Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-745bb68f8f-mzp66 Total loading time: 0 Render date: 2025-01-09T11:23:46.512Z Has data issue: false hasContentIssue false

Chapter 21 - Regenerative Strategies for Parkinson’s Disease

from Section 2: - Hypokinetic Movement Disorders

Published online by Cambridge University Press:  07 January 2025

By
Thomas Stoker  and
Daniela Noain
Edited by
Erik Ch. Wolters  and
Christian R. Baumann
Erik Ch. Wolters
Affiliation:
Universität Zürich
Christian R. Baumann
Affiliation:
Universität Zürich
Get access

Summary

In Parkinson’s disease, parkinsonism occurs due to the loss of dopaminergic neurons of the substantia nigra. Existing treatments can enhance dopaminergic activity in the brain, but cause adverse effects due to the non-targeted, non-physiologic dopamine delivery, so there is interest in developing regenerative therapies to restore dopaminergic tone in the striatum in a targeted, physiologic manner. Experimental approaches include using viral vectors to deliver genes encoding growth factors or enzymes involved in dopamine synthesis, or to target nucleic acids and gene expression. A number of cell types have been considered potential sources of cell-based therapies for PD and have been trialled in humans and animals, but all have been limited by either poor efficacy, poor graft survival, or logistical barriers. However, stem cells offer a renewable source of dopaminergic cells and hold great promise as potential regenerative treatments, and human trials have begun. Although these treatments remain experimental, some are entering clinical trials and there is hope that they will become available for clinical use in the future.

Keywords

Cell therapiesfetal ventral mesencephalongene therapiesiPSCsneural graftingParkinson’s diseaseregenerative therapiesstem cellsviral vectors
Type
Chapter
Information
International Compendium of Movement Disorders , pp. 252 - 263
Publisher: Cambridge University Press
Print publication year: 2025

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Stoker, TB, Barker, RA. Recent developments in the treatment of Parkinson’s disease. F1000Res 2020;9:F1000 Faculty Rev-862.CrossRefGoogle ScholarPubMed
Braak, H, Del Tredici, K, Rüb, U, et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003;24(2):197–211.CrossRefGoogle ScholarPubMed
Klawans, HL, Goetz, C, Nausieda, PA, Weiner, WJ. Levodopa-induced dopamine receptor hypersensitivity. Trans Am Neurol Assoc 1977;102:80–83.Google ScholarPubMed
Rylander, D, Parent, M, O’Sullivan, SS, et al. Maladaptive plasticity of serotonin axon terminals in levodopa-induced dyskinesia. Ann Neurol 2010;68(5):619–628.CrossRefGoogle ScholarPubMed
Cenci, MA, Lundblad, M. Post- versus presynaptic plasticity in L-DOPA-induced dyskinesia. J Neurochem 2006;99(2):381–392.CrossRefGoogle ScholarPubMed
Cenci, MA. Presynaptic mechanisms of l-DOPA-induced dyskinesia: the findings, the debate, and the therapeutic implications. Front Neurol 2014;5:242.CrossRefGoogle ScholarPubMed
Mukherjee, S, Thrasher, AJ. Gene therapy for PIDs: progress, pitfalls and prospects. Gene 2013;525(2):174–181.CrossRefGoogle ScholarPubMed
Iarkov, A, Barreto, GE, Grizzell, JA, Echeverria, V. Strategies for the treatment of Parkinson’s disease: beyond dopamine. Front Aging Neurosci 2020;12:4.CrossRefGoogle ScholarPubMed
Penaud-Budloo, M, Le Guiner, C, Nowrouzi, A, et al. Adeno-associated virus vector genomes persist as episomal chromatin in primate muscle. J Virol 2008;82(16):7875–7885.CrossRefGoogle ScholarPubMed
Naso, MF, Tomkowicz, B, Perry, WL, Strohl, WR. Adeno-associated virus (AAV) as a vector for gene therapy. BioDrugs 2017;31(4):317–334.CrossRefGoogle ScholarPubMed
Wu, Z, Yang, H, Colosi, P. Effect of genome size on AAV vector packaging. Mol Ther 2010;18(1):80–86.CrossRefGoogle ScholarPubMed
Palfi, S, Gurruchaga, JM, Ralph, GS, et al. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: a dose escalation, open-label, phase 1/2 trial. Lancet 2014;383(9923):1138–1146.CrossRefGoogle ScholarPubMed
Maes, ME, Colombo, G, Schulz, R, Siegert, S. Targeting microglia with lentivirus and AAV: recent advances and remaining challenges. Neurosci Lett 2019;707:134310.CrossRefGoogle ScholarPubMed
Marks, WJ, Ostrem, JL, Verhagen, L, et al. Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson’s disease: an open-label, phase I trial. Lancet Neurol 2008;7(5):400–408.CrossRefGoogle ScholarPubMed
Marks, WJ, Bartus, RT, Siffert, J, et al. Gene delivery of AAV2-neurturin for Parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol 2010;9(12):1164–1172.CrossRefGoogle ScholarPubMed
Warren Olanow, C, Bartus, RT, Baumann, TL, et al. Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: a double-blind, randomized, controlled trial. Ann Neurol 2015;78(2):248–257.CrossRefGoogle ScholarPubMed
Heiss, JD, Lungu, C, Hammoud, DA, et al. Trial of magnetic resonance-guided putaminal gene therapy for advanced Parkinson’s disease. Mov Disord 2019;34(7):1073–1078.CrossRefGoogle ScholarPubMed
Redmond, DE, McEntire, CR, Kingsbery, JP, et al. Comparison of fetal mesencephalic grafts, AAV-delivered GDNF, and both combined in an MPTP-induced nonhuman primate Parkinson’s model. Mol Ther 2013;21(12):2160–2168.CrossRefGoogle Scholar
Bankiewicz, KS, Forsayeth, J, Eberling, JL, et al. Long-term clinical improvement in MPTP-lesioned primates after gene therapy with AAV-hAADC. Mol Ther 2006;14(4):564–570.CrossRefGoogle ScholarPubMed
Christine, CW, Starr, PA, Larson, PS, et al. Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology 2009;73(20):1662–1669.CrossRefGoogle ScholarPubMed
Muramatsu, S, Fujimoto, K, Kato, S, et al. A phase I study of aromatic l-amino acid decarboxylase gene therapy for Parkinson’s disease. Mol Ther 2010;18(9):1731–1735.CrossRefGoogle ScholarPubMed
Palfi, S, Gurruchaga, JM, Lepetit, H, et al. Long-term follow-up of a phase I/II Study of ProSavin, a lentiviral vector gene therapy for Parkinson’s disease. Hum Gene Ther Clin Dev 2018;29(3):148–155.CrossRefGoogle ScholarPubMed
Christine, CW, Bankiewicz, KS, Van Laar, AD, et al. Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson’s disease. Ann Neurol 2019;85(5):704–714.CrossRefGoogle ScholarPubMed
Kaplitt, MG, Feigin, A, Tang, C, et al. Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson’s disease: an open label, phase I trial. Lancet 2007;369(9579):2097–2105.CrossRefGoogle ScholarPubMed
LeWitt, PA, Rezai, AR, Leehey, MA, et al. AAV2-GAD gene therapy for advanced Parkinson’s disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol 2011;10(4):309–319.CrossRefGoogle ScholarPubMed
Niethammer, M, Tang, CC, LeWitt, PA, et al. Long-term follow-up of a randomized AAV2-GAD gene therapy trial for Parkinson’s disease. JCI Insight 2017;2(7):e90133.CrossRefGoogle ScholarPubMed
Niethammer, M, Tang, CC, Vo, A, et al. Gene therapy reduces Parkinson’s disease symptoms by reorganizing functional brain connectivity. Sci Transl Med 2018;10(469):eaau0713.CrossRefGoogle ScholarPubMed
Vierbuchen, T, Ostermeier, A, Pang, ZP, et al. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 2010;463(7284):1035–1041.CrossRefGoogle ScholarPubMed
Rivetti di Val Cervo, P, Romanov, RA, Spigolon, G, et al. Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson’s disease model. Nat Biotechnol 2017;35(5):444–452.CrossRefGoogle Scholar
Zharikov, AD, Cannon, JR, Tapias, V, et al. shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson’s disease model. J Clin Invest 2015;125(7):2721–2735.CrossRefGoogle Scholar
Kim, YC, Miller, A, Lins, LC, et al. RNA interference of human α-synuclein in mouse. Front Neurol 2017;8:13.CrossRefGoogle Scholar
Burré, J, Sharma, M, Südhof, TC. Cell biology and pathophysiology of α-synuclein. Cold Spring Harb Perspect Med 2018;8(3):a024091.CrossRefGoogle ScholarPubMed
Chmielarz, P, Konovalova, J, Najam, SS, et al. Dicer and microRNAs protect adult dopamine neurons. Cell Death Dis 2017;8(5):e2813.CrossRefGoogle ScholarPubMed
Guo, CH, Cao, T, Zheng, LT, Waddington, JL, Zhen, XC. Development and characterization of an inducible Dicer conditional knockout mouse model of Parkinson’s disease: validation of the antiparkinsonian effects of a sigma-1 receptor agonist and dihydromyricetin. Acta Pharmacol Sin 2020;41(4):499–507.CrossRefGoogle ScholarPubMed
Uehara, T, Choong, CJ, Nakamori, M, et al. Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting α-synuclein as a novel therapy for Parkinson’s disease. Sci Rep 2019;9(1):7567.CrossRefGoogle ScholarPubMed
Cole, TA, Zhao, H, Collier, T, et al. Alpha-synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson’s disease. JCI Insight 2021;6(5):e135633.CrossRefGoogle ScholarPubMed
Martin, I, Kim, JW, Dawson, VL, Dawson, TM. LRRK2 pathobiology in Parkinson’s disease. J Neurochem 2014;131(5):554–565.CrossRefGoogle ScholarPubMed
Zhao, HT, John, N, Delic, V, et al. LRRK2 antisense oligonucleotides ameliorate α-synuclein inclusion formation in a Parkinson’s disease mouse model. Mol Ther Nucleic Acids 2017;8:508–519.CrossRefGoogle Scholar
Frangoul, H, Altshuler, D, Cappellini, MD, et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N Engl J Med 2021;384(3):252–260.CrossRefGoogle ScholarPubMed
Lino, CA, Harper, JC, Carney, JP, Timlin, JA. Delivering CRISPR: a review of the challenges and approaches. Drug Deliv 2018;25(1):1234–1257.CrossRefGoogle ScholarPubMed
Zhou, H, Su, J, Hu, X, et al. Glia-to-neuron conversion by CRISPR-CasRx alleviates symptoms of neurological disease in mice. Cell 2020;181(3):590–603.CrossRefGoogle ScholarPubMed
Li, W, Englund, E, Widner, H, et al. Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc Natl Acad Sci U S A 2016;113(23):6544–6549.CrossRefGoogle ScholarPubMed
Thompson, WG. Successful brain grafting. N Y Med J 1890;51:701–702.Google Scholar
Freed, WJ, Morihisa, JM, Spoor, E, et al. Transplanted adrenal chromaffin cells in rat brain reduce lesion-induced rotational behaviour. Nature 1981;292(5821):351–352.CrossRefGoogle ScholarPubMed
Barker, R, Dunnett, S. The biology and behaviour of intracerebral adrenal transplants in animals and man. Rev Neurosci 1993;4(2):113–146.CrossRefGoogle Scholar
Madrazo, I, Drucker-Colín, R, Díaz, V, et al. Open microsurgical autograft of adrenal medulla to the right caudate nucleus in two patients with intractable Parkinson’s disease. N Engl J Med 1987;316(14):831–834.CrossRefGoogle Scholar
Björklund, A, Stenevi, U, Dunnett, SB, Iversen, SD. Functional reactivation of the deafferented neostriatum by nigral transplants. Nature 1981;289(5797):497–499.CrossRefGoogle ScholarPubMed
Lindvall, O, Brundin, P, Widner, H, et al. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson’s disease. Science 1990;247(4942):574–577.CrossRefGoogle ScholarPubMed
Barker, RA, Drouin-Ouellet, J, Parmar, M. Cell-based therapies for Parkinson disease – past insights and future potential. Nat Rev Neurol 2015;11(9):492–503.CrossRefGoogle ScholarPubMed
Langston, JW, Ballard, P, Tetrud, JW, Irwin, I. Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983;219(4587):979–980.CrossRefGoogle ScholarPubMed
Olanow, CW, Goetz, CG, Kordower, JH, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol 2003;54(3):403–414.CrossRefGoogle ScholarPubMed
Freed, CR, Greene, PE, Breeze, RE, et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med 2001;344(10):710–719.CrossRefGoogle ScholarPubMed
Gross, RE, Watts, RL, Hauser, RA, et al. Intrastriatal transplantation of microcarrier-bound human retinal pigment epithelial cells versus sham surgery in patients with advanced Parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol 2011;10(6):509–519.CrossRefGoogle ScholarPubMed
Arjona, V, Mínguez-Castellanos, A, Montoro, RJ, et al. Autotransplantation of human carotid body cell aggregates for treatment of Parkinson’s disease. Neurosurgery 2003;53(2):321–328; discussion 328–330.CrossRefGoogle ScholarPubMed
Mínguez-Castellanos, A, Escamilla-Sevilla, F, Hotton, GR, et al. Carotid body autotransplantation in Parkinson disease: a clinical and positron emission tomography study. J Neurol Neurosurg Psychiatry 2007;78(8):825–831.CrossRefGoogle ScholarPubMed
Schumacher, JM, Ellias, SA, Palmer, EP, et al. Transplantation of embryonic porcine mesencephalic tissue in patients with PD. Neurology 2000;54(5):1042–1050.CrossRefGoogle ScholarPubMed
Thomson, JA, Itskovitz-Eldor, J, Shapiro, SS, et al. Embryonic stem cell lines derived from human blastocysts. Science 1998;282(5391):1145–1147.CrossRefGoogle ScholarPubMed
Takahashi, K, Tanabe, K, Ohnuki, M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007;131(5):861–872.CrossRefGoogle ScholarPubMed
Chen, Y, Dolt, KS, Kriek, M, et al. Engineering synucleinopathy-resistant human dopaminergic neurons by CRISPR-mediated deletion of the SNCA gene. Eur J Neurosci 2019;49(4):510–524.CrossRefGoogle ScholarPubMed
Tabar, V, Studer, L. Pluripotent stem cells in regenerative medicine: challenges and recent progress. Nat Rev Genet 2014;15(2):82–92.CrossRefGoogle ScholarPubMed
Cooper, O, Hargus, G, Deleidi, M, et al. Differentiation of human ES and Parkinson’s disease iPS cells into ventral midbrain dopaminergic neurons requires a high activity form of SHH, FGF8a and specific regionalization by retinoic acid. Mol Cell Neurosci 2010;45(3):258–266.CrossRefGoogle ScholarPubMed
Ono, Y, Nakatani, T, Sakamoto, Y, et al. Differences in neurogenic potential in floor plate cells along an anteroposterior location: midbrain dopaminergic neurons originate from mesencephalic floor plate cells. Development 2007;134(17):3213–3225.CrossRefGoogle ScholarPubMed
Chambers, SM, Fasano, CA, Papapetrou, EP, et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol 2009;27(3):275–280.CrossRefGoogle ScholarPubMed
Kirkeby, A, Nolbrant, S, Tiklova, K, et al. Predictive markers guide differentiation to improve graft outcome in clinical translation of hESC-based therapy for Parkinson’s disease. Cell Stem Cell 2017;20(1):135–148.CrossRefGoogle ScholarPubMed
Sonntag, KC, Pruszak, J, Yoshizaki, T, et al. Enhanced yield of neuroepithelial precursors and midbrain-like dopaminergic neurons from human embryonic stem cells using the bone morphogenic protein antagonist noggin. Stem Cells 2007;25(2):411–418.CrossRefGoogle ScholarPubMed
Takahashi, J. IPS cell-based therapy for Parkinson’s disease: a Kyoto trial. Regen Ther 2020;13:18–22.CrossRefGoogle ScholarPubMed
Taylor, CJ, Peacock, S, Chaudhry, AN, Bradley, JA, Bolton, EM. Generating an iPSC bank for HLA-matched tissue transplantation based on known donor and recipient HLA types. Cell Stem Cell 2012;11(2):147–152.CrossRefGoogle ScholarPubMed
Offen, D, Barhum, Y, Levy, YS, et al. Intrastriatal transplantation of mouse bone marrow-derived stem cells improves motor behavior in a mouse model of Parkinson’s disease. J Neural Transm Suppl. 2007(72):133–143.CrossRefGoogle Scholar
Hayashi, T, Wakao, S, Kitada, M, et al. Autologous mesenchymal stem cell-derived dopaminergic neurons function in parkinsonian macaques. J Clin Invest 2013;123(1):272–284.CrossRefGoogle ScholarPubMed
Venkataramana, NK, Kumar, SK, Balaraju, S, et al. Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson’s disease. Transl Res 2010;155(2):62–70.CrossRefGoogle ScholarPubMed
Gonzalez, R, Garitaonandia, I, Poustovoitov, M, et al. Neural stem cells derived from human parthenogenetic stem cells engraft and promote recovery in a nonhuman primate model of Parkinson’s disease. Cell Transplant 2016;25(11):1945–1966.CrossRefGoogle Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×