Cell therapies for Parkinson’s disease
Posted in Regeneration Series on 10th Sep 2014
Introduction to the Regeneration Series
In this issue of ACNR we start a new series on regenerative therapies. We hope to capture some of the new developments in this fast expanding field, a field that includes the prospect of stem cell based therapies in the treatment of a range of neurodegenerative disorders. In this first article we have a fabulous overview of cell therapies for Parkinson’s disease from the team in Lund, Sweden, where the pioneering work developing this whole approach started over 30 years ago.
Roger Barker, Series Editor.
Cell therapies for Parkinson’s disease
- Grafted fetal dopaminergic cells can provide long-lasting benefit in PD patients
- For large-scale application, human embryonic stem cells, induced pluripotent cells and induced neurons are currently being developed
- Unique medical risks and ethical issues are connected with these new cell sources
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting an estimated 10 million people worldwide and approximately 100,000 people in the UK.1 Progressive loss of mainly (but not only) dopaminergic neurons, located in the substantia nigra and projecting to the striatum, leads to a striatal dopamine deficit, resulting in cardinal motor symptoms such as rigidity, bradykinesia and tremor. This relatively focal neuronal degeneration makes PD a good candidate for cell replacement therapies.
Proof-of-principle from foetal midbrain transplants
Studies in animal models of PD using foetal DA neurons, have shown that neuronal replacement and partial reconstruction of damaged neuronal circuits is possible. This work formed the basis for pioneering foetal cell transplantation trials in PD patients in 1987 in Lund, Sweden.2 Since then, many more trials have taken place worldwide with patients receiving foetal cell grafts. Trials were initially performed in a small group of patients using open-label study designs, and results were variable, spanning from no effect to impressive and long-lasting clinical benefit.3 Generally, in the open labelled trials approximately two thirds of the patients showed substantial improvement, whereas one third did not (for review see reference 3). Mean improvement in the United Parkinson’s disease rating sale (UPDRS, shown in % with 95% CI)) ranged from -43% (-65.02-21.38, n=12),3,4 37.79% (-49.95 to -25.64, n=14)3,5 to -11.47 (-21.83 to -1.12, n=10).3,6,7 Even though results were variable, the trials provided important proof-of-concept that a long-lasting and sustained clinical improvement is achievable with foetal cell transplantation. The clinical improvement was paralleled by an unbiased increase in dopamine transporter (DAT)-binding, a marker for striatal dopaminergic fibres. The increases have been shown to persist for up to 18 years after grafting, and in some cases have made pharmacological medication almost unnecessary.8 However, two NIH-sponsored, double-blind, placebo-controlled clinical trials performed in the USA failed to show clinical benefit.9,10 These studies also reported that a considerable proportion of patients (15%, 5/3310 and 57% 13/239) developed dyskinesias even in the OFF state (without medication). However, when these studies were further analysed, patients < 60 years10 or with less severe disease at baseline, did show a significant improvement,9 with similar observations in PET imaging results.
The current state – TransEuro
In order to gain an insight into what factors might determine a positive or negative clinical outcome post-transplantation, all available data from the open-label and double-blind, placebo-controlled trials were re-analysed with the aim of identifying clinical and PET-imaging variables that could identify a patient population with a better predicted outcome of this treatment.3 After careful meta-analysis of all trials conducted, the variation in results has been mainly attributed to major methodological differences in cell preparation and trial design. In addition, tissue preparation protocols, surgical methodology, graft composition, and immunosuppression strategies were carefully compared between centres. This analysis resulted in a new clinical trial design, sponsored by the European Union (NCT01898390; www.transeuro.org.uk) with the aim to develop an efficacious and safe treatment methodology for individuals suffering from PD using foetal cell based treatments.
Cell sources of the future
However, one has to keep in mind that even though foetal cells obtained from aborted embryos (Figure 1a) can be clinically effective,3 they are limited in availability, difficult to maintain at a high quality standard and are riddled with a number of ethical and logistical problems. In order to move to large-scale applications so that many patients can be treated, readily available, renewable cells that can be produced and stored in large quantities are needed. Thus the development of efficient protocols for the generation of midbrain dopamine neurons, from renewable cell sources, is an absolute necessity.
Figure 1 outlines the different cell sources currently being developed for clinical use.
Among the different stem cell sources available, human embryonic stem cells (hESCs, Figure 1b) have advanced the most with respect to clinical application in PD. Human ESCs cells are derived from pre-implantation blastocysts. They are distinguished by their ability to self renew and to differentiate into any cell type of the body (pluripotency). hESCs can be used to obtain dopamine neurons that survive well, and that can restore functional deficits when transplanted to rodent and primate models of PD.11,12 In 2006, the Nobel Prize was awarded to Shinya Yamanaka who demonstrated that fully differentiated cells could be reprogrammed into an induced pluripotent stem cell (iPS, Figure 1c).13 iPS cells are very similar to ESCs and share their characteristics of self-renewal and pluripotency. iPS cells derived from human fibroblasts can, like hESCs, be differentiated into dopamine neurons,11 thus creating the possibility of obtaining patient specific cells for grafting. However, with both these pluripotent stem cell types there is a concern about their safety as incomplete differentiation may result in contaminating pluripotent stem cells remaining in the cell preparation that can cause tumours and overgrowths after transplantation.14
Recently, a new methodology for reprogramming functional dopamine neurons from skin cells has emerged15,16 that circumvents the safety issues associated with pluripotent stem cells. The method is called direct neural conversion.17 Here, skin cells are directly converted into functional and sub-type specific neurons without passing via a pluripotent stem cell intermediate (Figure 1d). The resulting cells, termed induced neurons (iNs) are thus a promising alternative to iPS cells for generating cells for therapy. As for iPS cells, it is possible to obtain immunologically matched cells for grafting if fibroblasts are collected from the patient themselves or from a matched donor.
When it comes to using iN cells in the clinic, several concerns related to the method for reprogramming the cells still exist. The technology makes use of lentiviral vectors and although such vectors have recently been successfully used in clinical trials,18,19 one has to keep in mind that they integrate into the host cell genome and thus carry the ability to affect gene expression levels of endogenous genes. This in turn can lead to genomic changes that could have unwanted consequences on cell characteristics, including uncontrolled proliferation after transplantation. Therefore, before such cells can be used in a clinical trial, it is essential to establish clinically compatible reprogramming methodology in order to provide a safe and viable alternate cell source.
Ethical issues in the context of new cell sources
Stem cells and stem cell-based therapies are much observed by the media. This may create unrealistic expectations among the public, including patients and their caregivers. When stem cell research, combined with gene therapy and biobanking is taken to the clinic, many ethical issues to consider arise. This includes unique medical risks related to cell type specific issues (genetic modification, tumour risk etc. as outlined above) as well as cell processing and delivery method, and with possible conflicting requirements of traceability and anonymity.20
Other ethical issues concern informed consent and a number of regulatory hurdles in bringing new cell sources to the clinic. When new therapies are developed, uncertainties and gaps in knowledge make it difficult to assess risks and benefits affecting the ability to obtain a truly free and informed consent, especially for the first-in-human trials. Adequate patient information is also a major challenge as the perspective of what is regarded as an ‘effective treatment’ and what risks and benefits are considered important may differ considerably between researchers, clinicians, patients and their relatives.21,22 Furthermore, questions of access to the new treatment and issues of priority setting and financing may be raised.
The problems indicated above need to be examined and discussed, taking what is said in existing national and international guidelines as a point of departure, and updating of such guidelines whenever necessary, before we can take these therapies into the first clinical trials in humans. The successful translation of innovative stem cell therapies to the clinic will not only depend on scientific progress, but also on how we address the ethical and socio-political challenges that these treatments entail. A parallel can be drawn with the initial hope and excitement surrounding the first foetal transplants and the resulting media response when they did not turn out to be widely-replicated, or the recent controversy over the funding of human embryonic stem cell research in Europe.
- Dorsey ER, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 2007;68(5):384-6.
- Lindvall O, et al. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson’s disease. Science 1990;247(4942):574-7.
- Barker RA, et al. Fetal dopaminergic transplantation trials and the future of neural grafting in Parkinson’s disease. Lancet Neurol 2013.12(1):84-91.
- Mendez I, et al. Simultaneous intrastriatal and intranigral fetal dopaminergic grafts in patients with Parkinson disease: a pilot study. Report of three cases. J Neurosurg 2002;96(3):589-96.
- Widner H, et al. Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). N Engl J Med 1992;327(22):1556-63.
- Defer GL, et al. Long-term outcome of unilaterally transplanted parkinsonian patients. I. Clinical approach. Brain 1996;119(Pt 1):41-50.
- Peschanski M, et al. Bilateral motor improvement and alteration of L-dopa effect in two patients with Parkinson’s disease following intrastriatal transplantation of foetal ventral mesencephalon. Brain 1994;117( Pt 3):487-99.
- Kefalopoulou Z, et al. Long-term clinical outcome of fetal cell transplantation for Parkinson disease: two case reports. JAMA Neurol 2014;71(1):83-7.
- Olanow C.W, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol 2003;54(3):403-14.
- Freed C.R, et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med 2001;344(10):710-9.
- Kriks S, et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature 2011;480(7378):547-51.
- Kirkeby, A, et al. Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions. Cell Rep 2012;1(6):703-14.
- Takahashi K, S Yamanaka. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006;126(4):663-76.
- Tabar V, Studer L. Pluripotent stem cells in regenerative medicine: challenges and recent progress. Nat Rev Genet 2014;15(2):82-92.
- Pfisterer U, et al. Direct conversion of human fibroblasts to dopaminergic neurons. Proc Natl Acad Sci U S A 2011;108(25):10343-8.
- Caiazzo M, et al. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature, 2011;476(7359):224-7.
- Vierbuchen T, et al. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 2010;463(7284):1035-41.
- Biffi A, et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 2013;341(6148):1233158.
- Aiuti A, et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science 2013;341(6148):1233151.
- Hermeren G. Ethical challenges for using human cells in clinical cell therapy. Prog Brain Res 2012;200:17-40.
- Fargel M, et al. Treatment of Parkinson’s disease: a survey of patients and neurologists. Clin Drug Investig 2007;27(3):207-18.
- Mathews DJ. Deep brain stimulation, personal identity and policy. Int Rev Psychiatry 2011;23(5):486-92.
To cite: Parmar M, Hug K, Bjartmarz H, Jakobsson J, Hermerén G, and Paul G.
Published online 10/9/14