Primary tissue for cellular brain repair in Parkinson's disease: Promise, problems and the potential of biomaterials

Abstract

The dopamine precursor, levodopa, remains the "gold standard" treatment for Parkinson's disease, and, although it provides superlative efficacy in the early stages of the disease, its long-term use is limited by the development of severe motor side effects and a significant abating of therapeutic efficacy. Therefore, there remains a major unmet clinical need for the development of effective neuroprotective, neurorestorative or neuroreparatory therapies for this condition. The relatively selective loss of dopaminergic neurons from the nigrostriatal pathway makes Parkinson's disease an ideal candidate for reparative cell therapies, wherein the dopaminergic neurons that are lost in the condition are replaced through direct cell transplantation into the brain. To date, this approach has been developed, validated and clinically assessed using dopamine neuron-rich foetal ventral mesencephalon grafts which have been shown to survive and reinnervate the denervated brain after transplantation, and to restore motor function. However, despite long-term symptomatic relief in some patients, significant limitations, including poor graft survival and the impact this has on the number of foetal donors required, have prevented this therapy being more widely adopted as a restorative approach for Parkinson's disease. Injectable biomaterial scaffolds have the potential to improve the delivery, engraftment and survival of these grafts in the brain through provision of a supportive microenvironment for cell adhesion, growth and immune shielding. This article will briefly review the development of primary cell therapies for brain repair in Parkinson's disease and will consider the emerging literature which highlights the potential of using injectable biomaterial hydrogels in this context.

Strategies for the Treatment of Parkinson’s Disease: Beyond Dopamine

“…This includes fetal dopaminergic neurons (Thompson and Parish, 2013) as well as embryonic, adult, neural, mesenchymal, and induced pluripotent stem cells (Freed et al, 2003;Hedlund and Perlmann, 2009;Thompson and Parish, 2013;Barker et al, 2016;Xu et al, 2016;Venkatesh and Sen, 2017;Zhang et al, 2017). These efforts were accompanied by the development of biomaterial scaffolds to provide support materials for cell adhesion and growth (Moriarty et al, 2019).…”

Neuronal Replacement as a Tool for Basal Ganglia Circuitry Repair: 40 Years in Perspective

“…Also, there is an increasing interest in the role and potential of extracellular matrix proteins, such as laminin and fibronectin, due to their ability to promote the survival, proliferation, and differentiation of fetal and hPSC-derived neural progenitors (Kirkeby et al, 2017b;Somaa et al, 2017;Zhang et al, 2017). For a comprehensive overview of these promising developments, the reader is referred to the recent reviews by Bruggeman et al (2019) and Moriarty et al (2019b).…”

Harnessing stem cells and biomaterials to promote neural repair

“…On injection, the fluid flows to fill extracellular spaces in the brain, filling irregular voids (where required) and interfacing fully with surrounding tissue, then promptly selfassembling within minutes into a stiffer gel that can be tailored to match the mechnical properties of the brain, and support surrounding host, or newly implanted cells. Such materials [including hyaluronic acid (HA) and collagen gels] have been shown to support both fetal and human PSC-derived progenitors in vitro and cell engraftment in PD and stroke models (Jin et al, 2010;Yu et al, 2010;Zhong et al, 2010;Adil et al, 2017;Moriarty et al, 2017Moriarty et al, , 2018a; see also reviews -Jendelova et al, 2016; Moriarty and Dowd, 2018c;Moriarty et al, 2018b).…”

“…In an effort to improve cell-based therapies for neural repair, bioengineered scaffolds have been proposed. Biomaterials are being investigated for their potential to restore tissue architecture, enhance cell survival and differentiation, and promote plasticity and integration of both endogenous and transplanted stem cells (Rodriguez et al, 2012;Jendelova et al, 2016;Moriarty et al, 2018b). In this review, we will discuss the progress (and challenges) in stimulating endogenous repair and cell transplantation from the perspective of two common neural injuries; one that is chronic yet discrete in nature (PD) and an acute injury that is notably more diffuse and complex in its requirements for repair (stroke).…”