2017.02.007

Cited by 23 publications

(26 citation statements)

References 33 publications

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“…Serious adverse effects were reported in the clinical trial, but it was not clear whether the adverse effects were directly attributed to the AAV2 CU hCLN2 vector 23 . Currently, new viral vectors have been developed to treat various brain diseases; however, most approaches still followed direct injection into the brain 24 , 25 . Thus, safe and systemic delivery is the key focus in the development of novel viral vectors for brain gene therapy.…”

Section: Current Strategies To Deliver Drugs Into the Brainmentioning

confidence: 99%

Current Strategies for Brain Drug Delivery

2018

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The blood-brain barrier (BBB) has been a great hurdle for brain drug delivery. The BBB in healthy brain is a diffusion barrier essential for protecting normal brain function by impeding most compounds from transiting from the blood to the brain; only small molecules can cross the BBB. Under certain pathological conditions of diseases such as stroke, diabetes, seizures, multiple sclerosis, Parkinson's disease and Alzheimer disease, the BBB is disrupted. The objective of this review is to provide a broad overview on current strategies for brain drug delivery and related subjects from the past five years. It is hoped that this review could inspire readers to discover possible approaches to deliver drugs into the brain. After an initial overview of the BBB structure and function in both healthy and pathological conditions, this review re-visits, according to recent publications, some questions that are controversial, such as whether nanoparticles by themselves could cross the BBB and whether drugs are specifically transferred to the brain by actively targeted nanoparticles. Current non-nanoparticle strategies are also reviewed, such as delivery of drugs through the permeable BBB under pathological conditions and using non-invasive techniques to enhance brain drug uptake. Finally, one particular area that is often neglected in brain drug delivery is the influence of aging on the BBB, which is captured in this review based on the limited studies in the literature.

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Section: Current Strategies To Deliver Drugs Into the Brainmentioning

confidence: 99%

Current Strategies for Brain Drug Delivery

2018

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“…The FuG-E pseudotype was injected into the striatum of macaque monkeys, and the efficiency of retrograde gene transfer was compared to that of the parental FuG-C–pseudotyped vector. The FuG-E vector exhibited greater efficiency of retrograde gene transfer into various neuronal populations in subcortical regions innervating the striatum than the FuG-C vector; specifically, 1.2-, 2.0- and 1.4-fold elevation of transfer efficiency into the substantia nigra pars compacta, centromedian-parafascicular nuclear complex of the thalamus, and centrolateral nucleus of the thalamus, respectively (data from Tanabe et al, 2017 ). In cortical areas, the gene transfer efficiency of the FuG-E vector in the hemisphere ipsilateral to the vector-injected side was 2.2-, 2.1-, 2.1- and 1.7-fold higher in the primary motor area, supplementary motor area, Brodmann’s area 8b and Brodmann’s area 46d, respectively as compared with that of the FuG-C vector, and the efficiency of the FuG-E vector in the contralateral hemisphere was increased to 5.8-, 4.1-, 8.7- and 5.9-fold of the value of the FuG-C vector in the respective four areas (data from Tanabe et al, 2017 ).…”

Section: Gene Delivery Of Fug-e–pseudotyped Vector Into Nonhuman Primmentioning

confidence: 99%

“…The gene transfer pattern of the FuG-E–pseudotyped vector was investigated in the nonhuman primate brain (Tanabe et al, 2017 ). The FuG-E pseudotype was injected into the striatum of macaque monkeys, and the efficiency of retrograde gene transfer was compared to that of the parental FuG-C–pseudotyped vector.…”

Section: Gene Delivery Of Fug-e–pseudotyped Vector Into Nonhuman Primmentioning

confidence: 99%

“…The FuG-E vector achieves a higher efficiency of retrograde gene delivery compared with the previously developed NeuRet vector, and it permits neuron-specific gene transduction around the injection site in the brain (Kato et al, 2014 ). Interestingly, retrograde gene transfer of the FuG-E vector into mouse nigrostriatal dopaminergic neurons is less efficient, whereas the FuG-E vector displays remarkably high transduction efficiency into the dopaminergic neurons in monkeys (Tanabe et al, 2017 ). In the near future, our newly developed FuG-E vector system with these attractive characteristics may serve as a powerful genetic tool in gene therapy trials for Parkinson’s disease.…”

Section: Potential Use Of Fug-e Vector In Gene Therapy Trials For Parmentioning

confidence: 99%

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Pseudotyped Lentiviral Vectors for Retrograde Gene Delivery into Target Brain Regions

et al. 2017

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Gene transfer through retrograde axonal transport of viral vectors offers a substantial advantage for analyzing roles of specific neuronal pathways or cell types forming complex neural networks. This genetic approach may also be useful in gene therapy trials by enabling delivery of transgenes into a target brain region distant from the injection site of the vectors. Pseudotyping of a lentiviral vector based on human immunodeficiency virus type 1 (HIV-1) with various fusion envelope glycoproteins composed of different combinations of rabies virus glycoprotein (RV-G) and vesicular stomatitis virus glycoprotein (VSV-G) enhances the efficiency of retrograde gene transfer in both rodent and nonhuman primate brains. The most recently developed lentiviral vector is a pseudotype with fusion glycoprotein type E (FuG-E), which demonstrates highly efficient retrograde gene transfer in the brain. The FuG-E–pseudotyped vector permits powerful experimental strategies for more precisely investigating the mechanisms underlying various brain functions. It also contributes to the development of new gene therapy approaches for neurodegenerative disorders, such as Parkinson’s disease, by delivering genes required for survival and protection into specific neuronal populations. In this review article, we report the properties of the FuG-E–pseudotyped vector, and we describe the application of the vector to neural circuit analysis and the potential use of the FuG-E vector in gene therapy for Parkinson’s disease.

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“…Compared with traditional retrograde tracers, viral vectors can express genes in speci c neuron groups [9,13], and have been widely used to monitor and manipulate neuronal activities by expressing optogenetic [14,15], chemogenetic [16,17] and calcium-sensitive functional probes [18][19][20]. Some natural and engineered neurotropic viruses exhibit retrograde infection capabilities, including pseudorabies virus (PRV) [21], herpes simplex virus (HSV) [22], rabies virus (RABV) [13,23], lentivirus (LV) [24][25][26][27], canine adenovirus (CAV) [6,28], and adeno-associated virus (AAV) [5,[29][30][31], etc. Among them, PRV is highly toxic [4,32,33]; HSV and RV can express genes rapidly and have high retrograde labeling e ciency, but they are also toxic to cells, limiting long-term gene manipulation [4,13,34,35].…”

Section: Introductionmentioning

confidence: 99%

AAV9-Retro Mediates Efficient Transduction with Axon Terminal Absorption and Blood-brain Barrier Transportation

Lin

Zhong

et al. 2020

Preprint

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Recombinant adeno-associated viruses (rAAVs), especially which permit efficient gene transfer to neurons from axonal terminals or across the blood-brain barrier, are useful vehicles for the structural and functional studies of neural circuit, and for the treatment of many gene-deficient brain diseases that needs to compensate for the correct genes to every cell in the whole brain. However, AAVs with these two advantages have not been reported. Here, we describe a new capsid engineering method, which draws on advantage combination of different capsids, and aims to yield a capsid that can provide more alternative routes of administration, which are more suitable for wide-scale transduction of the CNS. A new AAV variant, AAV9-Retro, was developed by inserting the 10-mer peptide fragment from AAV2-Retro into the capsid of AAV9, and the biodistribution properties were evaluated in mice. By intracranial and intravenous injection in the mice, we found that AAV9-Retro can retrogradely infect projection neurons with efficiency comparable to AAV2-Retro, and retains the characteristic of AAV9 that can transport across the nervous system. Our strategy provides a new tool for the manipulation of neural circuits, and for the future preclinical and clinical treatment of some neurological and neurodegenerative disorders.

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The use of an optimized chimeric envelope glycoprotein enhances the efficiency of retrograde gene transfer of a pseudotyped lentiviral vector in the primate brain

Cited by 23 publications

References 33 publications

Current Strategies for Brain Drug Delivery

Current Strategies for Brain Drug Delivery

Pseudotyped Lentiviral Vectors for Retrograde Gene Delivery into Target Brain Regions

AAV9-Retro Mediates Efficient Transduction with Axon Terminal Absorption and Blood-brain Barrier Transportation

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