Gene therapy and transplantation in the retinofugal pathway.
Prog Brain Res
; 175: 151-61, 2009.
Article
em En
| MEDLINE
| ID: mdl-19660654
ABSTRACT
The mature CNS has limited intrinsic capacity for repair after injury; therefore, strategies are needed to enhance the viability and regrowth of damaged neurons. Here we review gene therapy studies in the eye, aimed at improving the survival and regeneration of injured retinal ganglion cells (RGCs). To target RGCs most current methods use recombinant adeno-associated viral vectors (AAV), usually serotype-2 (AAV2), that are injected into the vitreal chamber of the eye. This vector provides long-term transduction of adult RGCs. Strong, constitutive promoters such as CMV and/or beta-actin are commonly used but cell-specific promoters have also been tested. Transgenes encoded by AAV have been selected to limit cell death, enhance growth factor expression, or promote growth cone responsiveness. We have assessed the effects of AAV vectors in adult rodent models (i) after optic nerve (ON) crush and (ii) after transplantation of peripheral nerve (PN) onto the cut ON, a procedure that induces injured RGCs to regenerate axons over longer distances. AAV-CNTF-GFP promotes RGC survival and axonal regrowth in mice after ON crush, and in rats after ON crush or PN transplantation. In rats, intravitreal injection of AAV-BDNF-GFP also increases RGC viability but does not promote regeneration. RGC viability and axonal regrowth is further enhanced when AAV-CNTF-GFP is injected into transgenic mice that over-express bcl-2. Reconstituted PN grafts containing Schwann cells that were transduced ex vivo with lentiviral (LV) vectors encoding a secretable form of CNTF support RGC axonal regrowth, however grafts containing Schwann cells transduced with LV-BDNF or LV-GDNF are less successful. We have also quantified the transduction efficiency and tropism of different AAV vectors injected intravitreally. AAV 2/2 and AAV 2/6 showed highest levels of transduction, AAV 2/8 the lowest, and each serotype displayed different transduction profiles for retinal cells. We are also studying the long-term impact of AAV2-mediated CNTF or BDNF expression on the dendritic morphology of RGCs in normal and PN grafted retinas. Analysis of regenerating RGCs intracellularly injected with lucifer yellow indicates gene-specific changes in dendritic structure that likely impact upon visual function.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Nervos Periféricos
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Células Ganglionares da Retina
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Terapia Genética
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Traumatismos do Nervo Óptico
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Regeneração Nervosa
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Prog Brain Res
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Austrália