Bringing advanced therapy medicinal products (ATMPs) for Parkinson’s Disease to the clinic: The investigator’s perspective

J PARKINSONS Dis. – 2021;11(s2):S129-S134

Barker RA, Cutting EV, Daft, DM.

In this article, briefly discusses two key questions investigator’s should they ask themselves before embarking on cell and gene treatments in Parkinson’s disease. Firstly, why are they doing it, and, secondly, do they understand what is needed to conduct a clinical trial with that product.

The immunogenicity of midbrain dopaminergic neurons and the implications for neural grafting trials in Parkinson’s disease

NEURONAL SIGNAL – 13 September 2021, 13;5(3)

Qarin S, Howlett SK, Jones JL, Barker RA.

Guidelines for Stem Cell Research and Clinical Translation: The 2021 update

STEM CELL REPORTS – 2021 Jun 8;16(6):1398-1408

Lovell-Badge R, Anthony E, Barker RA, Bubela T, Brivanlou AH, Carpenter M, Charo RA, Clark A, Clayton E, Cong Y, Daley GQ, Fu J, Fujita M, Greenfield A, Goldman SA, Hill L, Hyun I, Isasi R, Kahn J, Kato K, Kim JS, Kimmelman J, Knoblich JA, Mathews D, Montserrat N, Mosher J, Munsie M, Nakauchi H, Naldini L, Naughton G, Niakan K, Ogbogu U, Pedersen R, Rivron N, Rooke H, Rossant J, Round J, Saitou M, Sipp D, Steffann J, Sugarman J, Surani A, Takahashi J, Tang F, Turner L, Zettler PJ, Zhai X.

A summary of the key updates to the International Society for Stem Cell Research Guidelines for Stem Cell Research.

Impact of α-synuclein pathology on transplanted hESC-derived dopaminergic neurons in a humanized α-synuclein rat model of PD

PNAS – 15 June 2020

Hoban D B, Shrigley S, Mattsson B, Breger L S, Jarl U, Cardoso T, Nelander Wahlestedt J, Luk K C, Björklund A, Parmar M.

In this study, we developed and characterized a new animal model for Parkinson’s disease,  which better resembles the behavioural and pathological features of the disease. We transplanted stem cell-derived dopamine neurons into this model and show that they survive, innervate, and integrate into the host brain, but that some grafted cells acquired pathological features at later time points. This has previously been observed in some patients who received foetal dopamine grafts, but has so far been difficult to model in animals.

Single cell transcriptomics identifies stem cell-derived graft composition in a model of Parkinson’s disease


Tiklová  K, Nolbrant S, Fiorenzano A, Björklund Å K, Sharma Y, Heuer A, Gillberg L, Hoban D B, Cardoso T, Adler A F, Birtele M, Lundén-Miguel H, Volakakis N, Kirkeby A, Perlmann T, Parmar M.

In this study, we take a closer look at the cell composition of the dopaminergic grafts after long term maturation in the rat brain. We use a technology known as single cell RNA sequencing to identify the cell types present in both stem cell-derived grafts and foetal cell-derived grafts. From these experiments we could confirm previous conceptions of the graft composition, but also discover an underappreciated cellular diversity of the dopaminergic transplant.

Cell Reports. VOLUME 28, ISSUE 13, P3462-3473.E5, 24 September 2019

Adler A. F., Cardoso T., Nolbrant S., Mattsson B., Hoban D.B., Jarl U., Nelander Wahlestedt J., Grealish Sh., Björklund A., Parmar M.

In this study, we show that factors which are intrinsic to the stem cell-derived dopamine neurons determine the innervation pattern of the cells following transplantation. We also show that these cells are synaptically connected with the types of neurons that are known to regulate endogenous dopamine neurons in the brain and that this holds true even when the cells are transplanted to their site of action instead of the midbrain where dopamine neurons would normally reside.

Designing stem-cell-based dopamine cell replacement trials for Parkinson’s disease

NATURE MEDICINE – 2019 Jul;25(7):1045-1053. PMID: 31263283

Barker RA; TRANSEURO consortium

In this publication, the investigators share the rationale for the design of, along with the lessons the investigators learned during the TRANSEURO trial; transplants of dopamine-producing cells derived from human pluripotent stem cells.

Target-specific forebrain projections and appropriate synaptic inputs of hESC-derived dopamine neurons grafted to the midbrain of parkinsonian rats 

J COMP NEUROL – 14 Juli 2018

Cardoso T, Adler AF, Mattsson B, Hoban DB, Nolbrant S, Wahlestedt JN, Kirkeby A, Grealish S, Björklund A, Parmar M.

In this study, we show that stem cell-derived dopaminergic progenitors  transplanted into the rat midbrain have the capacity to innervate far away forebrain regions and integrate into the host neuronal circuitry,  in a way that resembles that of endogenous dopamine neurons. We also show that dopamine neurons derived from both stem cells and foetal cells have the potential to send axons to the part of the brain that regulates motor function, and that this re-innervation is associated with functional recovery of motor deficits  in an animal model of Parkinson’s disease.

Generation of high-purity human ventral midbrain dopaminergic progenitors for in vitro maturation and intracerebral transplantation

NATURE PROTOCOLS 12 – 31 August 2017 (published online)

NolbrantS, Heuer A, Parmar M, Kirkeby A.

In this study, we developed a refined and clinically adapted version of our protocol for generating dopaminergic progenitors from pluripotent stem cells. We also show how these cells can be cryopreserved and thawed for transplantation on demand, which is essential for bringing the cells into a clinical setting. The transplantation of these cryopreserved cells into an animal model of Parkinson’s disease results in dopamine-rich grafts and a recovery of the motor deficits.

Predictive Markers Guide Differentiation to Improve Graft Outcome in Clinical Translation of hESC-Based Therapy for Parkinson’s Disease

CELL STEM CELL – 27 October 2016

Kirkeby A, Nolbrant S, Tiklova K, Heuer A, Kee N, Cardoso T, Rylander Ottosson D, Lelos M.J, Rifes P, Dunnett S.B, Grealish S, Perlmann T, Parmar M

In this study, we used data collected from over 30 batches of transplanted dopaminergic progenitors to identify new predictive markers that correlated with successful transplantation outcomes in terms of dopamine neuron numbers and reversal of motor deficits in an animal model of Parkinson’s disease. These genetic markers were then used to refine the protocol for making dopaminergic progenitors in order to better predict a successful transplantation outcome before transplanting the cells.

Monosynaptic Tracing using Modified Rabies Virus Reveals Early and Extensive Circuit Integration of Human Embryonic Stem Cell-Derived Neurons

STEM CELL REPORTS – 9 June 2015 (4(6):975-83)

Grealish S, Heuer A, Cardoso T, Kirkeby A, Jönsson M, Johansson J, Björklund A, Jakobsson J, Parmar M.

In this study, we use a modified rabies virus to map the connections between the transplanted dopamine neurons and the neurons in the host brain. The integration of the transplanted neurons into their new environment was rapid and extensive and resembles that of endogenous neurons.

Human ESC-Derived Dopamine Neurons Show Similar Preclinical Efficacy and Potency to Fetal Neurons when Grafted in a Rat Model of Parkinson’s Disease

CELL STEM CELL – 6 November 2014 (15(6): 653-665)

Grealish S, Diguet E, Kirkeby A, Mattsson B, Heuer A, Bramoulle Y, Van Camp N, Perrier A.L., Hantraye P,  Björklund A, Parmar M.

In this study, we show long term survival and function of transplanted dopamine neurons in a rat model of Parkinson’s disease. The function of the cells was assessed using MRI and PET imaging techniques, similar to what will be used in the clinical trial. By looking at the innervation that the new neurons provide, we could determine that they project sufficiently long distances for what will be required in the larger human brain. We also show that the function of the stem cell-derived dopamine neurons is comparable to the foetal-derived dopamine neurons that have been used previously in clinical trials.

Generation of Regionally Specified Neural Progenitors and Functional Neurons from Human Embryonic Stem Cells under Defined Conditions

CELL REPORTS – 26 May 2012

Kirkeby A, Grealish S, Wolf D A, Nelander J, Wood J, Lundblad M, Lindvall O, Parmar M.

In this study, we show how dopaminergic progenitors  can be generated from pluripotent stem cells in 16 days. After transplanting these cells into rats,  the progenitors matured into dopamine neurons that were able to release dopamine and reversed the motor deficits in a Parkinson’s disease animal model.