Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double‐blind, randomized, controlled trial

Abstract

AAV2-neurturin delivery to the putamen and substantia nigra bilaterally in PD was not superior to sham surgery. The procedure was well tolerated, and there were no clinically significant adverse events related to AAV2-neurturin.

A Small Molecule Activator of p300/CBP Histone Acetyltransferase Promotes Survival and Neurite Growth in a Cellular Model of Parkinson’s Disease

“…One of the most promising diseasemodifying therapies for PD involves the delivery of neurotrophic factors to the striatum and/or SNpc to protect DA neurons (Hegarty et al 2014b). While this is a promising approach, it has had limited success to date in clinical trials (Olanow et al 2015). In addition, such localised administration of neurotrophic factor ligands is unlikely to protect other neurons that are affected by the disease process.…”

Targeting bone morphogenetic protein signalling in midbrain dopaminergic neurons as a therapeutic approach in Parkinson's disease

“…However, the receptors and mechanisms of action of these two neurotrophic factors have not yet been well characterized. Given the lack of efficacy of AAV-NTN to date [21] and the fact GDNF ligands may not be able to signal in the PD brain due to down-regulation of Ret [22], it has recently been suggested that 'better results might be achieved with other trophic factors that are not Ret dependent' and that 'it might also be of value to assess trophic factors in animal models that overexpress α-synuclein prior to initiating translational clinical trials' [21]. Given that BMP ligands have the same efficacy as GDNF in 6-OHDA animal models of PD [18,19], and that their effects on mDA neurons are mediated in a Ret-independent manner through the Smad pathway [34], it will be crucial to determine if BMPR expression or key downstream effector proteins are affected by α-synuclein, and if the BMP ligands can exert neuroprotective effects in the α-synuclein model of PD.…”

“…These include glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN), which have been tested in clinical trials [19]. Despite initial promising results, these trials have not to date been successful [20,21]. Recent work has shown that the lack of efficacy of GDNF and NTN may result from alpha-synuclein-induced down-regulation of their common co-receptor, Ret, which is crucial for GDNF and NTN signalling [22] as GDNF did not confer neuroprotection in the α-synuclein rat model of PD [23].…”

“…Recent work has shown that the lack of efficacy of GDNF and NTN may result from alpha-synuclein-induced down-regulation of their common co-receptor, Ret, which is crucial for GDNF and NTN signalling [22] as GDNF did not confer neuroprotection in the α-synuclein rat model of PD [23]. As such the authors of the latest adeno-associated virus (AAV)-NTN trial stated that "better results might be achieved with other trophic factors that are not RET dependent" [21]. BMPs have been shown to exert neurotrophic effects on mDA neurons in a Ret-independent manner.…”

Nanoparticle-Mediated Upconversion of Near-Infrared Light: A Step Closer to Optogenetic Neuromodulation in Humans

“…It has been approved by the FDA for gene therapy from 1995 and for gene therapy in the brain from 2005 [19], and was consistently shown not to induce any significant immune or inflammatory response [10, 11, 19]. It has been safely used for the gene delivery in Parkinson’s disease gene therapy trials [20, 21] and is now under trial for optogenetic neuromodulation of retinal neurons in patients who are blind from retinitis pigmentosa [22] (NCT03326336, NCT02556736). Demonstrated safety in these human trials would provide compelling arguments for the safety of deep brain optogenetic neuromodulation in humans.…”