Striatal Delivery of Neurturin by CERE-120, an AAV2 Vector for the Treatment of Dopaminergic Neuron Degeneration in Parkinson's Disease

Abstract

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.

Practical Considerations of Convection Enhanced Delivery for Novel Therapies Treating Spinal Cord Injury Related Neuropathic Pain

“…CED-based in vitro, ex vivo and in vivo animal models have led to active genetherapy trials for treating Parkinson disease (PD)and are supported by histological studies on disease pathology [9].Use of MRI navigation in some clinical trials, helps accurately targeting and providing real time monitoring of viral vector delivery (rCED). Several researcher labs including ours adopted different small and large animal models exploring use of CED in brain [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. The results from these studies are promising with a suggestion of superiority over intrathecal (IT) injection.…”

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

“…AAV-2 vectors were produced by standard triple plasmid transfection technique in human embryonic kidney 293 cells and purified by multiple chromatography and filtration steps as described previously (53). After purification, vectors were resuspended in formulation buffer (PBS plus 2 mM MgCl2), and vector titer was determined by quantitative PCR and expressed as vector genomes/ml.…”

“…The AAV-2 vector genome backbone consisting of AAV-2 inverted terminal repeats flanking a neurotrophic factor transgene expression cassette with the ubiquitous CAG promoter and the human growth hormone gene polyadenylation signal (Stratagene) was described previously (53). The construction of the AAV-GFAP-NT4 vector genome was performed in 2 steps.…”

Protection Against Parkinson’s Disease Progression: Clinical Experience

“…108 This work is based in part on the positive results of gene therapy studies using recombinant adeno-associated virus carrying a gene for neurturin in monkeys previously exposed to MPTP. 109 Other gene therapy strategies have been proposed from preclinical evidence, based on the potentially neuroprotective activity of several biologically generated substances. Like neurturin, erythropoietin generated in situ has been proposed as another means for protection against degenerative changes in PD.…”