Biology Reference
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Fig. 1
Representative picture of the rat retina. The retina is organized into three
layers of cells: (1) the outer nuclear layer (ONL) composed by the photoreceptor
nuclei; (2) the inner nuclear layer (INL) composed by nuclei of amacrine, Muller,
bipolar, and horizontal cells, and (3) the ganglion cell layer (GCL) containing gan-
glion and displaced amacrine cells. The retinal pigment epithelium (RPE) lies above
the retina. The depicted retinal section is taken from a Lewis rat at postnatal day 65
and is stained with hematoxylin and eosin. The picture magnification is 20×
tools for retinal gene transfer given their capability to selectively
tranduce different retinal cell types and to ensure long-term gene
expression after a single vector administration (
8, 23
). In addition,
the safety and efficacy of AAV-mediated gene delivery has been
proven in preclinical models (
8, 24
) and clinical trials (
25-33
) aimed
at treating IRDs. Notably, the systemic AAV-mediated delivery of
EPO has resulted to be effective at protecting PRs in animal models
of induced and inherited retinal degeneration (
34
). However, the
systemic delivery of EPO (either as protein or gene) is associated
with undesirable side effects such as significant hematocrit increase
(
34, 35
), increased thrombotic risk (
36
), and platelet hyper-
reactivity (
37, 38
) that could lead to serious life-threatening conse-
quences (
39, 40
). EPO side effects may be particularly relevant
considering that the EPO doses required to achieve tissue-protec-
tion are higher than those required for erythropoiesis (i.e., for the
treatment of anemia) (
41
). Therefore, the treatment of chronic
and/or progressive conditions such as IRDs would require contin-
uous EPO delivery resulting in deleterious effects. To overcome
EPO side effects due to its function in the hematopoietic system
several EPO derivatives (EPO-Ds) have been generated that should
retain tissue protective functions while avoiding the EPO-mediated
erythropoiesis (
42-45
) as well as other hormone side effects (
38
).
Notably, we and others have showed that AAV-mediated delivery of
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