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      Suppression of experimental uveitis by a recombinant adeno-associated virus vector encoding interleukin-1 receptor antagonist

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          Abstract

          Purpose

          To evaluate the potential of gene therapy with a recombinant adeno-associated virus vector encoding the interleukin-1 receptor antagonist gene (rAAV-IL-1Ra) in the treatment of experimental uveitis.

          Methods

          The vitreal cavity of New Zealand white rabbits was injected with rAAV-IL-1Ra (4×10 7 infectious units), and the contralateral eye was injected with the same amount of rAAV-LacZ or PBS as a control. Transgene expression was evaluated by immunohistochemistry, ELISA, and RT-PCR. To evaluate the therapeutic potential of rAAV-IL-1Ra, experimental uveitis was induced by intravitreal injection of IL-1α at 10 and 100 days after rAAV–IL-1Ra administration. The effects of rAAV-IL-1Ra on experimental uveitis were investigated using histological and aqueous analysis.

          Results

          Following intravitreal injection of rAAV-IL-1Ra, transgene expression was found in various cell types of the ocular tissues, such as ciliary epithelial cells, retinal ganglion cells, and retinal pigment epithelial cells. RT-PCR and ELISA showed that the IL-1Ra transgene persisted in the rabbit eye for at least 100 days. Compared with the control eyes, the transgene expression ameliorated experimental uveitis at 10 and 100 days after a single administration of rAAV-IL-1Ra.

          Conclusions

          Intravitreal administration of rAAV-IL-1Ra led to sustained human IL-1Ra transgene expression in rabbit eyes for 100 days. The transgene expression suppressed uveitis episodes at 10 and 100 days after rAAV-IL-1Ra injection. Long-term suppression of experimental uveitis could be achieved by gene therapy with rAAV-IL-1Ra.

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          Extrachromosomal recombinant adeno-associated virus vector genomes are primarily responsible for stable liver transduction in vivo.

          L Meuse, T Storm, S Yant … (2001)
          Recombinant adeno-associated virus (rAAV) vectors stably transduce hepatocytes in experimental animals. Although the vector genomes are found both as extrachromosomes and as chromosomally integrated forms in hepatocytes, the relative proportion of each has not yet been clearly established. Using an in vivo assay based on the induction of hepatocellular regeneration via a surgical two-thirds partial hepatectomy, we have determined the proportion of integrated and extrachromosomal rAAV genomes in mouse livers and their relative contribution to stable gene expression in vivo. Plasma human coagulation factor IX (hF.IX) levels in mice originating from a chromosomally integrated hF.IX-expressing transposon vector remained unchanged with hepatectomy. This was in sharp contrast to what was observed when a surgical partial hepatectomy was performed in mice 6 weeks to 12 months after portal vein injection of a series of hF.IX-expressing rAAV vectors. At doses of 2.4 x 10(11) to 3.0 x 10(11) vector genomes per mouse (n = 12), hF.IX levels and the average number of stably transduced vector genomes per cell decreased by 92 and 86%, respectively, after hepatectomy. In a separate study, one of three mice injected with a higher dose of rAAV had a higher proportion (67%) of integrated genomes, the significance of which is not known. Nevertheless, in general, these results indicate that, in most cases, no more than approximately 10% of stably transduced genomes integrated into host chromosomes in vivo. Additionally, the results demonstrate that extrachromosomal, not integrated, genomes are the major form of rAAV in the liver and are the primary source of rAAV-mediated gene expression. This small fraction of integrated genomes greatly decreases the potential risk of vector-related insertional mutagenesis associated with all integrating vectors but also raises uncertainties as to whether rAAV-mediated hepatic gene expression can persist lifelong after a single vector administration.
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            Adeno-associated virus vector genomes persist as episomal chromatin in primate muscle.

            Philippe Moullier, Pierre Chenuaud, Caroline Le Guérinel … (2008)
            Recombinant adeno-associated virus (rAAV) vectors are capable of mediating long-term gene expression following administration to skeletal muscle. In rodent muscle, the vector genomes persist in the nucleus in concatemeric episomal forms. Here, we demonstrate with nonhuman primates that rAAV vectors integrate inefficiently into the chromosomes of myocytes and reside predominantly as episomal monomeric and concatemeric circles. The episomal rAAV genomes assimilate into chromatin with a typical nucleosomal pattern. The persistence of the vector genomes and gene expression for years in quiescent tissues suggests that a bona fide chromatin structure is important for episomal maintenance and transgene expression. These findings were obtained from primate muscles transduced with rAAV1 and rAAV8 vectors for up to 22 months after intramuscular delivery of 5 x 10(12) viral genomes/kg. Because of this unique context, our data, which provide important insight into in situ vector biology, are highly relevant from a clinical standpoint.
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              Adeno-associated virus vector carrying human minidystrophin genes effectively ameliorates muscular dystrophy in mdx mouse model.

              X. Xiao, Yi-Shuan Li, Jonathan Wang (2000)
              Duchenne muscular dystrophy (DMD) is the most common and lethal genetic muscle disorder, caused by recessive mutations in the dystrophin gene. One of every 3,500 males suffers from DMD, yet no treatment is currently available. Genetic therapeutic approaches, using primarily myoblast transplantation and adenovirus-mediated gene transfer, have met with limited success. Adeno-associated virus (AAV) vectors, although proven superior for muscle gene transfer, are too small (5 kb) to package the 14-kb dystrophin cDNA. Here we have created a series of minidystrophin genes (<4.2 kb) under the control of a muscle-specific promoter that readily package into AAV vectors. When injected into the muscle of mdx mice (a DMD model), two of the minigenes resulted in efficient and stable expression in a majority of the myofibers, restoring the missing dystrophin and dystrophin-associated protein complexes onto the plasma membrane. More importantly, this AAV treatment ameliorated dystrophic pathology in mdx muscle and led to normal myofiber morphology, histology, and cell membrane integrity. Thus, we have defined minimal functional dystrophin units and demonstrated the effectiveness of using AAV to deliver the minigenes in vivo, offering a promising avenue for DMD gene therapy.
              Article 0 comments Cited 91 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Vis
                Journal ID (publisher-id): MV
                Title: Molecular Vision
                Publisher: Molecular Vision
                ISSN (Electronic): 1090-0535
                Publication date Collection: 2009
                Publication date (Electronic): 08 August 2009
                Volume: 15
                Pages: 1542-1552
                Affiliations
                [1 ]Department of Ophthalmology, Tri-Service General Hospital, Taipei, Taiwan
                [2 ]Department of Ophthalmology, Mackay Memorial Hospital, Taipei, Taiwan
                [3 ]Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA
                [4 ]Department of Microbiology and Immunology, National Taiwan University, Taipei, Taiwan
                [5 ]Department of Ophthalmology, Kaohsiung Armed Force General Hospital, Kaohsiung, Taiwan
                [6 ]Department of Pharmacy, Tajen University, Pintung, Taiwan
                [7 ]Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, Taipei, Taiwan
                [8 ]Department of Ophthalmology, Taichung Veterans General Hospital, Taichung, Taiwan
                [9 ]Department of Ophthalmology, National Defense Medical Center, Taipei, Taiwan
                Author notes
                Correspondence to: Yeou-Ping Tsao M.D. Ph.D., Department of Ophthalmology, Mackay Memorial Hospital, Taipei, Taiwan Mackay Memorial Hospital., Taipei, Taiwan.
Department of Ophthalmology, No. 92, Section 2, Chungshan North Road, Taipei, Taiwan; Phone: 886-2-25433535; FAX:886-2-25433642; email: yptsao@ 123456yahoo.com
                Article
                Publisher ID: 165 Publisher ID: 2008MOLVIS0185
                PMC ID: 2723168
                PubMed ID: 19693263
                SO-VID: 54623389-45ca-4067-94a7-ba975817c907
                Copyright statement: Copyright @ 2009
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 16 April 2008
                Date accepted : 05 August 2009
                Categories
                Subject: Research Article
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                corr-author Tsao

                ScienceOpen disciplines: Vision sciences
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                ScienceOpen disciplines: Vision sciences

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