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.
Emerging therapies for Parkinson disease (PD) have focused largely on disease modification and on dopamine resistance symptoms, which are both important unmet needs.
Some new disease-modifying therapies target α-synuclein and its pathways, whereas others target different genes and proteins implicated in PD pathogenesis, including leucine-rich repeat kinase 2, parkin and glucocerebrosidase.
Disease-modifying pharmacotherapies (such as nilotinib, inosine and isradipine) are being repurposed to treat PD; antibody therapies, vaccines and immune-mediated therapies that aim to clear abnormal proteins have also emerged as promising approaches.
Cellular therapies can be divided into rescue and restoration therapies; rescue therapy aims to salvage neurons and slow the progression of the disease whereas restoration therapy focuses on replacing neurons.
Adaptive deep brain stimulation is an alternative symptomatic therapy that can be used to target dopamine-responsive and dopamine-resistant symptoms.
Current efforts to overcome challenges in therapeutic development have focused on individualization of therapy and precision in treatment; these principles are especially important given the heterogeneity of clinical PD subtypes.
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The authors are supported by NIH grants R01 NR014852 and R01NS096008; NIH/National Center for Advancing Translational Sciences Clinical and Translational Science Awards to the University of Florida (UL1TR001427, KL2TR001429 and TL1TR001428); and the Parkinson's Foundation.
V.V.-M. is supported by a grant for the deep brain stimulation brain bank from Abbott. M.S.O. serves as a consultant for the Parkinson's Foundation and has received research grants from NIH, NPF, the Michael J. Fox Foundation, the Parkinson Alliance, the Smallwood Foundation, the Bachmann–Strauss Foundation, the Tourette Syndrome Association and the UF Foundation. M.S.O. has previously received honoraria but in the past >60 months has received no support from industry. M.S.O. has received royalties for publications with Demos, Manson, Amazon, Smashwords, Books4Patients and Cambridge (movement disorder books). M.S.O. is an associate editor for the New England Journal of Medicine: Journal Watch Neurology. M.S.O. has participated in continuing medical education and educational activities on movement disorders (in the past 36 months) sponsored by PeerView, Prime, QuantiaMD, WebMD, Medicus, MedNet, Henry Stewart and Vanderbilt University. M.S.O. has participated as a site principal investigator (PI) and/or co-PI for several NIH, foundation and industry-sponsored trials over the years but has not received honoraria. A.E. and R.S.E. have no competing interests.
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Elkouzi, A., Vedam-Mai, V., Eisinger, R.S. et al. Emerging therapies in Parkinson disease — repurposed drugs and new approaches. Nat Rev Neurol 15, 204–223 (2019). https://doi.org/10.1038/s41582-019-0155-7
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