Growth Factor Therapy for Parkinson’s Disease: Alternative Delivery Systems

Abstract

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.

TrkB Truncated Isoform Receptors as Transducers and Determinants of BDNF Functions

“…The delivery of BDNF has universally failed as a therapeutic agent probably due to its inability to cross the BBB, the short half-life, and the difficulties of delivery to specific brain areas in a precise spatio-temporal fashion ( Miranda-Lourenco et al, 2020 ). A variety of approaches are currently being pursued to address the issue of BDNF delivery, including the use of biomaterials and nanoparticles, viral mediated gene delivery and transplantation of neurotrophin-producing cells ( Houlton et al, 2019 ; Jarrin et al, 2021 ). Unfortunately, most of these approaches ignore the possibility that changes at the level of TrkB receptor, including TrkB.T1 upregulation, may influence the downstream BDNF signaling and therefore the therapeutic outcome.…”

Gold Nanoparticles in Parkinson’s Disease Therapy: A Focus on Plant-Based Green Synthesis

“…Another example of a positive role for NPS in PD therapy is neurotrophic factor (NTF)-based therapies. They show promise in treating neurodegenerative diseases by slowing and potentially reversing neurodegeneration [25]. However, their short in vivo half-life, poor pharmacokinetics, and difficulty in penetrating the blood-brain barrier limit their access to neuronal targets.…”

Mitochondrial Dysfunction in Parkinson’s Disease: From Mechanistic Insights to Therapy

“…Lack of success in clinical trials can be attributed to an incomplete understanding of the molecular pathways and targets in PD, the heterogeneity of patient populations, a lack of adequate biomarkers to monitor drug efficacy, distinguish patient subtypes, and limited understanding of the sequence in which different cellular mechanisms lead to neuronal loss, see Lang and Espay’s (2018) review. Furthermore, PD presents many challenges to therapeutic approaches, including the difficulty of introducing therapeutics into the brain, target specificity, potential inflammatory responses, safety concerns, tolerability for geriatric patients, ethical implications, and the mechanistic heterogeneity of the disease, refer to these reviews by Jarrin et al (2021) and Vijiaratnam et al (2021) . A major challenge for any preventative therapy is that much of the mitochondrial dysfunction in the brain of PD patients may have already occurred before the point of diagnosis during the prodromal period, see the excellent review by Schapira and Tolosa (2010) .…”