Increased brain bio-distribution and chemical stability and decreased immunogenicity of an engineered variant of GDNF

Experimental Neurology
Rosamund C SmithMichael J O'Neill

Abstract

Several lines of evidence indicate that Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor for dopaminergic neurons. Direct parenchymal administration of GDNF is robustly neuroprotective and neurorestorative in multiple neurotoxin-based animal models (rat and non-human primate (NHP)) of Parkinson's Disease (PD), suggesting its potential as a therapeutic agent. Although small, open-label clinical trials of intra-putamenal administration of bacteria-derived, full length, wild type GDNF (GDNFwt) were efficacious in improving standardized behavioral scores, a double-blinded, randomized controlled trial failed to do so. We hypothesize that the lack of clinical efficacy of GDNFwt in the larger randomized trial was due to poor bio-distribution in the putamen and/or poor chemical stability while in the delivery device for prolonged time periods at 37°C. The development of neutralizing antibodies in some patients may also have been a contributing factor. GDNFv is an engineered form of GDNFwt, expressed and purified from mammalian cells, designed to overcome these limitations, including removal of the N-terminal heparin-binding domain to improve its diffusivity in brain parenchyma by reducing its binding to extracellu...Continue Reading

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Citations

Jul 30, 2020·Cell and Tissue Research·Pia Runeberg-Roos, Richard D Penn
Mar 27, 2020·Frontiers in Cell and Developmental Biology·Samuele LaudaniFulvia Sinatra
Sep 8, 2017·Frontiers in Molecular Neuroscience·Daniel CortésIván Velasco
Oct 12, 2021·PloS One·Dzhirgala V ShamadykovaGalina V Pavlova

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