AAV Mediated GDNF Secretion From Retinal Glia Slows Down Retinal Degeneration in a Rat Model of Retinitis Pigmentosa

Department of Molecular and Cell Biology and the Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720-3190, USA.
Molecular Therapy (Impact Factor: 6.23). 04/2011; 19(9):1602-8. DOI: 10.1038/mt.2011.62
Source: PubMed


Mutations in over 80 identified genes can induce apoptosis in photoreceptors, resulting in blindness with a prevalence of 1 in 3,000 individuals. This broad genetic heterogeneity of disease impacting a wide range of photoreceptor functions renders the design of gene-specific therapies for photoreceptor degeneration impractical and necessitates the development of mutation-independent treatments to slow photoreceptor cell death. One promising strategy for photoreceptor neuroprotection is neurotrophin secretion from Müller cells, the primary retinal glia. Müller glia are excellent targets for secreting neurotrophins as they span the entire tissue, ensheath all neuronal populations, are numerous, and persist through retinal degeneration. We previously engineered an adeno-associated virus (AAV) variant (ShH10) capable of efficient and selective glial cell transduction through intravitreal injection. ShH10-mediated glial-derived neurotrophic factor (GDNF) secretion from glia, generates high GDNF levels in treated retinas, leading to sustained functional rescue for over 5 months. This GDNF secretion from glia following intravitreal vector administration is a safe and effective means to slow the progression of retinal degeneration in a rat model of retinitis pigmentosa (RP) and shows significant promise as a gene therapy to treat human retinal degenerations. These findings also demonstrate for the first time that glia-mediated secretion of neurotrophins is a promising treatment that may be applicable to other neurodegenerative conditions.

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Available from: David Vernon Schaffer, Jul 27, 2015
    • "Another AAV mutant identified by directed evolution is named ShH10, an AAV6 variant with improved glial tropism after intravitreal administration [73] . Further investigations showed that ShH10 mediated expression of the glial-derived neurotrophic factor (GDNF) in Müller glia can rescue the retinal function of a retinitis pigmentosa rat model for at least 5 months [74]. These strategies allow overcoming problems related to the ability of AAVs to localize and bind to the target cells. "
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    ABSTRACT: Adeno-associated virus (AAV) vectors are the most widely used vehicle systems for neuronal gene transfer. This popularity is based on the non-pathogenic nature of AAVs and their versatility making them a multifunctional vector system for basic research and clinical applications. AAVs are successfully applied in clinical and pre-clinical gene therapy studies for inherited retinal disorders. Their excellent transduction profile and efficiency also boosted the use of AAV vectors in basic research. The AAV vector system can be easily modified and adjusted at multiple levels to allow for optimized and specific gene expression in target cells. Here, we will provide an overview on the AAV vector system and its applications focusing on gene transfer into retinal cells. Furthermore, we will outline and discuss strategies for the optimization of AAV gene transfer by modifications to the AAV vector expression cassette, the AAV capsid or the routes of vector administration. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Jan 2015 · European Journal of Pharmaceutics and Biopharmaceutics
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    • "Although more than 160 IPD-associated genes have been identified in humans, with many of these mutations modeled in mouse, relatively few studies have examined the biochemical mechanisms that promote or resist death in the mutant PR [1], [2]. Factors shown to promote the survival of mutant or injured PRs include IL-6 cytokines [3], [4], [5], [6], [7], STAT3 [8], and neurotrophic factors including FGF2 [9], [10], [11], [12], [13]. In contrast, other molecules including GFAP and vimentin [14], [15], complement factor D [16], TNFα [17] and poly-ADP-ribose polymerase-1 [18] have been shown to contribute to the death of mutant or injured PRs. "
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    ABSTRACT: Expression of the mRNA is greatly increased in the photoreceptors (PRs) of mouse models of inherited PR degeneration (IPD). To examine the role of in mutant PR survival, we generated mice carrying homozygous alleles or the transgene. In the background, PR survival increased 110% in mice at post-natal (PN) day 15, and 60% in mice at PN40. In contrast, PR survival was not increased in retinal explants of ; mice. This finding, together with systemic abnormalities in mice, suggested that the increased survival of mutant PRs in the background resulted at least partly from the systemic EDN2 loss of function. To examine directly the role of EDN2 in mutant PRs, we used a scAAV5- cDNA vector to restore expression in ; PRs and observed an 18% increase in PR survival at PN14. Importantly, PR survival was also increased after injection of scAAV5- into retinas, by 31% at PN15. Together, these findings suggest that increased expression is protective to mutant PRs. To begin to elucidate -mediated mechanisms that contribute to PR survival, we used microarray analysis and identified a cohort of 20 genes with >4-fold increased expression in retinas, including . Notably, increased expression of the FGF2 protein in PRs was ablated in ; retinas. Our findings indicate that the increased expression of PR increases PR survival, and suggest that the -dependent increase in PR expression of FGF2 may contribute to the augmented survival.
    Full-text · Article · Feb 2013 · PLoS ONE
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    • "These results indicate that gene therapy may be a useful technique in the treatment of other neurological disorders as it allows for the localised, targeted, stable and efficient introduction of a gene or genes. Neuroprotective and regenerative therapies using trophic factors, such as NTs, have garnered much attention of late, particularly in the areas of Parkinson’s disease, retinitis pigmentosa and spinal cord injury, just to name a few [48], [49], [50]. Initial clinical studies involving Parkinson’s disease patients, for example, used a mechanical pump to infuse glial cell-derived neurotrophic factor (GNDF) into the lateral ventricles. "
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    ABSTRACT: The cochlear implant provides auditory cues to profoundly deaf patients by electrically stimulating the residual spiral ganglion neurons. These neurons, however, undergo progressive degeneration after hearing loss, marked initially by peripheral fibre retraction and ultimately culminating in cell death. This research aims to use gene therapy techniques to both hold and reverse this degeneration by providing a sustained and localised source of neurotrophins to the deafened cochlea. Adenoviral vectors containing green fluorescent protein, with or without neurotrophin-3 and brain derived neurotrophic factor, were injected into the lower basal turn of scala media of guinea pigs ototoxically deafened one week prior to intervention. This single injection resulted in localised and sustained gene expression, principally in the supporting cells within the organ of Corti. Guinea pigs treated with adenoviral neurotrophin-gene therapy had greater neuronal survival compared to contralateral non-treated cochleae when examined at 7 and 11 weeks post injection. Moreover; there was evidence of directed peripheral fibre regrowth towards cells expressing neurotrophin genes after both treatment periods. These data suggest that neurotrophin-gene therapy can provide sustained protection of spiral ganglion neurons and peripheral fibres after hearing loss.
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