Emerging therapies in Parkinson disease - repurposed drugs and new approaches

Abstract

Parkinson disease (PD) treatment options have conventionally focused on dopamine replacement and provision of symptomatic relief. Current treatments cause undesirable adverse effects, and a large unmet clinical need remains for treatments that offer disease modification and that address symptoms resistant to levodopa. Advances in high-throughput drug screening methods for small molecules, developments in disease modelling and improvements in analytical technologies have collectively contributed to the emergence of novel compounds, repurposed drugs and new technologies. In this Review, we focus on disease-modifying and symptomatic therapies under development for PD. We review cellular therapies and repurposed drugs, such as nilotinib, inosine, isradipine, iron chelators and anti-inflammatories, and discuss how their success in preclinical models has paved the way for clinical trials. We provide an update on immunotherapies and vaccines. In addition, we review non-pharmacological interventions targeting motor symptoms, including gene therapy, adaptive deep brain stimulation (DBS) and optogenetically inspired DBS. Given the many clinical phenotypes of PD, individualization of therapy and precision of treatment are likely to become important in the future.

Fig. 1 |. Mechanisms of potential therapies for Parkinson disease.

Numerous potential therapies for Parkinson disease (PD) are at various stages of preclinical and clinical testing. These agents target many aspects of PD pathogenesis. Therapies in bold are at advanced stages of testing. Several basic pathophysiological pathways are depicted, including those that lead to Lewy bodies, and those involving inflammatory factors, mitochondrial dysfunction and oxidative stress. A synapse to the right illustrates the potential spread of pathological α-synuclein to nearby cells. Bars indicate either inhibition or decrease and arrows indicate activation or increase. Arrows are also used for a sequence of events in a pathway. The exclamation marks inside the mitochondrion represent a dysfunctional mitochondrion. AKT, protein kinase B; β2-AR, β2-adrenergic receptor; DJ1, protein deglycase DJ1; DRP1, dynamin-1-like protein; ER, endoplasmic reticulum; GBA, glucocerebrosidase; GDNF, glial cell-derived neurotrophic factor; LAG3, lymphocyte-activation gene 3; LRRK2, leucine- rich repeat kinase 2; Mdivi-1, mitochondrial division inhibitor 1; MIRO, mitochondrial Rho GTPase 1; MitoQ, mitoquinone; PINK1, PTEN-induced kinase 1; PPARγ, peroxisome proliferator-activated receptor-γ; siRNA, small interfering RNA.

Fig. 2 |. Basal ganglia neurotransmitter network.

A classic model of the basal ganglia is shown with a striatonigral direct pathway through the globus pallidus internus (GPi), an indirect pathway reaching the globus pallidus externus (GPe) and subthalamic nucleus (STN) before the GPi and a hyperdirect pathway to the STN. Dopaminergic input to the striatum is supplied by the substantia nigra (SN). Other neurotransmitter foci are also depicted, including the pedunculopontine nucleus (PPN) and nucleus basalis of Meynert (NbM) for acetylcholine (ACh), the raphe nucleus (RN) for serotonin (5-hydroxytryptamine (5-HT)) and the locus coeruleus (LC) for noradrenaline (NE). These neurotransmitters travel throughout the basal ganglia and related structures and play an important part in Parkinson disease motor symptoms. Several existing and investigational therapies that aim to address abnormal levels of neurotransmitters are shown. DA, dopamine; mGluR, metabotropic glutamate receptor; NMDA, N-methyl-d-aspartate.

Fig. 3 |. Extraction and induction of dopaminergic cells for neuronal restoration.

There are several emerging approaches for extracting dopaminergic cells. Fetal mesencephalic cell (FMC) transplantation initially seemed promising, but runaway dyskinesias halted further trials. The TRANSEURO consortium will comprehensively re-evaluate this therapy. Embryonic stem cells (ESCs) can be used for transplantation but carry the same ethical challenges as FMCs (the ethical challenge is visually depicted by the locks in the figure). Red blood cell (RBC) and fibroblast induced pluripotent stem cells (iPSCs) are an alternative approach that eliminates this ethical challenge, but, similar to other pluripotent stem cells, these cells carry neoplastic potential. Finally, neurons induced by direct programming from somatic cells might be a viable but technically challenging route. The figure depicts some transcription factors used in reprogramming cells. ASCL1, achaete– scute homologue 1; FOXA2, hepatocyte nuclear factor 3β; KLF4, Krüppel-like factor 4; LMX1A, LIM homeobox transcription factor 1α; MYC; Myc proto-oncogene protein; NURR1, nuclear receptor related-1 protein; OCT4, organic cation/carnitine transporter 4; SOX2, transcription factor SOX2; TH, tyrosine 3-monooxygenase.

Fig. 4 |. Neuromodulation.

Deep brain stimulation is an established therapy for Parkinson disease, but there is growing interest in non-invasive electrical stimulation modalities and optogenetic stimulation modalities. Non-invasive electrical stimulation might be achieved with interference of two electric fields with slightly different frequencies (temporal interference), leading to localized stimulation. In optogenetic stimulation, an opsin is delivered to specific neurons that then express a light-sensitive channel on their membrane, permitting their stimulation with direct light source. Alternatively, certain nanoparticles, if delivered inside the brain, are able to convert infrared light from an extracranial source to visible light in the brain and hence permit the non-invasive stimulation of optogenetically modified neurons. Electrical stimulation approaches are generally non-specific, whereas optogenetic approaches have the potential for targeting specific neurons.