Antioxidant or neurotrophic factor treatment preserves function in a mouse model of neovascularization-associated oxidative stress.

In several disease states, abnormal growth of blood vessels is associated with local neuronal degeneration. This is particularly true in ocular diseases such as retinal angiomatous proliferation (RAP) and macular telangiectasia (MacTel), in which, despite the absence of large-scale leakage or hemorrhage, abnormal neovascularization (NV) is associated with local neuronal dysfunction. We describe here a retinal phenotype in mice with dysfunctional receptors for VLDL (Vldlr-/- mice) that closely resembles human retinal diseases in which abnormal intra- and subretinal NV is associated with photoreceptor cell death. Such cell death was evidenced by decreased cone and, to a lesser extent, rod opsin expression and abnormal electroretinograms. Cell death in the region of intraretinal vascular abnormalities was associated with an increased presence of markers associated with oxidative stress. Oral antioxidant supplementation protected against photoreceptor degeneration and preserved retinal function, despite the continued presence of abnormal intra- and subretinal vessels. What we believe to be novel, Müller cell-based, virally mediated delivery of neurotrophic compounds specifically to sites of NV was also neuroprotective. These observations demonstrate that neuronal loss secondary to NV can be prevented by the use of simple antioxidant dietary measures or cell-based delivery of neurotrophic factors, even when the underlying vascular phenotype is not altered.

Striatal delivery of neurturin by CERE-120, an AAV2 vector for the treatment of dopaminergic neuron degeneration in Parkinson's disease.

Glial cell line-derived neurotrophic factor (GDNF) or its naturally occurring analog, neurturin (NTN), can potentially improve the function and delay the rate of degeneration of dopaminergic neurons in Parkinson's disease (PD). However, their delivery to the central nervous system has proven to be a significant challenge. Viral vector-mediated gene transfer offers a practical means to continuously supply neurotrophic factors in targeted areas of the brain. CERE-120 is an adeno-associated viral vector encoding NTN, developed for the treatment of PD. We found that the kinetics and pattern of NTN expression in the rat striatum following injection of CERE-120 is rapid, increases significantly up to 4 weeks, and exhibits a stable volume of distribution thereafter for at least 1 year, the longest time-point evaluated. Quantitative enzyme-linked immunosorbent assay confirmed that steady-state levels are maintained from 4 weeks onward. We demonstrated that NTN volume of distribution can be controlled by varying the dose of vector injected and that NTN delivered via CERE-120 was bioactive, as evidenced by the neuroprotection of DA neurons in the rat 6-hydroxydopamine lesion model. These data provided the foundation for further non-clinical development of CERE-120, leading to an ongoing clinical trial in PD patients.