drugset / Trial / NCT05635409
A Trial to Determine the Safety and Tolerability of Transplanted Stem Cell Derived Dopamine Neurons to the Brains of Individuals With Parkinson's Disease
Phase 1
Active not recruiting
8 enrolled
Region Skane
Cambridge University Hospitals NHS Foundation Trust · collabLund University · collabUniversity of Cambridge · collab
Non-randomizedSequentialOpen-labelTreatment
Summary
Parkinson's disease (PD) occurs when an area of the brain begins to lose nerve cells that produce a chemical called dopamine. Dopamine is an important chemical, and one of its functions is that it helps to regulate body movement. The loss of these nerve cells leads to a reduction of dopamine in the brain. Medications used to treat PD temporarily replace this lost dopamine, but they do not repair the underlying disease. One of the most promising PD therapies to date has been the transplantation of dopamine producing cells into the brain. Unlike current treatments, these therapies may be able to repair the damage caused in PD. In this trial, the investigators will transplant a new stem cell therapy, called the STEM-PD product, into the area of the brain affected in people with PD. These stem cells can develop into many different cell types, including dopamine-producing nerve cells. The investigators will transplant the stem cells using a device that has been previously used for similar transplants in Lund. This is the first time that the STEM-PD product will be given to humans. The trial aims to assess whether the STEM-PD product is safe to use in people with PD. The investigators will also be looking for preliminary signs of efficacy. The trial will recruit participants with PD from the UK and Sweden. Eight participants will undergo the STEM-PD product transplant. Participants will receive a single dose of the STEM-PD product. Participants will attend for 25 visits primarily at their local recruiting hospital. For participants from the UK, some of the imaging will be performed at Invicro (London), and the surgery (including some visits before and after) and some imaging will be performed in Lund. All participants will be followed up for 36 months following surgery
Timeline
- Start
- 2022-11-30
- Primary completion
- 2027-01
- Completion
- 2027-11
Outcome
Results reported · no primary-endpoint met/missed verdict (typical of a dose-finding / safety study)
paper The primary outcome of the trial is safety and tolerability, assessed by the number and nature of adverse events and serious adverse events PMID 41469040 ↗
paper No serious adverse events were attributed to the cell product, no graft-induced dyskinesias were observed and serial magnetic resonance imaging showed no evidence of tumor formation. PMID 42426223 ↗
Publications
- Background Adler AF, Cardoso T, Nolbrant S, Mattsson B, Hoban DB, Jarl U, Wahlestedt JN, Grealish S, Bjorklund A, Parmar M. hESC-Derived Dopaminergic Transplants Integrate into Basal Ganglia Circuitry in a Preclinical Model of Parkinson's Disease. Cell Rep. 2019 Sep 24;28(13):3462-3473.e5. doi: 10.1016/j.celrep.2019.08.058.
- Background Aldrin-Kirk P, Heuer A, Wang G, Mattsson B, Lundblad M, Parmar M, Bjorklund T. DREADD Modulation of Transplanted DA Neurons Reveals a Novel Parkinsonian Dyskinesia Mechanism Mediated by the Serotonin 5-HT6 Receptor. Neuron. 2016 Jun 1;90(5):955-68. doi: 10.1016/j.neuron.2016.04.017. Epub 2016 May 5.
- Background Barker RA, Barrett J, Mason SL, Bjorklund A. Fetal dopaminergic transplantation trials and the future of neural grafting in Parkinson's disease. Lancet Neurol. 2013 Jan;12(1):84-91. doi: 10.1016/S1474-4422(12)70295-8.
- Background Barker RA; TRANSEURO consortium. Designing stem-cell-based dopamine cell replacement trials for Parkinson's disease. Nat Med. 2019 Jul;25(7):1045-1053. doi: 10.1038/s41591-019-0507-2. Epub 2019 Jul 1.
- Background Barker RA, Foltynie T. The future challenges in Parkinson's disease. J Neurol. 2004 Mar;251(3):361-5. doi: 10.1007/s00415-004-0320-8. No abstract available.
- Background Barker RA, Parmar M, Studer L, Takahashi J. Human Trials of Stem Cell-Derived Dopamine Neurons for Parkinson's Disease: Dawn of a New Era. Cell Stem Cell. 2017 Nov 2;21(5):569-573. doi: 10.1016/j.stem.2017.09.014.
- Background Braak H, Bohl JR, Muller CM, Rub U, de Vos RA, Del Tredici K. Stanley Fahn Lecture 2005: The staging procedure for the inclusion body pathology associated with sporadic Parkinson's disease reconsidered. Mov Disord. 2006 Dec;21(12):2042-51. doi: 10.1002/mds.21065.
- Background Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res. 2004 Oct;318(1):121-34. doi: 10.1007/s00441-004-0956-9. Epub 2004 Aug 24.
- Background Brundin P, Pogarell O, Hagell P, Piccini P, Widner H, Schrag A, Kupsch A, Crabb L, Odin P, Gustavii B, Bjorklund A, Brooks DJ, Marsden CD, Oertel WH, Quinn NP, Rehncrona S, Lindvall O. Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson's disease. Brain. 2000 Jul;123 ( Pt 7):1380-90. doi: 10.1093/brain/123.7.1380.
- Background Cardoso T, Adler AF, Mattsson B, Hoban DB, Nolbrant S, Wahlestedt JN, Kirkeby A, Grealish S, Bjorklund A, Parmar M. Target-specific forebrain projections and appropriate synaptic inputs of hESC-derived dopamine neurons grafted to the midbrain of parkinsonian rats. J Comp Neurol. 2018 Sep 1;526(13):2133-2146. doi: 10.1002/cne.24500. Epub 2018 Jul 31.
- Background Defer GL, Geny C, Ricolfi F, Fenelon G, Monfort JC, Remy P, Villafane G, Jeny R, Samson Y, Keravel Y, Gaston A, Degos JD, Peschanski M, Cesaro P, Nguyen JP. Long-term outcome of unilaterally transplanted parkinsonian patients. I. Clinical approach. Brain. 1996 Feb;119 ( Pt 1):41-50. doi: 10.1093/brain/119.1.41.
- Background Evans JR, Barker RA. Neurotrophic factors as a therapeutic target for Parkinson's disease. Expert Opin Ther Targets. 2008 Apr;12(4):437-47. doi: 10.1517/14728222.12.4.437.
- Background Freed CR, Breeze RE, Rosenberg NL, Schneck SA, Kriek E, Qi JX, Lone T, Zhang YB, Snyder JA, Wells TH, et al. Survival of implanted fetal dopamine cells and neurologic improvement 12 to 46 months after transplantation for Parkinson's disease. N Engl J Med. 1992 Nov 26;327(22):1549-55. doi: 10.1056/NEJM199211263272202.
- Background Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, Fahn S. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med. 2001 Mar 8;344(10):710-9. doi: 10.1056/NEJM200103083441002.
- Background Grealish S, Heuer A, Cardoso T, Kirkeby A, Jonsson M, Johansson J, Bjorklund A, Jakobsson J, Parmar M. Monosynaptic Tracing using Modified Rabies Virus Reveals Early and Extensive Circuit Integration of Human Embryonic Stem Cell-Derived Neurons. Stem Cell Reports. 2015 Jun 9;4(6):975-83. doi: 10.1016/j.stemcr.2015.04.011. Epub 2015 May 21.
- Background Hagell P, Piccini P, Bjorklund A, Brundin P, Rehncrona S, Widner H, Crabb L, Pavese N, Oertel WH, Quinn N, Brooks DJ, Lindvall O. Dyskinesias following neural transplantation in Parkinson's disease. Nat Neurosci. 2002 Jul;5(7):627-8. doi: 10.1038/nn863.
- Background Hagell P, Schrag A, Piccini P, Jahanshahi M, Brown R, Rehncrona S, Widner H, Brundin P, Rothwell JC, Odin P, Wenning GK, Morrish P, Gustavii B, Bjorklund A, Brooks DJ, Marsden CD, Quinn NP, Lindvall O. Sequential bilateral transplantation in Parkinson's disease: effects of the second graft. Brain. 1999 Jun;122 ( Pt 6):1121-32. doi: 10.1093/brain/122.6.1121.
- Background Hauser RA, Freeman TB, Snow BJ, Nauert M, Gauger L, Kordower JH, Olanow CW. Long-term evaluation of bilateral fetal nigral transplantation in Parkinson disease. Arch Neurol. 1999 Feb;56(2):179-87. doi: 10.1001/archneur.56.2.179.
- Background Heuer A, Kirkeby A, Pfisterer U, Jonsson ME, Parmar M. hESC-derived neural progenitors prevent xenograft rejection through neonatal desensitisation. Exp Neurol. 2016 Aug;282:78-85. doi: 10.1016/j.expneurol.2016.05.027. Epub 2016 May 25.
- Background Hoban DB, Shrigley S, Mattsson B, Breger LS, Jarl U, Cardoso T, Nelander Wahlestedt J, Luk KC, Bjorklund A, Parmar M. Impact of alpha-synuclein pathology on transplanted hESC-derived dopaminergic neurons in a humanized alpha-synuclein rat model of PD. Proc Natl Acad Sci U S A. 2020 Jun 30;117(26):15209-15220. doi: 10.1073/pnas.2001305117. Epub 2020 Jun 15.
- Background Kefalopoulou Z, Politis M, Piccini P, Mencacci N, Bhatia K, Jahanshahi M, Widner H, Rehncrona S, Brundin P, Bjorklund A, Lindvall O, Limousin P, Quinn N, Foltynie T. Long-term clinical outcome of fetal cell transplantation for Parkinson disease: two case reports. JAMA Neurol. 2014 Jan;71(1):83-7. doi: 10.1001/jamaneurol.2013.4749.
- Background Kirkeby A, Grealish S, Wolf DA, Nelander J, Wood J, Lundblad M, Lindvall O, Parmar M. Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions. Cell Rep. 2012 Jun 28;1(6):703-14. doi: 10.1016/j.celrep.2012.04.009. Epub 2012 May 26.
- Background Kirkeby A, Nolbrant S, Tiklova K, Heuer A, Kee N, Cardoso T, Ottosson DR, Lelos MJ, Rifes P, Dunnett SB, Grealish S, Perlmann T, Parmar M. Predictive Markers Guide Differentiation to Improve Graft Outcome in Clinical Translation of hESC-Based Therapy for Parkinson's Disease. Cell Stem Cell. 2017 Jan 5;20(1):135-148. doi: 10.1016/j.stem.2016.09.004. Epub 2016 Oct 27.
- Background Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, Carrillo-Reid L, Auyeung G, Antonacci C, Buch A, Yang L, Beal MF, Surmeier DJ, Kordower JH, Tabar V, Studer L. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature. 2011 Nov 6;480(7378):547-51. doi: 10.1038/nature10648.
- Background Lang AE, Lozano AM. Parkinson's disease. First of two parts. N Engl J Med. 1998 Oct 8;339(15):1044-53. doi: 10.1056/NEJM199810083391506. No abstract available.
- Background Lang AE, Lozano AM. Parkinson's disease. Second of two parts. N Engl J Med. 1998 Oct 15;339(16):1130-43. doi: 10.1056/NEJM199810153391607.
- Background Lehnen D, Barral S, Cardoso T, Grealish S, Heuer A, Smiyakin A, Kirkeby A, Kollet J, Cremer H, Parmar M, Bosio A, Knobel S. IAP-Based Cell Sorting Results in Homogeneous Transplantable Dopaminergic Precursor Cells Derived from Human Pluripotent Stem Cells. Stem Cell Reports. 2017 Oct 10;9(4):1207-1220. doi: 10.1016/j.stemcr.2017.08.016. Epub 2017 Sep 21.
- Background Lewis SJ, Caldwell MA, Barker RA. Modern therapeutic approaches in Parkinson's disease. Expert Rev Mol Med. 2003 Mar 28;5(10):1-20. doi: 10.1017/S1462399403006008.
- Background Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Bjorklund A, Widner H, Revesz T, Lindvall O, Brundin P. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med. 2008 May;14(5):501-3. doi: 10.1038/nm1746. Epub 2008 Apr 6.
- Background Li JY, Englund E, Widner H, Rehncrona S, Bjorklund A, Lindvall O, Brundin P. Characterization of Lewy body pathology in 12- and 16-year-old intrastriatal mesencephalic grafts surviving in a patient with Parkinson's disease. Mov Disord. 2010 Jun 15;25(8):1091-6. doi: 10.1002/mds.23012.
- Background Li W, Englund E, Widner H, Mattsson B, van Westen D, Latt J, Rehncrona S, Brundin P, Bjorklund A, Lindvall O, Li JY. Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc Natl Acad Sci U S A. 2016 Jun 7;113(23):6544-9. doi: 10.1073/pnas.1605245113. Epub 2016 May 2.
- Background Lindvall O, Rehncrona S, Brundin P, Gustavii B, Astedt B, Widner H, Lindholm T, Bjorklund A, Leenders KL, Rothwell JC, Frackowiak R, Marsden D, Johnels B, Steg G, Freedman R, Hoffer BJ, Seiger A, Bygdeman M, Stromberg I, Olson L. Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson's disease. A detailed account of methodology and a 6-month follow-up. Arch Neurol. 1989 Jun;46(6):615-31. doi: 10.1001/archneur.1989.00520420033021.
- Background Mendez I, Dagher A, Hong M, Gaudet P, Weerasinghe S, McAlister V, King D, Desrosiers J, Darvesh S, Acorn T, Robertson H. Simultaneous intrastriatal and intranigral fetal dopaminergic grafts in patients with Parkinson disease: a pilot study. Report of three cases. J Neurosurg. 2002 Mar;96(3):589-96. doi: 10.3171/jns.2002.96.3.0589.
- Background Nolbrant S, Heuer A, Parmar M, Kirkeby A. Generation of high-purity human ventral midbrain dopaminergic progenitors for in vitro maturation and intracerebral transplantation. Nat Protoc. 2017 Sep;12(9):1962-1979. doi: 10.1038/nprot.2017.078. Epub 2017 Aug 31.
- Background Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V, Brin MF, Shannon KM, Nauert GM, Perl DP, Godbold J, Freeman TB. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease. Ann Neurol. 2003 Sep;54(3):403-14. doi: 10.1002/ana.10720.
- Background Palfi S, Gurruchaga JM, Ralph GS, Lepetit H, Lavisse S, Buttery PC, Watts C, Miskin J, Kelleher M, Deeley S, Iwamuro H, Lefaucheur JP, Thiriez C, Fenelon G, Lucas C, Brugieres P, Gabriel I, Abhay K, Drouot X, Tani N, Kas A, Ghaleh B, Le Corvoisier P, Dolphin P, Breen DP, Mason S, Guzman NV, Mazarakis ND, Radcliffe PA, Harrop R, Kingsman SM, Rascol O, Naylor S, Barker RA, Hantraye P, Remy P, Cesaro P, Mitrophanous KA. 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 Mar 29;383(9923):1138-46. doi: 10.1016/S0140-6736(13)61939-X. Epub 2014 Jan 10.
- Background Schade S, Mollenhauer B, Trenkwalder C. Levodopa Equivalent Dose Conversion Factors: An Updated Proposal Including Opicapone and Safinamide. Mov Disord Clin Pract. 2020 Mar 16;7(3):343-345. doi: 10.1002/mdc3.12921. eCollection 2020 Apr. No abstract available.
- Background Schuepbach WM, Rau J, Knudsen K, Volkmann J, Krack P, Timmermann L, Halbig TD, Hesekamp H, Navarro SM, Meier N, Falk D, Mehdorn M, Paschen S, Maarouf M, Barbe MT, Fink GR, Kupsch A, Gruber D, Schneider GH, Seigneuret E, Kistner A, Chaynes P, Ory-Magne F, Brefel Courbon C, Vesper J, Schnitzler A, Wojtecki L, Houeto JL, Bataille B, Maltete D, Damier P, Raoul S, Sixel-Doering F, Hellwig D, Gharabaghi A, Kruger R, Pinsker MO, Amtage F, Regis JM, Witjas T, Thobois S, Mertens P, Kloss M, Hartmann A, Oertel WH, Post B, Speelman H, Agid Y, Schade-Brittinger C, Deuschl G; EARLYSTIM Study Group. Neurostimulation for Parkinson's disease with early motor complications. N Engl J Med. 2013 Feb 14;368(7):610-22. doi: 10.1056/NEJMoa1205158.
- Background Schupbach WM, Maltete D, Houeto JL, du Montcel ST, Mallet L, Welter ML, Gargiulo M, Behar C, Bonnet AM, Czernecki V, Pidoux B, Navarro S, Dormont D, Cornu P, Agid Y. Neurosurgery at an earlier stage of Parkinson disease: a randomized, controlled trial. Neurology. 2007 Jan 23;68(4):267-71. doi: 10.1212/01.wnl.0000250253.03919.fb. Epub 2006 Dec 6.
- Background Tiklova K, Nolbrant S, Fiorenzano A, Bjorklund AK, Sharma Y, Heuer A, Gillberg L, Hoban DB, Cardoso T, Adler AF, Birtele M, Lunden-Miguel H, Volakakis N, Kirkeby A, Perlmann T, Parmar M. Single cell transcriptomics identifies stem cell-derived graft composition in a model of Parkinson's disease. Nat Commun. 2020 May 15;11(1):2434. doi: 10.1038/s41467-020-16225-5.
- Background Voon V, Krack P, Lang AE, Lozano AM, Dujardin K, Schupbach M, D'Ambrosia J, Thobois S, Tamma F, Herzog J, Speelman JD, Samanta J, Kubu C, Rossignol H, Poon YY, Saint-Cyr JA, Ardouin C, Moro E. A multicentre study on suicide outcomes following subthalamic stimulation for Parkinson's disease. Brain. 2008 Oct;131(Pt 10):2720-8. doi: 10.1093/brain/awn214.
- Background Wider C, Pollo C, Bloch J, Burkhard PR, Vingerhoets FJ. Long-term outcome of 50 consecutive Parkinson's disease patients treated with subthalamic deep brain stimulation. Parkinsonism Relat Disord. 2008;14(2):114-9. doi: 10.1016/j.parkreldis.2007.06.012. Epub 2007 Sep 5.
- Background Wijeyekoon R, Barker RA. Cell replacement therapy for Parkinson's disease. Biochim Biophys Acta. 2009 Jul;1792(7):688-702. doi: 10.1016/j.bbadis.2008.10.007. Epub 2008 Oct 25.
- Background Witt K, Daniels C, Reiff J, Krack P, Volkmann J, Pinsker MO, Krause M, Tronnier V, Kloss M, Schnitzler A, Wojtecki L, Botzel K, Danek A, Hilker R, Sturm V, Kupsch A, Karner E, Deuschl G. Neuropsychological and psychiatric changes after deep brain stimulation for Parkinson's disease: a randomised, multicentre study. Lancet Neurol. 2008 Jul;7(7):605-14. doi: 10.1016/S1474-4422(08)70114-5. Epub 2008 Jun 4.
- Background Lansing AE, Ivnik RJ, Cullum CM, Randolph C. An empirically derived short form of the Boston naming test. Arch Clin Neuropsychol. 1999 Aug;14(6):481-7.
- Paul G, Bjartmarz H, Kirkeby A, Nelander J, Smith R, Kayhanian S, Evans A, Harry B, Cutting E, Fazal S, Lao-Kaim NP, van Vliet T, Ullen S, Grubor I, Hansson O, Piccini P, Lindvall O, Bjorklund A, Widner H, Parmar M, Barker RA. Human embryonic stem cell-derived dopaminergic cells for Parkinson's disease: a phase 1/2 open-label trial. Nat Med. 2026 Jul 9. doi: 10.1038/s41591-026-04525-0. Online ahead of print.
- Paul G, Bjartmarz H, Bjorklund A, Cutting E, Evans A, Harry B, Hansson O, Kayhanian S, Kirkeby A, Lao-Kim N, Lindvall O, Nelander J, Piccini P, Smith R, Ullen S, Van Vliet T, Widner H, Parmar M, Barker RA. STEM-PD trial protocol: a multi-centre, single-arm, first-in-human, dose-escalation trial, investigating the safety and tolerability of intraputamenal transplantation of human embryonic stem cell-derived dopaminergic cells for Parkinson's disease. BMJ Open. 2025 Dec 30;15(12):e107597. doi: 10.1136/bmjopen-2025-107597.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | STEM-PD | Cell therapy | 3.54e+06 cells | Other |
| Subject | STEM-PD | Cell therapy | 7.08e+06 cells | Other |