Following his Olympic victory in 1960, Muhammad Ali earned the World-Heavyweight-Champion title in 1964 in one of the most celebrated upsets in boxing history. The much-anticipated fight opened with the then World-Heavyweight-Champion Sonny Liston rushing at Ali looking to end the fight quickly with a decisive knockout. However, something unusual happened to the reigning champion. Ali’s superior footwork and superb reflexes allowed him to dodge Liston’s lunging punch, effectively making the 7-1 favorite Champion awkwardly miss a well-calibrated blow. With time, the entire world came to embrace the unique boxing style of this phenomenal athlete, better epitomized by his own words: ‘Float like a butterfly, sting like a bee’.
After years of jab-taking fights and head-blowing victories, in 1984 Ali was diagnosed with Parkinson’s disease (PD), an incurable disease associated with the irreversible loss of dopaminergic neurons in the substantia nigra (SN). These neurons are part of a network better known as the basal ganglia, where together with other groups of neurons serve essential functions in fine motor control and initiation of movement. Needless to say, dysfunction of this brain circuit leads to a wide range of movement deficits including tremor, slowed movement and muscle stiffness. These symptoms are often accompanied by neuropsychiatric disturbances, such as depression, which gradually lead to reduced health status, social withdrawal and isolation, significantly altering an individual’s quality of life.
“Right when this research started to appear hopeless, a major upset in scientists’ fight with Parkinson’s occurred. “
Given its debilitating nature, many life-changing treatments could be expected to be available for PD. However, the current reality is more complicated. Dopamine is a key neurotransmitter involved in the regulation of reward and voluntary movement. For many years, scientists believed that reduced dopamine transmission underlies the main motor symptoms of PD. Therefore, current treatments aim at replenishing lost dopamine in the diseased brain following the rationale that pumping dopamine back into the SN could be enough to ward off the symptoms. But does this really work? Several peer-reviewed studies demonstrate that while replenishing dopamine with bespoke drugs can provide initial relief from the symptoms, their effects diminish with time. This is what experts call ‘wearing off’ and means that patients need to be administered a higher dose to experience the same therapeutic benefit.
Since PD is caused by the irreversible loss of SN dopaminergic neurons, one could argue that implanting new, fully functioning cells to replace lost neurons could reverse or slow down the progression of the disease. This strategy, known as cell replacement therapy, is not new to scientists at Universidad Nacional Autónoma de México, who, over 20 years ago performed the first transplants of fetal ventral mesencephalic tissue – a tissue rich in cells that would later develop into dopaminergic neurons -into the basal ganglia of PD patients. While many patients benefited from this procedure, things did not go as planned for everyone. In fact, later analysis showed that some patients developed surgery-related side effects, some of which were attributed to the non-dopaminergic portions of the transplant. In addition, the use of aborted fetal tissue raised ethical concerns which prompted an intense research for a new, safe and ethically acceptable cell source for transplantation.
Right when this research started to appear hopeless, a major upset in scientists’ fight with Parkinson’s occurred. In 2006, a research group at Kyoto University led by Shinya Yamanaka devised a method to obtain any of the body’s specialized cells from a culture of adult skin cells. These cells were called “induced pluripotent stem cells” (iPSCs) and to the millions of patients fighting PD, their discovery offered the exciting possibility that scientists might one day be able to reprogram iPSCs into dopaminergic cells before implanting them permanently into their brains.
“Whilst it is unlikely that iPSC technology will defeat PD in a first-round knockout, further clinical trials will help to corner PD against the ropes.”
After years of painstaking research, it seems that that day has finally come. On July 30th, neurosurgeon Jun Takahashi at Kyoto University announced that his team will start a clinical trial evaluating the safety and efficacy of human iPSCs to treat PD. The trial will take place at the Kyoto University’s Centre for iPS Cell Research and Application (CiRA) in Japan and represents the world’s first-of-its-kind trial to use reprogrammed adult stem cells to treat PD. Last year, Takahashi’s group demonstrated that iPSCs differentiate into dopamine-producing neurons in monkey models of PD, leading to significant improvement in motor function over a two-year period.
Galvanized by these encouraging results, the team now hopes to restore normal dopamine levels in treated patients whilst avoiding important complications, such as tumor formation or uncontrolled growth. In particular, the possibility of immune rejection remains a source of great criticism among experts, as it remains unclear what protocol should be used to promote cell survival and avoid tissue rejection upon transplantation. The general consensus is that iPSCs created from the patient’s own cells are less likely to be rejected by the patient’s body; however, the team at CiRA derived their stocks from third-party donors, raising important questions regarding the safety and tolerability of their procedure.
iPSCs have the potential of answering many unresolved issues. Will iPSC cell replacement therapies be available in the foreseeable future? There is no correct answer to this, but it is likely that many years will pass before this technology could turn into a mainstay treatment for PD. Clearly there is much more work to do and, as with other cell therapies, any sign of clinical improvement may take 3-5 years before becoming maximally evident. Therefore, scientists at Kyoto University will wait a few years before publishing their results on this ground-breaking clinical trial so that any sign of success can be correctly measured. In the meantime, many more groups in Europe and US have announced their intention to undertake their own clinical trial in the next 1-2 years. Knowledge accumulated from these trials will likely benefit the development of new and better-informed treatments for PD. Therefore, whilst it is unlikely that iPSC technology will defeat PD in a first-round knockout, further clinical trials will help to corner PD against the ropes.
There is hope that butterflies will be able to fly again!
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