Cell replacement therapy in Parkinson's disease

Volume Cell replacement therapy in Parkinson's disease Tom Robert Barrow 0 1 0 Supervisor: Dr Jane L. Saffell, Imperial College London , South Kensington, London, SW7 2AZ, England 1 Imperial College London , South Kensington, London SW7 2AZ, England With an ageing population, the incidence of Parkinson's disease is increasing. The disease has an overwhelming impact on those it affects and has a limited repertoire of drug therapies available, each with problematic side effects. Stem cell therapy is an exciting prospect in the treatment of several neurodegenerative conditions. This article takes an in depth look at the great potential of cell replacement therapy for Parkinson's disease, providing supporting evidence for investment in this potential treatment. After considering the basis for cell replacement therapy, the article looks at stem cells of different origins, summing up the strengths and limitations of each in relation to Parkinson's disease. In addition to highlighting the cell replacement therapies available, the article also provides a chronology of research into this emerging field over the last 30 years. Parkinson's disease; stem cells; cell replacement therapy; stem cell transplant; regeneration; clinical trials Introduction In 1984, Muhammad Ali, the former heavyweight champion of the world, was diagnosed with Parkinsons disease (PD); he began to experience tremors and a slowness in his movements, known as bradykinesia. After years of battling with the disease, Ali now has difficulty speaking and coordinating his movements but remains an inspiration to many (The Guardian, 2009; Tim Dahlberg, The Seattle Times, 2012). PD affects around 6.3 million people worldwide, with most diagnoses being made over the age of 60. It is currently an incurable disease associated with irreversible loss of the dopaminergic neurons in the substantia nigra (SN) and striatum, which are structures of the basal ganglia, essential for fine motor control and initiation of movement (Barker, Cicchetti and Neal, 2012). As the central nervous system (CNS) has a limited capacity to regenerate its neurons, this has a devastating effect on motor function. Consequently, the four hallmark symptoms of PD are rigidity, tremor at rest, bradykinesia and postural instability. Current drug therapies target symptom management, and at present there are no cures for PD. This begs the question, is there potential for a treatment in the future and how does cell replacement therapy fit into the picture? What is PD? In 1817 James Parkinson documented six cases he had been observing in An Essay on The Shaking Palsy, describing the classic motor symptoms of the disease that now bears his name and establishing it as a medical condition (Parkinson, 1817). Today there is a greater understanding of the underlying causes of these symptoms. However, what triggers degeneration of the dopaminergic neurons in the first place remains unknown. Only 5% of PD cases can be attributed to specific heritable genes such as PARK1, a gene responsible for encoding the neural protein -synuclein (Dawson and Dawson, 2003), the remaining 95% are idiopathic. Diagnosis of PD is still a clinical diagnosis based on the four cardinal symptoms, as there is no definitive test. Symptoms become apparent once over 80% of the dopaminergic neurons have been lost (Miller and OCallaghan, 2014). On post-mortem examination, the SN of PD patients has a pale appearance. This is because dopaminergic neurons are rich in neuromelanin, the substance that gives rise to the dark pigmentation of the SN in normal adults (Zecca et al., 2003). Under a microscope abnormal aggregates of protein can be seen, known as Lewy bodies. The specific cause of idiopathic PD is uncertain, it is likely to be a combination of genetic and environment influences. For instance, MPTP exposure, a compound initially synthesized as a narcotic, induces symptoms of PD. This demonstrates the potential of environmental toxins having a role and has provided one of the principal animal models of PD (Sian et al., 1999). The two leading theories for the pathogenesis of PD centre around the aggregation of misfolded proteins (such as -synuclein) and oxidative stress caused by mitochondrial dysfunction (Dauer and Przedborski, 2003). Current drug therapy As PD is caused by a loss of the dopaminergic neurons, the main drug therapies focus on replenishing the dopamine within the basal ganglia. By replacing the dopamine, motor symptoms are reduced, and this has a significant impact on patients quality of life. Dopamine precursors such as Levodopa and dopamine agonists form the basis of current therapy. Levodopa is augmented with a DOPA decarboxylase inhibitor to reduce peripheral conversion, ensuring the majority of Levodopa is converted to dopamine within the CNS (Poewe and Antonini, 2014). Monoamine oxidase B inhibitors can also be prescribed to reduce the breakdown of dopamine within the brain. While these drugs initially relieve patients of their symptoms, their therapeutic benefit diminishes with time. This is known as wearing off and means patients require a higher dose to experience the same benefit (Stocchi, 2006). Unfortunately, these drugs also have unpleasant side effects such as dyskinesia, which is the occurrence of involuntary movements. Although medication is the mainstay of PD management, there are alternative treatments such as speech and language therapy or surgical options such as deep brain stimulation (DBS) (Odekerken et al., 2013). Current therapies have their limitations as they focus on symptomatic relief only and do nothing to reverse or slow down the progression of the disease. As PD is caused by degeneration of dopaminergic neurons, it stands to reason that differentiated stem cells could be implanted to replace lost neurons and consequently re-innervate the striatum. The case for cell replacement therapy Cell replacement therapy is a promising avenue into the investigation and treatment of neurodegenerative diseases. The CNS is unable to regenerate its own neurons, due to the physical and chemical barriers formed by glial scars (Ohtake and Li, 2014). Stem cells have the ability to multiply and differentiate down any cell line, this is known as pluripotency. Current research is focussing on the pluripotent potential of various forms of stem cells. By inducing stem cells to differentiate under the correct conditions, dopaminergic neurons can be created. These neurons can be transplanted into a patient with PD, replacing their dopamine levels and providing symptomatic relief. Both the Michael J Fox Foundation and Parkinsons UK refer to stem cell therapies on their websites and actively back research into this potential therapy. The idea of treating PD using cell replacement therapy is not a new one; research in this area started in the early 1990s. Studies investigating the effects of foetal neuronal tissue in PD patients yielded promising results. A (...truncated)