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Stephanie Philippe, Corinne Kostic, Jacques Mallet, Chamsy Sarkis, Yvan Arsenijevic; Non-integrative Lentiviral Vector-mediated GDNF Expression In The Rd1 Mouse Retina Partially Rescues Photoreceptors. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4356.
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© ARVO (1962-2015); The Authors (2016-present)
Our aim is to develop a general strategy for the treatment of retinal degenerations, independently of their aetiology, based on the local delivery of a neurotrophic factor using non-integrative lentiviral vectors (NILVs). We previously showed that NILVs are very similar to their integrative counterparts (LVs) in the rodent retina (tropism, long-term expression), but with a lower level of transgene expression. In the present study, we focus on effects of GDNF expression mediated by LVs and NILVs in the Rd1 mouse retina.
LVs and NILVs expressing GDNF and pseudotyped with the Mokola envelope were injected into P4-P6 C3H rd1/rd1 mice. Functional and histological investigations were performed at P20.
We first measured photopic ERG response of LV-GDNF- or NILV-GDNF-treated mice as well as control mice and surprisingly found that NILV-GDNF allows a higher rescue of retinal function than LV-GDNF. These results were in line with histological observations: ONL thickness was measured on cryosections and found to be significantly increased in NILV-GDNF group compared to the LV-GDNF group. To better understand the differences in NILV- and LV-treated groups, different parameters are currently being investigated, such as glia activation as well as expression and localisation of GDNF and various markers of photoreceptor and bipolar cells. The correlation of these parameters with functional and histological rescue will be evaluated.
Our results show that NILVs are suitable tools for gene transfer into the retina and can be advantageously used to develop neuroprotective strategies aimed at rescuing photoreceptors from death. Such a strategy can be of particular interest to treat retinal degenerations of unknown origin as well as in combination with specific replacement strategies. We also report that the high level of GDNF delivered by LVs may be deleterious for the retina, showing that the level of transgene expression has to be tightly controlled to ensure safety of the therapy.
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