Date: 3rd March 2021
More than 10 million people worldwide are living with Parkinson’s disease (PD) which is caused by the degeneration of dopamine (DA) neurons in the midbrain. Typically patients in the early stages of PD are treated with drugs like L-DOPA, which pass into the brain and are converted into dopamine. However, such treatments are often only effective temporarily and treat symptoms rather than the cause. Furthermore, side-effects from the drugs means that drug regimes are complex and require frequent fine tuning. Now, scientists have shown that the transplant of autologous neurons derived from induced pluripotent stem cells (iPSCs) can relieve motor and depressive symptoms that arise from PD.
Dopamine is a key neurotransmitter that helps coordinate the millions of nerve and muscle cells and is involved in the control of executive function, motor control, motivation, arousal, reinforcement, and reward. In PD the disrupted signals make it progressively harder to coordinate muscles, and manifests as tremors, stiffness, poor balance and co-ordination as well as slow spontaneous movements.
The efforts to progress a dopamine cell replacement therapy for PD have spanned over more than three decades. Experiments to alleviate symptoms using transplantation of foetal mesencephalic tissues have shown improvements to motor symptoms in animals, but results have been mixed due to the use of tissue that has been undefined and unstandardised.
Now, researchers at the University of Wisconsin-Madison, US, led by Su-Chun Zhang, have demonstrated that autologous cell transplant therapy derived from iPSCs, delivered to the striatum of PD monkey brains, reversed motor and depressive signs.
The team started by establishing five rhesus iPSC (RhiPSC) lines from five of the ten rhesus monkeys, which were induced to differentiate to midbrain DA neural progenitors. Then they generated a stable hemiparkinsonian model in these animals, and to mimic the clinical setting the DA progenitors were transplanted 1-3 years after PD intoxication, and without the use of immunosuppression. Around 5.5–6 million total cells were transplanted into allogenic animals, whilst 11-22 million total cells were transplanted into autologous animals. Due to differences in differentiation efficiencies this was estimated to deliver comparable numbers of DA neurons to each animal.
Data was collected over 24 months and the autologous graft cohort showed signs of recovery whilst the allogenic group remained unchanged. Here, they saw an increase in amount of movement of the autologous animals, and this was quicker and more fluid. Their gait was less laboured, climbing skills were greatly enhanced and the fine motor skills such as grasping also improved.
Mental health symptoms alleviated
Anxiety and depression are two of the most common mental health symptoms that affect PD patients. Here, the PD monkeys also showed signs of mood disorders. In the autologous group, the anxious pacing and lack of motivation that was seen before grafting, was resolved in a significant proportion of this cohort but not in the allogenic group.
Engraftment and DA activity success
Whilst, the data indicated a positive response to the autologous cell grafts for alleviating symptoms the team wanted to assess DA activity and engraftment success. Here, they used Positron Emission Tomography (PET), which is a validated method for monitoring PD progression.
They found DA activity increased only in the autologous group, within a year post treatment their dopamine levels had up to tripled. Histological analysis showed that allogenic grafts often had a clear boundary, whereas autologous grafts usually merged in to the host tissues. This group, showed persistent DA neurons and their fibres extended at length, this was observed for up to 2 years after transplantation. The lack of grafts in some of the allogenic cohort was attributed to the immunologic response, in these animals higher immunoreactivity was observed around the grafts when compared to the autologous group.
Lastly, the group determined that mathematical modelling showed a correlation between the number of surviving DA neurons with PET signal intensity and behaviour recovery.
Conclusions and future applications
The work presented here shows that autologous cell transplantation can substantially mitigate the debilitating movement and depression symptoms associated with PD.
Whilst allogenic transplants were safe and represent a simplified method to produce a large quantity of standardised cells – reducing costs and time to treatment – the disadvantage lay in the small or absent grafts without immunosuppression. Translation to the clinic for this type of transplant would then require immunosuppressing drugs at least for a period of time. Therefore, considering the increased waiting time and associated cost needed for the iPSC workflow for autologous grafts together with the absent complication of evoking the immune response, autologous transplants represent a more attractive clinical option. Furthermore, ongoing technological advances are likely to accelerate this further, resulting in a more efficient and cost effective therapy.
On the back of such promising results the Zhang lab hope to begin work on applications for human patients soon, with the predictive mathematical modelling playing a key role in determining the relationship between symptom improvement, graft size and the subsequent dopamine production.
This preclinical study will add weight to the novel and innovative technologies that are starting to filter through for the treatment of PD. We have recently reported the use of smartwatches to continuously track fluctuation in resting tremors and other involuntary movements and would likely make a powerful tool to effectively monitor the efficacy of therapies such autologous cell transplants.
Researchers have also used machine learning to predict multiregional dynamics of brain networks in response to temporally varying patterns of ongoing microstimulation, enabling precise neuromodulation for the treatment of disease – this type of deep brain stimulation is often used for the treatment of PD symptoms. This is an exciting area of personalised medicine, which autologous cell transplants would also contribute to. Personalised medicine offers tailored therapies which drive the best responses, highest safety margins and facilitates better patient care. For diseases with complex pathologies such as PD this is likely to provide the best patient outcomes.
A final consideration is the prevention of such diseases. Here, there has been progress made in the form of nanoparticles delivering gene silencing drugs to inhibit the expression of key neurodegenerative players. Whilst, not the only cause of PD, traumatic brain injury (TBI) has been implicated is the development of the disease, timely treatment of TBI could reduce the incidents of PD later in life.
Whilst current clinical treatment options are limited for PD, our increased understanding of PD pathologies is expanding such that novel therapeutic avenues are rapidly emerging. Together, these new tools will drive the evolution of PD management over the coming years, providing hope to those patients suffering from debilitating symptoms.
For more information please see the press release from the University of Wisconsin-Madison
Tao, Y., S. C. Vermilyea, M. Zammit, J. Lu, M. Olsen, J. M. Metzger, L. Yao, Y. Chen, S. Phillips, J. E. Holden, V. Bondarenko, W. F. Block, T. E. Barnhart, N. Schultz-Darken, K. Brunner, H. Simmons, B. T. Christian, M. E. Emborg and S.-C. Zhang (2021). “Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys.” Nature Medicine.
https://doi.org/10.1038/s41591-021-01257-1
