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Alphavirus Vectors for Therapy of Neurological Disorders Kenneth Lundstrom* Pantherapeutics, Rue Des Remparts 4, CH1095 Lutry, Switzerland

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Alphavirus Vectors for Therapy of Neurological Disorders Kenneth Lundstrom* Pantherapeutics, Rue Des Remparts 4, CH1095 Lutry, Switzerland ell Res C ea m rc te h S & f o T h l Journal of Lundstrom, J Stem Cell Res Ther 2012, S4 e a r n a r p u DOI: 10.4172/2157-7633.S4-002 y o J ISSN: 2157-7633 Stem Cell Research & Therapy Review Article Open Access Alphavirus Vectors for Therapy of Neurological Disorders Kenneth Lundstrom* PanTherapeutics, Rue des Remparts 4, CH1095 Lutry, Switzerland Abstract Alphavirus vectors engineered for gene delivery and expression of heterologous proteins have been considered as valuable tools for research on neurological disorders. They possess a highly efficient susceptibility for neuronal cells and can provide extreme levels of heterologous gene expression. However, they generally generate short-term transient expression, which might limit their therapeutic use in many neurological disorders often requiring long-term even life-long presence of therapeutic agents. Recent development in gene silencing applying both RNA interference and microRNA approaches will certainly expand the application range. Moreover, alphaviruses provide interesting models for neurological diseases such as demyelinating and spinal motor diseases. Keywords: Alphaviruses; Gene delivery; Neuronal expression; Gene injections into the caudate nucleus showed strong neuronal expression silencing. throughout the 6 month study. No expression was observed in astrocytes and oligodendroglial cells. SV40-based delivery caused no Introduction evidence of inflammation or tissue damage. Both viral and non-viral vectors have provided interesting novel Despite these encouraging results obtained with both non-viral approaches in research on neurological disorders with a great potential and viral vectors described above alternative gene delivery methods for future therapeutic applications too [1,2]. The advantages of using are in demand. This review will focus uniquely on alphaviruses, which non-viral vectors are the simple, rapid and relatively inexpensive vector possess various features related to CNS delivery and make them production although they have suffered from inefficient gene delivery attractive candidates as gene delivery vehicles. Interestingly, these and therefore limited efficacy. Viral vectors have provided excellent viruses have a dual function as they are responsible for involvement in delivery and high expression of heterologous genes. On the other hand, production of large quantities of viral vectors is often more complicated certain neurological disorders and simultaneously can be engineered to and expensive. Furthermore, the application of viral delivery has gene delivery vectors for therapeutic function. raised some considerations related to safety issues. Among the non- Basics of Alphaviruses viral vectors, plasmid DNA complexed with polyethyleneimine (PEI) has been applied for targeting of neuronal stem cells [3]. Moreover, Alphaviruses belong to the family of Togaviridae and possess a intravenous administration of pegylated immunoliposomes (PIL) single-stranded RNA of positive polarity surrounded by a capsid and an carrying plasmid DNA expressing shRNA against the human epidermal envelope structure [10]. Several of the members of the alphaviruses are growth factor receptor demonstrated 90% gene silencing in mice [4]. considered as pathogens and have caused epidemics. Recently, a global There are a number of viral vectors, which have been evaluated for CNS fever outbreak occurred for Chikungunya [11]. Similarly, Semliki delivery and even such therapeutic indications as Alzheimer’s disease, Forest virus (SFV) and Venezuelan equine encephalitis (VEE) virus Parkinson’s disease and amyotrophic lateral sclerosis in rodent and have been associated with febrile illness in Africa [12] and epidemics in primate models [2]. In this context, adeno-associated virus (AAV), horses and humans in South America [13], respectively. Despite that, herpes simplex virus (HSV), lentivirus and SV-40 virus vectors have SFV [14], Sindbis virus [15] and VEE [16] have been engineered to been applied. For instance, AAV vectors expressing NGF prevented efficient gene expression vectors, albeit based on attenuated strains. In age-related memory deficit and increased the cholinergic neuron size this context, three major approaches have been taken (Figure 1). (A) by 34% after intraseptal injections [5]. Furthermore, AAV-based NGF Replication-competent expression can be obtained by the addition of a therapy in a phase I clinical trial in 8 patients with mild Alzheimer’s second subgenomic promoter and the gene of interest to the full-length disease demonstrated no long-term adverse effects, suggested reduced genome. These vectors can provide high levels of heterologous gene rate of cognitive decline and increase in cortical 18-fluorodeoxyglucose expression and simultaneously generate new viral particles. They can based on PET scans [6]. Similarly, helper-free HSV-1 vectors expressing sustain longer duration of expression and in vivo re-infect additional GDNF and BDNF were evaluated in a rat model for Parkinson’s disease [7]. In rats sacrificed 7 months after intrastriatal HSV-1 administration, significantly superior benefits measured as correction of behavioral *Corresponding author: Kenneth Lundstrom, PanTherapeutics, Rue des deficits and protection of nigrostriatal dopaminergic neurons were Remparts 4, CH1095 Lutry, Switzerland, Tel: +41 79 776 6351; E-mail: observed for GDNF in comparison to BDNF. Lentivirus-based [email protected] GDNF delivery to the striatum and substantia nigra was evaluated in Received November 18, 2011; Accepted December 22, 2011; Published January a primate model for Parkinson’s disease, in which prevention of loss 02, 2012 of dopaminergic neurons and improved motor performance were Citation: Lundstrom K (2012) Alphavirus Vectors for Therapy of Neurological observed. In aged animals dopaminergic neurons were protected from Disorders. J Stem Cell Res Ther S4:002. doi:10.4172/2157-7633.S4-002 cell death [8]. Copyright: © 2012 Lundstrom K. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted Moreover, in vivo delivery of SV40 vectors expressing HIV- use, distribution, and reproduction in any medium, provided the original author and 1 RevM10 was studied in rhesus monkey CNS [9]. Stereotactic source are credited. J Stem Cell Res Ther Cell Therapy for neurological disorders ISSN:2157-7633 JSCRT, an open access journal Citation: Lundstrom K (2012) Alphavirus Vectors for Therapy of Neurological Disorders. J Stem Cell Res Ther S4:002. doi:10.4172/2157-7633.S4- 002 Page 2 of 5 (A) Replication-competent (B) Replication-deficient (C) DNA-layered replicase structural foreign replicase foreign replicase foreign PS PS PS in vitro transcription in vitro transcription structural PtSransfection electroporation electroporation mammalian cells mammalian cells protein expression virus production virus production infection infection mammalian cells protein expression protein expression virus production Figure 1: Various types of SFV vectors used for heterologous gene expression. (A) Replication-competent vector: Full-length genome of SFV with an additional SFV 26S subgenomic promoter ( ) upstream of the foreign gene of interest. This vector system generates replication-proficient particles, which after infection produces new progeny and recombinant protein. (B) Replication-deficient vector: In this system, expression and helper vectors are co-electroporated in parallel to generate replication-deficient particles due to the packaging of only RNA carrying the packaging signal (PS). Infection results in recombinant protein expression, but no virus progeny. (C) DNA layered vector: The presence of a CMV promoter (►) allows direct use of plasmid DNA for cell transfection to generate recombinant protein. cells. However, the downside of this approach is the potential unwanted in large numbers [21]. Moreover, they have demonstrated neuron- spread of viral infection. (B) Replication-deficient expression requires specific gene expression in primary neurons [22], in hippocampal the use of a dual vector system consisting of an expression vector slice cultures [23] and in vivo in rodent brain [24]. The local high-level including the non-structural replicase genes, a strong subgenomic expression of β-galactosidase in the striatum and amygdale of rat brain promoter and the gene of interest. The other vector provides the viral without any detectable adversity compared to control animals [24] structural genes and is therefore named helper vector. In attempts to suggested potential use of alphavirus-based delivery for research and generate the highest possible safety of the system, a second generation even therapy. Additionally, replication-proficient SFV vectors based on helper vector was engineered, which rendered the produced viral the avirulent strain A7(74) have been used for gene delivery in primary particles conditionally infectious [17]. Moreover, the design of split neurons and in hippocampal slices [25]. Interestingly, the expression helper vectors provided additional safety and guaranteed no production was highly glial cell specific at 37°C, but at 31°C the GFP expression of unwanted wild type recombined virus [18]. Due to the presence of was similar to the wild type phenotype demonstrating neuron-specific an RNA packaging signal uniquely located on the expression vector, (up to 94%) expression. Further development has included using recombinant particles contains only the replicase genes and the
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