Raoul, C., Barker, S. D. & Aebischer, P. Viral-based modeling and correction of neurodegenerative diseases by RNA interference. Gene Ther. 13, 487-495

Institute of Neurosciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Gene Therapy (Impact Factor: 3.1). 04/2006; 13(6):487-95. DOI: 10.1038/
Source: PubMed


Experimental recapitulation of recessive human genetic neurodegenerative disease in rodents can be classically addressed through genetic disruption of the related gene. Although very informative, this specific gene targeting is restricted to mice and precludes a species scale-up towards non-human primates. Concomitantly, this requirement to silence a specific gene in a broad range of animal models is important in the design of therapeutic approaches to dominantly inherited neurodegenerative diseases. The emergence of RNA interference (RNAi), a highly specific mechanism of post-translational gene silencing, has opened a plethora of biological application ranging from reverse genetic analysis to therapeutic schemes. Recombinant viral vectors, by promoting a long-lasting delivery of genetic instructions in a broad range of cellular types of different species origins, represent potential platforms mandating silencing of specific gene products through RNAi. This review aims at providing an overview of the different viral systems engineered so far for efficient in vitro and in vivo delivery of RNAi instructions. Additionally, the potential of RNAi for functional analysis and therapy for polyglutamine disorders or amyotrophic lateral sclerosis is discussed.

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    • "The main diseases treated using RNAi gene therapy include hepatitis B, human immunodeficiency virus (HIV) infection [14], cancer [15] [16], neurodegenerative disorders [17], ocular diseases [18], respiratory diseases [19], and arthritis [20]. We have previously described the feasibility of silence HLA class I and class II expression using RNAi technology [21] [22] [23]. "
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    ABSTRACT: Cell, tissue, and organ transplants are commonly performed for the treatment of different diseases. However, major histocompatibility complex (MHC) diversity often prevents complete donor-recipient matching, resulting in graft rejection. This study evaluates in a preclinical model the capacity of MHC class I-silenced cells to engraft and grow upon allogeneic transplantation. Short hairpin RNA targeting β2-microglobulin (RN_shβ2m) was delivered into fibroblasts derived from LEW/Ztm () (RT1-) rats using a lentiviral-based vector. MHC class I (RT1-A-) expressing and -silenced cells were injected subcutaneously in LEW rats () and MHC-congenic LEW.1W rats (), respectively. Cell engraftment and the status of the immune response were monitored for eight weeks after transplantation. In contrast to RT1-A-expressing cells, RT1-A-silenced fibroblasts became engrafted and were still detectable eight weeks after allogeneic transplantation. Plasma levels of proinflammatory cytokines IL-1α, IL-1β, IL-6, TNF-α, and IFN-γ were significantly higher in animals transplanted with RT1-A-expressing cells than in those receiving RT1-A-silenced cells. Furthermore, alloantigen-specific T-cell proliferation rates derived from rats receiving RT1-A-expressing cells were higher than those in rats transplanted with RT1-A-silenced cells. These data suggest that silencing MHC class I expression might overcome the histocompatibility barrier, potentially opening up new avenues in the field of cell transplantation and regenerative medicine.
    10/2013; 2013(8). DOI:10.1155/2013/796046
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    • "In the past, viral vectors have frequently and successfully been employed for the delivery of protein-encoding DNA sequences into living organisms. Consequently , they have also been adopted for the delivery of shRNAs and amiRNAs (Liu and Berkhout, 2011; Mowa et al., 2010; Raoul et al., 2006). Depending on the type of target cell, organ, or delivery route, they may still outperform nonviral delivery systems in certain instances. "
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    ABSTRACT: Human adenoviruses are rarely associated with life-threatening infections in healthy individuals. However, immunocompromised patients, and particularly allogeneic hematopoietic stem cell transplant recipients, are at high risk of developing disseminated and potentially fatal disease. The efficacy of commonly used drugs to treat adenovirus infections (i.e., cidofovir in most cases) is limited, and alternative treatment options are needed. Artificial microRNAs (amiRNAs) are a class of synthetic RNAs resembling cellular miRNAs, and, similar to their natural relatives, can mediate the knockdown of endogenous gene expression. This process, termed RNA interference, can be harnessed to target and potentially silence both cellular and viral genes. In this study, we designed amiRNAs directed against adenoviral E1A, DNA polymerase, and preterminal protein (pTP) mRNAs in order to inhibit adenoviral replication in vitro. For the expression of amiRNA-encoding sequences, we utilized replication-deficient adenoviral vectors. In cells transduced with the recombinant vectors and infected with the wild-type (wt) adenovirus, one particular amiRNA that was directed against the pTP mRNA was capable of decreasing the output of infectious wt virus progeny by 2.6 orders of magnitude. This inhibition rate could be achieved by concatemerizing amiRNA-encoding sequences to allow for high intracellular amiRNA concentrations. Because superinfecting wt virus induces the replication and amplification of the recombinant adenoviral vector, amiRNA concentrations were increased in cells infected with wt adenovirus. Furthermore, a combination of amiRNA expression and treatment of infected cells with cidofovir resulted in additive effects that manifested as a total reduction of infectious virus progeny by greater than 3 orders of magnitude.
    Antiviral research 11/2012; 97(1). DOI:10.1016/j.antiviral.2012.10.008 · 3.94 Impact Factor
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    • "RNAi, initiated by double-stranded RNA (dsRNA) that is homologous in sequence to the target gene, is a process of post-transcriptional silencing of the expression of a specific gene in cells, animals and plants [1]. There has been rapid progress in RNAi as a therapeutic tool against a host of disorders, from neurological diseases [2] to cancer [3], as well as various viral diseases [4e6]. For efficient gene silencing the small interfering RNAs (siRNAs) must be delivered into specific tissues or cells and be present in the cytoplasm stably at a sufficient concentration. "
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    ABSTRACT: In recent years, researchers have expressed an ongoing interest in developing RNA interference (RNAi) technology for therapeutic gene suppression in various diseases. Preclinical studies in animal models and cultured cell studies indicated that RNAi technology was an effective experimental tool against a variety of ocular diseases, and some small interference RNA (siRNA) drugs have been entered into clinical trials in Stage I and Stage II. However, in these studies siRNAs were delivered into ocular tissues via either systemic or subconjunctival/intravitreous injection, which is invasive and harmful if repeated. Based on this evidence, we hypothesize that topical application of siRNA eye drops may be a safe and effective therapeutic option in ocular surface diseases with temporary changes of gene expression. Furthermore, siRNA eye drops targeting different genes may simultaneously treat several ocular surface diseases.
    Bioscience Hypotheses 01/2009; 2(4):223-225. DOI:10.1016/j.bihy.2009.04.003
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