Parkinson’s disease is a neurodegenerative disease which affects millions of people worldwide. According to the National Institute on Aging, the most prominent symptoms of this illness involve tremors and loss of mobility and balance. Parkinson’s can, however, also affect the functioning of muscles in the digestive and cardiovascular system and is associated with the development of mood disorders, such as depression and anxiety.
Parkinson’s disease occurs when dopamine-producing brain cells known as “dopaminergic neurons” die. An area of the brain called the substantia nigra produces a substantial amount of dopamine and is the structure which is primarily affected in Parkinson’s disease. When connections from the substantia nigra to other parts of the brain, such as the striatum, degenerate, the result is the loss of dopamine in many important brain structures.
Medical Physics Professor at University of Wisconsin Dr. Marina Emborg said Parkinson’s disease develops in the brain long before symptoms begin to manifest — more than 50% of the substantia nigra is lost before most patients develop early symptoms, such as tremors.
To combat the symptoms and slow the progression of the disease, patients are administered L-DOPA, which the body can use to produce more dopamine, or undergo other forms of dopamine replacement therapy to boost dopamine levels throughout the brain, Emborg said. There are limitations to L-DOPA, however. Increasing dopamine levels do not alleviate certain symptoms and complications caused by Parkinson’s, such as heart problems and mood disorders, Emborg said.
This could be different. UW researchers developed a new treatment for Parkinson’s disease which showed significant reversal of Parkinsonian symptoms in rhesus monkeys at the Wisconsin National Primate Research Center.
The study, published in the science journal “Nature Medicine,” shows that when rhesus monkeys were implanted with dopaminergic neurons which were grown from their own cells, also known as an autologous transplant, symptoms of Parkinson’s significantly improved. This discovery was part of a large, interdisciplinary effort between neurobiologists, engineers and physicists across campus.
Researchers worked meticulously through each step of the research process to address many minute details of the study and the surgical procedures.
“To practice the surgeries, we used gels — like a jello — to mimic a brain, so when we are practicing how to do the injections … [we] make sure we have the right amount of cells and … rate of infusion of the cell in the brain … we do all that work before we go to primates,” Emborg said.
Emborg also met with physicists and engineers to determine how to optimize the catheter design and successfully deliver brain tissue to the correct locations. There was a multistep process in ensuring the animal subjects would be treated in a humane and ethical way. Researchers used a live MRI technique, developed by UW Biomedical Engineer Walter Block, to help visualize the brain during the procedure and to improve accuracy.
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“When you have Parkinson’s, you lose dopaminergic neurons, dopaminergic innervation,” Emborg said. “So what we did with the therapy was replace the dopaminergic neurons that were lost in the disease.”
This was done using cell grafts — lines of cells which were grown in a lab then implanted in an organism.
The idea of using cell grafts to combat the effects of Parkinson’s was first proposed in 1917, and the first treatment ideas centered around the use of fetal tissue to grow neurons and replace damaged cells, Emborg said. This approach fell short — in a double-blind controlled trial, fetal tissue did not prove to be effective in repairing damage. In addition, fetal tissue grafts caused dyskinesia, or abnormal movement, in 56% of its patients as a side effect, Emborg said. There are also ethical concerns with using and sourcing fetal tissue, as well as inconsistencies with cell quality.
UW Professor Su Chun Zhang and his lab group developed the next approach using embryonic stem cells. The neurons grown from embryonic stem cells, however, required a lot of immunosuppression, because the brains of the monkeys were rejecting the cells instead of incorporating them into the body.
Finally, induced pluripotent cells, or iPSCs, derived from the skin of the rhesus monkey, were grown to produce dopaminergic cells. Injecting genetic material into an undifferentiated, developing cell via a virus made sure the cell would develop into a dopaminergic brain cell.
The discovery of a substance called 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, or MPTP, which causes Parkinson-like illness in both humans and nonhuman primates, was critical in developing a Parkinsonian disease model from which treatments can be developed and tested. When MPTP enters the body and passes the blood-brain barrier, it is metabolized and forms neurotoxin MPP+, which kills dopaminergic cells by inhibiting the mitochondria in the cell body.
In order to produce Parkinsonian symptoms in monkeys, researchers injected MPTP into the unilateral intracarotid artery — this was also to produce symptoms in just one side of the body and to minimize the suffering of the animals. The researchers then evaluated the monkeys using a clinical rating used to assess Parkinson’s in people and gave them tasks which tested their mobility, such as grabbing their favorite treat with one hand.
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Out of the 10 rhesus monkeys chosen for this study, scientists injected five of them with dopaminergic cells which were grown from their own stem cells — an autologous transplant. The other five were injected with dopaminergic cells which were from other monkeys, which is an allogenic transplant. Their symptoms and behavior were then monitored for the next two years.
The difference between the autologous and allogenic transplant results were crucial. While monkeys with allogenic grafts did not see much improvement and sometimes worsened, monkeys who received the autologous transplants saw an average of 40% improvement of symptoms and significantly higher levels of dopamine in their brains within six months of surgery.
Emborg said the autologous implanted cells integrated into the body seamlessly. The body accepted them as their own and saw extended growth. Meanwhile, because the allogenic grafts were sourced from other monkeys, an immune response meant cell growth and innervation was limited.
“The reason that this [treatment] works so well is because the cells are autologous … that’s the reason why the cells were able to integrate really well,” Emborg said. “And that made a huge difference because they work much better in the brain.”
An interesting additional effect of treatment was the improvement of mood in monkeys who received an autologous transplant. When monitored before and after treatment, monkeys with an autologous graft had dramatically reduced symptoms of depression (disinterest in tasks), anxiety (pacing around or agitated behavior) and self-injurious behavior. Monkeys with allogenic transplants saw no such improvements in mood.
The results of this study are promising for the future of Parkinson’s disease treatment. The next steps would be to translate the results and procedures from rhesus monkeys to humans and further study whether this would be a safe, viable treatment.
“The next thing you need to do is work with the Food and Drug Administration … if we are going to go into clinical trials … usually they would like to see tolerability … so when you are thinking about clinical translation, you need to think, what can go wrong,” Emborg said. “I need to test how many cells will be safe to inject, I need to test if the cells become tumorigenic … that’s what we are looking for, that is the plan.”
