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Walker, B. Reprogramming axonal behavior by axon-specific viral transduction. Wang, C. Recombinant AAV serotype 1 transduction efficiency and tropism in the murine brain. Astrocytic expression of transgene in the rat brain mediated by baculovirus vectors containing an astrocyte-specific promoter. Wang, L.
Wanisch, K. Integration-deficient lentiviral vectors: a slow coming of age. An improvement in motor function was observed at 6-months relative to pre-treatment assessment Palfi, ; Jarraya et al. The understanding of astrocyte functions in normal and altered brain strongly relies on the availability of experimental systems to specifically target astrocytes in vivo. However, the first generation CNS viral vectors had a strong neurotropism in vivo Naldini et al.
Indeed, the injection of AAV2 into adult rodent brains was associated with neuronal transgene expression when using ubiquitous promoters Bartlett et al. Similarly, stereotaxic injection into rat or mouse brain of LVs pseudotyped with the vesicular stomatitis virus glycoprotein VSV-G with CMV cytomegalovirus or PGK phosphoglycerate kinase 1 promoters, leads to the specific transduction of neurons with very limited transgene expression in other cell types Naldini et al.
Finally, the Ad5 displays a partial neurotropism with the transduction of other cell types, especially astrocytes Smith et al. However, it is important to mention that a number of parameters could alter the tropism. These include, amongst other factors, the purity of the vector, the mode of production, the site of administration, species, the developmental stage, and normal or pathophysiological conditions.
Unfortunately, data gathered in primary cultures neurons and astrocytes are not predictive of the in vivo tropism and a systematic evaluation of each vector is still required. This phenomenon was also observed with AAV2, which efficiently targets astrocytes in vitro but not in vivo Gong et al.
The purification method has also a major impact on the tropism of AAV8. Foust et al. Finally, discrepancies have been observed on the transduction efficiency and tropism of various AAV serotypes between species rodent, cat, and primates; Davidson et al. Additional studies are therefore still warranted to fully characterize the tropism of these vectors in the CNS. AAV1, 2, 5, 7, and 8 mainly transduce neurons green while AAV4, 9, rh43 display a partial astrocytic tropism.
The miR is exclusively expressed in neurons. As a consequence the miRT is only recognized in neurons and the transgene expression is blocked mRNA degraded. The tropism of a virus is first determined by its binding with a specific receptor at the surface of the host cell Lutschg et al. For example, the tropism of Ad5 vectors is regulated by the binding to its primary cellular receptor; the coxsackie and adenoviral vectors receptor CAR.
Tissues refractory to Ad5 infection do not express CAR. The limited expression of CAR in dopaminergic neurons of the substantia nigra of mice explains the poor transduction of these cells and transgene expression in astrocytes and other non-neuronal cells Lewis et al.
However, the expression of CAR in the nervous system and in particular in glial cells has not been extensively examined and CAR-independent forms of Ad have been developed to shift the tropism Grellier et al. Indeed, for most of them, only limited data are available concerning their receptors and their pattern of expression in the brain.
The earliest and most used serotype is the AAV2, which has a natural tropism for neurons Bartlett et al. However, HSPG is necessary, but not wholly sufficient, for the transduction of permissive cells. The AAV1, 5, 7, 8, and 9 not only infect astrocytes in vivo but also neurons and other cells Davidson et al.
Recently, it has been shown that AAV9 uses galactose at the N-linked glycans as a receptor Bell et al. The identification of the amino acids of the AAV9 capsid necessary for binding to galactose opens the possibility to modify the tropism Bell et al. Lentiviral vectors are increasingly being used in neuroscience research and are unique in the sense that they are enveloped viruses that can be pseudotyped i.
It dramatically broadens LV tropism by facilitating transduction of various cell types in different species, it stabilizes the vector particles from shear forces during centrifugation thereby allowing vector concentration and it directs LV to an endocytic pathway, which reduces the requirements of viral accessory proteins for transduction Cockrell and Kafri, In conclusion, specific serotypes or envelopes only partially improve the astrocytic targeting of viral vectors.
However, engineering chimeric capsids or envelopes targeting astrocytes is difficult and time-consuming. In order to optimize viral vectors tropism, strategies aiming at restraining transgene expression with astrocytic promoters, or by blocking expression in unwanted cells, mainly in neurons, were developed. Different astrocytic promoters have been used to restrict transgene expression into glial cells. However, the packaging size of each viral vector limits the type of promoters which can be inserted.
The cloning of the gfa2 fragment into Ad5 and AAVrh43 vectors restricts transgene expression in rat astrocytes Do Thi et al. However, no quantification was performed to determine the number of transduced astrocytes.
In the study by Lawlor et al. The Gfa2-AAV8 vector infects mainly astrocytes in the striatum but a low transgene expression was still observed in neurons. It was shown recently that injection of high titer of AAV5-gfa2-eGFP into the striatum or the substantia nigra provides an astrocyte-specific expression with no residual expression into neurons or microglial cells.
In addition, the expression was stable until 12 weeks post-injection. Stereological analysis of transgene expression reveals that a mean of 15, astrocytes per mm 3 of striatal tissue were transduced Drinkut et al. However, no quantification was performed although some neurons expressed the transgene. To develop an expression system activated in pathological conditions, Jakobsson et al.
Using toxin-induced lesion models 6-hydroxy-dopamine and ibotenic acid lesions , they showed that the transgene expression is eightfold higher in reactive astrocytes: a finding which correlates with the activity of the endogenous GFAP gene Jakobsson et al. In addition, most studies rely on the use of the GFAP promoter. Large initiatives are underway to characterize the regulatory elements of the whole human genome Gerstein et al.
Analysis of GLAST and GLT1-GFP mice has revealed an unexpected non-overlapping pattern between the two transporters and confirmed the differential activation of the promoters during embryogenesis and in adulthood. GLAST activity was low in the forebrain and high in the cerebellum, whereas GLT1 expression was higher in the cortex than in the cerebellum, consistent with the prominent role of GLT-1 in glutamate uptake in the forebrain.
Combining data from the ENCODE project and the gene expression cartography in human and mouse brain will provide additional and essential information to identify minimal fragments necessary for cell-type-specific transgene expression in viral vectors Hawrylycz et al. This strategy has already been developed by the Pleiade Project, which integrated information from genomic databases to construct synthetic MiniPromoters for viral vectors containing only the indispensable regulatory elements to achieve gene expression Portales-Casamar et al.
To further improve viral vector tropism, post-transcriptional regulatory elements have been integrated into viral vectors to block transgene expression in non-targeted cells. These miRNA are differentially distributed in distinct brain regions and show cell-type specificity with even differential intraneuronal miRNA compartmentalization Bak et al.
Since miRNAs target most genes, they represent important regulators of expression and are implicated in a large range of biological activities. To restrict transgene expression in a specific cell population, a miRNA present in unwanted cells but not expressed in targeted cells is chosen.
This detargeting strategy was first demonstrated in the CNS with the neuron-specific miR Colin et al. In this context, miR is a promising candidate because it is highly expressed in neurons Lagos-Quintana et al. This detargeting approach was used to shift the tropism of LV toward astrocytes. This effect was not restricted to the striatum as similar results were obtained in the hippocampus and cerebellum. Thanks to the unique features of these new viral vectors, it has already been possible to make significant advances in two areas of research related to the development of innovative therapies and the modeling of neurological disorders.
Overview depicting the tropisms of viral vectors in the CNS. References used for this figure are detailed and cited in the text. There is evidence to support the idea that the mechanisms responsible for selective neurodegeneration in some brain disorders are non-cell autonomous and based upon pathological cell—cell interactions.
The selective death of the neuronal population at risk in each disorder can be better explained by the convergence of multiple pathogenic mechanisms which provoke damage within the vulnerable neuron and neighboring cell types rather than by autonomous cell mechanisms Ilieva et al. In order to dissect out the specific role of different cell populations in vivo neurons, astrocytes, microglia , two different strategies were recently used.
The opposite strategy consists of selectively expressing the mutant protein in specific cell types using either specific promoters such as GFAP or by crossing different Cre-expressing transgenic mice with transgenic mice expressing the mutant protein after a STOP cassette flanked by loxP sites. These two strategies were useful in providing evidence that astrocytes play a key role in the pathogenesis of ALS Ilieva et al.
However, an alternative strategy based upon the use of viral vectors to selectively and locally express the mutant protein has also proven to be very useful and complementary to the development of transgenic mice in particular to test whether a local expression is sufficient to induce pathological mechanisms.
Through the use of a newly developed LV Colin et al. It has been shown that these glial cells developed a progressive phenotype of reactive astrocytes that was characterized by a marked decreased expression of both glutamate transporters, GLAST and GLT-1, and of glutamate uptake. Consistent with the above findings, a histological re-evaluation of potential astrocyte reactivity within postmortem brains of HD patients showed the presence of astrogliosis in the caudate nucleus of Grade 0 patients and confirmed the colocalization of mHtt in astrocytes with a grade-dependent reduction in GLT Through the use of viral vectors that target astrocytes locally, we were able to show that the presence of mHtt in astrocytes is sufficient to alter the glial glutamate transport capacity early in the disease process and may contribute to pathogenesis of HD.
Glioblastoma multiform GBM is the most common primary tumor developing in the brain from astrocytes. Due to the quick proliferation and its infiltrative nature, complete ablation by surgery is almost impossible. The prognosis is very poor, with a median survival of Viral-mediated gene therapy aiming to reduce glial proliferation represents, therefore, an alternative therapy Murphy and Rabkin, Indeed, GBM is a good candidate for gene therapy because tumor cells rarely develop metastasis outside of the brain and most cells in the CNS are post-mitotic, reducing side effects of therapeutic strategies targeting dividing cells.
However, appropriate viral vectors for the treatment of GBM are different from those developed for the treatment of neurodegenerative diseases. For GBM therapy, the aim is to mediate destruction of proliferating cells. Glial targeting is achieved either by the injection of the vector into the tumor mass, by choosing a vector which target dividing cells or having a partial tropism for glial cells, as it is the case for Ad Asadi-Moghaddam and Chiocca, The first studies used a replication-deficient mouse moloney leukemia virus MLV that infected dividing cells and expressed a suicide gene thymidine kinase, TK; Ram et al.
Thymidine kinase is a phosphotransferase enzyme that incorporates dGTP analogs in the presence of ganciclovir instead of cellular dGTP and leads to the blockade of cellular replication Boivin et al. But the low transduction efficiency neither improved tumor progression nor the overall survival time Ram et al. To improve the efficacy of the treatment, vector-producing cells VPC releasing MLV particles expressing the TK suicide gene were injected into the brain after surgical resection of the tumor.
However, no significant decrease of tumor mass occurred despite the bystander effect Ram et al. Interestingly, it was shown that the preferential transduction of glioma cells is not dependent on the expression of known Ad receptors on tumor cells Candolfi et al. Expressing the therapeutic suicide gene under the control of a strong ubiquitous promoter in combination with an immune stimulator may increase therapeutic efficacy and prevent relapse Candolfi et al.
As an alternative strategy to improve the therapeutic efficacy, conditionally replicative or replicative viruses were developed. The principle of oncolytic therapy is to inject directly into the tumoral cells a lytic replicative-competent cytotoxic virus, such as HSV, VSV, Ad, or retroviruses, which will induce apoptosis in proliferative cells during replication Parker et al.
However, the high worldwide HSV seropositivity limits their use in the clinic and as a consequence has led to the development of other oncolytic viruses. A deletion of E1B region on Ad genome Ad-ONYX was introduced to favor apoptosis in infected glioma cells but the efficiency of this approach was too low to reach a phase II of clinical trial Moran, ; Chiocca et al.
In addition, replicative adenoviral vectors expressing therapeutic genes were used to mediate tumoral cells destruction. The candidate genes are inserted in the E3 deleted region and a CAR-independent entry mechanism enhancing the transduction efficiency of tumoral cells has been proposed for these new generation oncolytic viruses. To favor replication in GFAP-positive cells, three copies of glial specific B enhancer were added on the gfa2 promoter gfa2B3 , leading to a decreased growth of glioma cells Horst et al.
Degeneration of the nigro-striatal projection represents the major pathological hallmark of PD. Preclinical rodent and non-human primate models demonstrated a strong protective effect of glial cell line-derived neurotrophic factor GDNF on the nigro-striatal dopaminergic system Gash et al. However, intrathecal infusion of GDNF protein or viral vector-mediated expression of neurturin in the striatum of late stage PD patients showed no significant clinical benefit Lang et al. Current gene therapeutic trials in the brain predominantly use AAV2 due to its proven safety record.
However, the expression of neurotrophic factors in neurons may impose a serious safety issue since the factors can be secreted from the soma, unmyelinated projections, or synaptic sites of transduced neurons, thereby delivering a complex signaling-inducing molecule to potential off-target sites.
One alternative strategy would be to restrict their impact to the immediate vicinity of the site of the lesion. In terms of safety, unilateral striatal GDNF expression in astrocytes did not result in delivery of bio-active GDNF to the contralateral hemispheres potential off-target sites as was the case when GDNF was expressed in neurons.
This suggests that astrocytic neurotrophic factor expression achieved by a viral vector can be considered an efficient alternative to current gene therapeutic strategies. Astrocyte activation, characterized by hypertrophic somata and processes, is an early hallmark in most neurodegenerative conditions. The functional impact of this activation on the progression of these diseases is still elusive and their therapeutic potential is yet unexploited.
This result represents a proof-of-principle that astrocytes can be considered as significant therapeutic targets not only in AD but also for other neurodegenerative diseases. Because of its specificity, lack of toxicity and capacity for widespread and long-lasting transgene expression, AAV appears to be an ideal vehicle for directing therapeutics to astrocytes. The growing importance of astrocytes in crucial brain functions and also dysfunctions has led to the development of new genetic tools to label and manipulate these glial cells in vivo.
Thanks to these tools that include targeted transgenesis and viral transduction, considerable advances were made in the understanding of astroglial biology. This first generation of astrocytic viral vectors was instrumental to start depicting their role in specific brain regions of different species. However, a better determination of the numerous functions played by astrocytes during development, in adulthood and disease will require new viral vectors that can further resolve the intimate relationship between neurons and glia in the maturing brain Molofsky et al.
One important issue relates to the recent but well-accepted notion that astrocytes do not represent a homogenous population of cells. This is, of course, thoroughly demonstrated for neurons Miller and Gauthier, but is just starting to be studied for astrocytes in particular because of the lack of reliable markers to follow these different cell populations. The launching of recent initiatives such as the Human Brain Project and ENCODE will increase our knowledge on the functions of astrocytes and may help to refine strategies previously developed to drive transgene expression into specialized astrocytes at different stages of development either in normal or diseased states.
A comprehensive mapping of the cell-type-specific expression of miRNAs, the development and in vivo assessment of efficient miRT sequences will also permit one to ameliorate the detargeting strategy. Similarly, the identification of the receptors required for the binding of the viral particles to astrocyte subpopulations will represent a major step toward the production of more efficient astrocytic viral vectors.
In addition to these strategies which are already used to drive the tropism of viral vectors toward astrocytes, new viral vectors could be developed. Among these emerging viral vectors, baculoviral vectors take advantage of their natural tropism for astrocytes Boulaire et al. Their large genome size kb is suitable for the incorporation of large genes of interest and complex regulatory elements Wang and Wang, Clinical observations in patients suffering from neurological pathologies following viral infections suggest that other viruses could have a cerebrotropism e.
This illustrates the need for multidisciplinary programs that would share the expertise of neurobiologists, virologists, geneticists, and clinicians in order to overcome the limitations of current vectors and discover innovative gene transfer systems. Considering how much more might be discovered about the functions of normal or diseased astrocytes, it is tempting to suggest that we are just at the beginning of the development of astrocentric viral vectors.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors gratefully acknowledge Dr. Alan R. Young for careful editing of the manuscript. National Center for Biotechnology Information , U.
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The campus is located on acres 1. TCU is affiliated with, but not governed by, the Disciples of Christ. Its mascot is the "horned frog", and women's teams are known as the Lad y Frogs. The university enrolls around 9, students, with 8, being undergraduates. Stay informed and up-to-date on your network with RelSci news and business alerting service.
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