Failure of Glial Cell-Line Derived Neurotrophic Factor (GDNF) in Clinical Trials Orchestrated By Reduced NR4A2 (NURR1) Transcription Factor in Parkinson’s Disease. A Systematic Review

Abstract

Parkinson’s disease (PD) is one of the most common neurodegenerative maladies with unforeseen complex pathologies. While this neurodegenerative disorder’s neuropathology is reasonably well known, its etiology remains a mystery, making it challenging to aim therapy. Glial cell-line derived neurotrophic factor (GDNF) remains an auspicious therapeutic molecule for treating PD. Neurotrophic factor derived from glial cell lines is effective in rodents and nonhuman primates, but clinical findings have been equivocal. Laborious exertions have been made over the past few decades to improve and assess GDNF in treating PD (clinical studies). Definitive clinical trials have, however, failed to demonstrate a survival advantage. Consequently, there seemed to be a doubt as to whether GDNF has merit in the potential treatment of PD. The purpose of this cutting edge review is to speculate as to why the clinical trials have failed to meet the primary endpoint. We introduce a hypothesis, “Failure of GDNF in clinical trials succumbed by nuclear receptor-related factor 1 (Nurr1) shortfall.” We demonstrate how Nurr1 binds to GDNF to induce dopaminergic neuron synthesis. Due to its undisputable neuro-protection aptitude, we display Nurr1 (also called Nr4a2) as a promising therapeutic target for PD.

Bimodal regulation of axonal transport by the GDNF-RET signalling axis in healthy and diseased motor neurons

“…Although edaravone, one of only two FDA-approved therapeutics for ALS, has been shown to increase RET, GDNF and GFR α 1 protein levels 29 , enhancing GDNF signalling in ALS has so far either induced adverse effects 32 or failed to translate to significant clinical improvements 31 . These negative outcomes align to independent clinical trials in Parkinson’s disease 44 . Together with our results, these findings support the conclusion that dampening rather than enhancing RET signalling may have therapeutic promise in ALS.…”

Lmx1a-Dependent Activation of miR-204/211 Controls the Timing of Nurr1-Mediated Dopaminergic Differentiation

“…Interestingly, most of the miR-204/211 targets we identified are directly linked to Nurr1. These include Gdnf [65], Elavl2 [66], Itpr1, Elavl4, Khdrbs1 [67], Rasgef1b [67], and Tcf12 [68]. Some of them are also involved in the differentiation of retinal progenitor cells and in the development of the eye (Nurr1, Elavl2, Plxna2, Rasgef1b, Wnt4, Sox11), tissues in which miR-204/211 shows a relevant role [42,44,66,[69][70][71][72][73] In a precise time window during embryonic development, miR-204/211 holds Nurr1 and its downstream targets repressed, preventing an early DA maturation.…”

Progress, Opportunities, and Challenges of Magneto-Plasmonic Nanoparticles under Remote Magnetic and Light Stimulation for Brain-Tissue and Cellular Regeneration

“…This role renders it a potential treatment in NDs-particularly in the treatment of PD. Unfortunately, GDNF has demonstrated little success in clinical trials, despite its perceived potential in the neuroprotection and regeneration of neural cells [65]. There exist possible explanations, which include a reduction in Nuclear-receptor-related 1 Considering the unique property of magneto-plasmonic NPs, the external stimulation also plays a significant role in determining their BBB-passage efficiency, as illustrated in Figure 4 and summarized in Table 1.…”

“…This role renders it a potential treatment in NDs-particularly in the treatment of PD. Unfortunately, GDNF has demonstrated little success in clinical trials, despite its perceived potential in the neuroprotection and regeneration of neural cells [65]. There exist possible explanations, which include a reduction in Nuclear-receptor-related 1 (Nurr1) expression [65], the use of GDNFs in late-stage Parkinson's, where it would not be as effective [66], inaccurate representations of PD in preclinical animal models [67], and poorly designed catheter systems in the intracranial delivery of GDNF [68].…”

“…Unfortunately, GDNF has demonstrated little success in clinical trials, despite its perceived potential in the neuroprotection and regeneration of neural cells [65]. There exist possible explanations, which include a reduction in Nuclear-receptor-related 1 (Nurr1) expression [65], the use of GDNFs in late-stage Parkinson's, where it would not be as effective [66], inaccurate representations of PD in preclinical animal models [67], and poorly designed catheter systems in the intracranial delivery of GDNF [68]. One of the more pertinent issues, however, is the inability of GDNF to cross the BBB without outside stimulation or the use of invasive neurosurgical procedures-the latter being where GDNF delivery has seen more success.…”