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Cell transplantation research in HD and PD

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Alexandra Callaway

Rehabilitation Engineer


06 December 2018


At the PMG Conference 2018, Dr Sarah Mason (University of Cambridge), presented a talk entitled Cell transplantation research into Huntington’s and Parkinson’s diseases outlining the pathological and clinical features of each, and current treatments for both, before expanding on what cell replacement therapies are, and how they have been used in trials for Parkinson’s Disease (PD) and Huntington’s Disease (HD) to date.

HD and PD are both progressive, neurodegenerative disorders involving the basal ganglia, categorised largely by the effect they have on movement. HD predominantly affects the caudate and putamen of the basal ganglia, which primarily mediate motor function and certain executive cognitive functions, in addition to involvement in the reward system (Malenka, et al., 2009). Outputs from this region are mainly composed of medium spiny neurons, described as GABAergic neurons, which have inhibitory action at receptors; the loss of these neurons gives rise to the hyperkinetic motor effects (Siegel & Sapru, 2014). Dr Mason described the resultant symptoms, which include changes to saccadic eye movements, unusual posturing, wide gait, poor balance, choreic movements, difficulty swallowing and slurred speech. In contrast, Parkinson’s disease affects a different part of the basal ganglia: the pars compacta of the substantia nigra, with the most prominent function of this region being motor function. The loss of dopaminergic neurons in this region leads to a reduction in dopamine in the striatum (Siegel & Sapru, 2014) giving rise to a variety of symptoms. Symptoms highlighted during the talk were stooped posture, rigidity, flexed elbows and wrists, trembling of extremities, shuffling, short-stepped gait, slightly flexed hips & knees, reduced arm swinging, forward tilt of trunk and masked facial expressions.

Symptoms of the two diseases are not restricted to motor function. Non-motor symptoms can include sleep abnormalities, hallucinations, depression, anxiety, apathy and cognitive problems. Combinations of these symptoms often cause a significant impact on a patient’s everyday life and, crucially, on their independence. Unfortunately, there are currently no disease modifying therapies, therefore treatment relies heavily on pharmaceuticals (also, in the case of PD, deep brain stimulation) which have associated side effects and decreased usefulness over time. As such, finding long-term management for these problems is greatly needed to improve the quality of life of these patients.  

Cell transplantation was the key novel and experimental approach discussed by Dr Mason.  Its aim is to replace lost neurons in Parkinson’s and Huntington’s disease by replacing the dead cells with healthy ones to restore functional loss.  It was highlighted that this form of therapy works best for certain conditions where:

  • there is a focal loss of a defined set of neurons
  • the affected neurons have relatively non-specific modulatory actions
  • the function of the neurons doesn’t depend on precise and complex patterned connectivity

Previously the source of tissue for cell transplantation had been from ventral mesencephalic tissue taken from donor embryos of terminated pregnancies.  The tissue is homogenised for transplantation, then injected into regions of the basal ganglia, along with immunosuppressants to reduce the risk of rejection (Angot, et al., 2010).  

 

Clinical Trials

Dr Mason (pictured) gave an overview of several clinical trials, with corresponding results, carried out to date.  The first trial for cell transplantation in PD began in 1987 in Sweden and was an “open label study” involving a 15-patient cohort.  The results were variable with 2 patients showing positive effects.  Double-blind controlled clinical trials have since been carried out with PD with mixed results: a 34-patient trial concluding in 2003 that, based on their results, “foetal nigral transplantation currently cannot be recommended as a therapy for PD” (Olanow, et al., 2003); a 40-patient trial concluding in 2001 that by using human embryonic dopamine neurons, grafts did survive in patients, and some positive results were seen in younger patients (Freed, et al., 2001).   

The first trials for HD began in the late 1990s.  Dr Mason told us that there have been 7 open-label studies worldwide which have helped establish the safety, feasibility and tolerability of cell transplantation in HD. However, the efficacy results are much less conclusive than for PD.  In certain patients, Huntington’s “dots” (pathologies) were visible in the grafts after time, raising the question of what allowed them to transfer into the healthy tissue.

Dr Mason explained that it is possible to successfully graft transplanted cells which survive, although functional restoration is not consistently observed in all patients.  There are several factors that could influence the outcome of these grafts such as: tissue survival; protocols for preparing the tissue; variation in the source tissue supplied to each patient; different patient populations e.g. age, severity of disease and rate of progression; other treatment a patient may be undergoing related to disease and lifestyle.  It can be difficult to determine which aspects are most influential, and whether this would differ from patient to patient. 

TRANSEURO is a research consortium consisting of experts that include clinicians, scientists, industrial partners, ethicists and patient representatives.  Their principal objective is to “develop an efficacious and safe treatment methodology for patients suffering from PD using cell-based treatments” (TRANSEURO, 2017).  They are trying to answer questions about how certain factors influence the treatment, for example:

Are there some patients who are more likely to benefit and less likely to experience side-effects from cell replacement therapies? 

This is being assessed by reviewing all current data from existing trials for patients meeting certain criteria

Does the way the tissue is prepared influence the efficacy of the trials and the likelihood of side-effects?

This study currently has 11 patients that have undergone a new approach and are being followed up.

One of the key limitations regarding the foetal tissue approach concerns the ethics surrounding sourcing and using of the tissue, and whether the supply is sustainable.  In an attempt to address these problems, alternative sources have been explored. 

My colleagues and I found the talk very interesting and thought-provoking and, although not directly related to our work at the wheelchair service, we do see many clients with life-limiting conditions. It was interesting therefore to see an alternative approach to treatment.  The reason for finding alternative treatments for PD and HD is largely centred on improving the quality of life of patients. Working in posture and mobility services we are constantly trying to improve a patient’s quality of life, through clinical assessment, equipment provision, modification and adaptation, postural management, and by identifying areas where a need is not being met.  We try to achieve this by improving independence and attempting to reduce the impact of the condition on a patient’s everyday life; these are shared goals with cell transplantation therapies. 

Thank you to Dr Mason for delivering this talk which allowed me to see potential interventions that lie outside my own field of work.  It demonstrated the importance of research in trying to improve patient treatment.  Unfortunately we seldom get time or funding to do research - but it has encouraged me to question more when there is a need not met, or where there may be opportunities for further work.

 

References

Angot, E. et al., 2010. Are synucleinopathies prion-like disorders?. The Lancet (Neurology), 9(11), pp. 1128-38.

Freed, C. et al., 2001. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. The New England Journal of Medicine, 10(344), pp. 710-9.

Malenka, R., Nestler, E. & Hyman, S., 2009. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience. 2nd ed. New York: McGraw-Hill Medical.

Olanow, C. et al., 2003. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease. Annals of Neurology, 3(54), pp. 403-14.

Siegel, A. & Sapru, H. N., 2014. Essential Neuroscience. 3rd ed. s.l.:Wolters Kluwer Health.

TRANSEURO, 2017. Innovative Approach for the Treatment of Parkinson's Disease. [Online]
Available at: http://www.transeuro.org.uk/
[Accessed 22 October 2018].

 

Photography by Jonathan Rourke

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