Targeting delivery in Parkinson's disease

Disease-modifying therapies for Parkinson's disease (PD), with the potential to halt the neurodegenerative process and to stimulate the protection, repair, and regeneration of dopaminergic neurons, remain a vital but unmet clinical need. Targeting the delivery of current and new therapeutics directly to the diseased brain region (in particular the nigrostriatal pathway) could result in greater improvements in the motor functions that characterise PD. Here, we highlight some of the opportunities and challenges facing the development of the next generation of therapies for patients with PD

Growth factor therapy for Parkinson's disease: alternative delivery systems

Despite decades of research and billions in global investment, there remains no preventative or curative treatment for any neurodegenerative condition, including Parkinson’s disease (PD). Arguably, the most promising approach for neuroprotection and neurorestoration in PD is using growth factors which can promote the growth and survival of degenerating neurons. However, although neurotrophin therapy may seem like the ideal approach for neurodegenerative disease, the use of growth factors as drugs presents major challenges because of their protein structure which creates serious hurdles related to accessing the brain and specific targeting of affected brain regions. To address these challenges, several different delivery systems have been developed, and two major approaches—direct infusion of the growth factor protein into the target brain region and in vivo gene therapy—have progressed to clinical trials in patients with PD. In addition to these clinically evaluated approaches, a range of other delivery methods are in various degrees of development, each with their own unique potential. This review will give a short overview of some of these alternative delivery systems, with a focus on ex vivo gene therapy and biomaterial-aided protein and gene delivery, and will provide some perspectives on their potential for clinical development and translation

Cryogel microcarriers for sustained local delivery of growth factors to the brain

Neurotrophic growth factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) have been considered as potential therapeutic candidates for neurodegenerative disorders due to their important role in modulating the growth and survival of neurons. However, clinical translation remains elusive, as their large size hinders translocation across the blood-brain barrier (BBB), and their short half-life in vivo necessitates repeated administrations. Local delivery to the brain offers a potential route to the target site but requires a suitable drug-delivery system capable of releasing these proteins in a controlled and sustained manner. Herein, we develop a cryogel microcarrier delivery system which takes advantage of the heparin-binding properties of GDNF and BDNF, to reversibly bind/release these growth factors via electrostatic interactions. Droplet microfluidics and subzero temperature polymerization was used to create monodisperse cryogels with varying degrees of negative charge and an average diameter of 20 μm. By tailoring the inclusion of 3-sulfopropyl acrylate (SPA) as a negatively charged moiety, the release duration of these two growth factors could be adjusted to range from weeks to half a year. 80% SPA cryogels and 20% SPA cryogels were selected to load GDNF and BDNF respectively, for the subsequent biological studies. Cell culture studies demonstrated that these cryogel microcarriers were cytocompatible with neuronal and microglial cell lines, as well as primary neural cultures. Furthermore, in vivo studies confirmed their biocompatibility after administration into the brain, as well as their ability to deliver, retain and release GDNF and BDNF in the striatum. Overall, this study highlights the potential of using cryogel microcarriers for long-term delivery of neurotrophic growth factors to the brain for neurodegenerative disorder therapeutics

Brain repair for Parkinson's disease: is the answer in the matrix?

Two hundred years after James Parkinson first described the cardinal motor symptoms of the disorder that would later bear his name, there is still an irrefutable need for a therapy that targets the underlying pathophysiology of the disease and not solely its symptoms. Parkinson’s disease (PD) is classically characterised by Lewy body formation and a relatively selective degeneration of nigrostriatal dopaminergic neurons (Schapira and Jenner, 2011). The loss of dopaminergic neurons from the substantia nigra pars compacta causes a consequential depletion of the neurotransmitter dopamine from the striatum, and it is this loss that causes the motor symptoms experienced by patients. To date, all treatments for this condition are symptomatic in that they simply endeavour to correct the neurochemical and/or electrical anomalies caused by striatal dopaminergic deafferentation in an attempt to improve motor function (LeWitt and Fahn, 2016). While such symptomatic approaches show extraordinary efficacy in the early years after initiating treatment, the underlying disease pathology continues to progress, and eventually their efficacy subsides. In view of this, there remains an urgent need for an alternative treatment approach that is capable of protecting or repairing the brain in order to provide a more sustained benefit to patients.Our research in this field is supported by the European Union Horizon 2020 Programme (H2020-MSCA-ITN-2015) under the Marie Sklodowska-Curie Innovative Training Networks and Grant Agreement No. 676408, Science Foundation Ireland (11/RFP/NES/3183), and through a postgraduate scholarship from the Irish Research Council to Niamh Moriarty.peer-reviewe

Brain repair for Parkinson\u27s disease: is the answer in the matrix?

Two hundred years after James Parkinson first described the cardinal motor symptoms of the disorder that would later bear his name, there is still an irrefutable need for a therapy that targets the underlying pathophysiology of the disease and not solely its symptoms. Parkinson’s disease (PD) is classically characterised by Lewy body formation and a relatively selective degeneration of nigrostriatal dopaminergic neurons (Schapira and Jenner, 2011). The loss of dopaminergic neurons from the substantia nigra pars compacta causes a consequential depletion of the neurotransmitter dopamine from the striatum, and it is this loss that causes the motor symptoms experienced by patients. To date, all treatments for this condition are symptomatic in that they simply endeavour to correct the neurochemical and/or electrical anomalies caused by striatal dopaminergic deafferentation in an attempt to improve motor function (LeWitt and Fahn, 2016). While such symptomatic approaches show extraordinary efficacy in the early years after initiating treatment, the underlying disease pathology continues to progress, and eventually their efficacy subsides. In view of this, there remains an urgent need for an alternative treatment approach that is capable of protecting or repairing the brain in order to provide a more sustained benefit to patients.Our research in this field is supported by the European Union Horizon 2020 Programme (H2020-MSCA-ITN-2015) under the Marie Sklodowska-Curie Innovative Training Networks and Grant Agreement No. 676408, Science Foundation Ireland (11/RFP/NES/3183), and through a postgraduate scholarship from the Irish Research Council to Niamh Moriarty

A role for viral infections in Parkinson's etiology?

Despite over 200 years since its first description by James Parkinson, the cause(s) of most cases of Parkinson’s disease (PD) are yet to be elucidated. The disparity between the current understanding of PD symptomology and pathology has led to numerous symptomatic therapies, but no strategy for prevention or disease cure. An association between certain viral infections and neurodegenerative diseases has been recognized, but largely ignored or dismissed as controversial, for decades. Recent epidemiological studies have renewed scientific interest in investigating microbial interactions with the central nervous system (CNS). This review examines past and current clinical findings and overviews the potential molecular implications of viruses in PD pathology.peer-reviewe