Transplanting dopamine-producing nerve cells grown from monkeys’ own cells back into their brains relieved motor and depression symptoms associated with Parkinson’s disease, a study demonstrated.
This approach avoided transplant-associated tissue rejection and supports further research as a treatment option for people with the condition.
The study, “Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys,” was published in the journal Nature Medicine.
Parkinson’s disease is characterized by the loss of nerve cells in the brain that produce dopamine (dopaminergic neurons), a chemical that transmits signals between nerve cells.
Levodopa (L-DOPA) — a precursor of dopamine — is one of the main medications used to treat Parkinson’s symptoms. Still, its effectiveness can fade over time, and long-term use may result in spontaneous involuntary body movements (dyskinesia). Furthermore, L-DOPA supplementation does not prevent the progressive loss of dopaminergic neurons.
“Those drugs work well for many patients, but the effect doesn’t last,” said study lead Marina Emborg, MD, PhD, in a press release. “Eventually, as the disease progresses and their motor symptoms get worse, they are back to not having enough dopamine, and side effects of the drugs appear.”
Studies have demonstrated the implantation of healthy cells from fetal tissue to stimulate the growth of new dopaminergic neurons can alleviate motor symptoms in primates, which led to clinical trials in late-stage Parkinson’s patients. However, outcomes were mixed, and further research was limited by the availability of useful cells and rejection from patients’ immune systems to foreign tissue.
Induced pluripotent stem cells (iPSCs) are a type of stem cell generated directly from most cells in the body. As stem cells can be reprogrammed into other cell types, iPSCs may be used to create dopamine-producing neurons, which can be placed back into the original donor (autologous transplant) or into others (allogeneic transplant). Because autologous transplants come from the original donor, immune responses leading to tissue rejection are avoided.
“The idea is very simple,” said co-lead Su-Chun Zhang, MD, PhD. “When you have stem cells, you can generate the right type of target cells in a consistent manner. And when they come from the individual you want to graft them into, the body recognizes and welcomes them as their own.”
Scientists at the University of Wisconsin–Madison tested this approach in rhesus macaques with induced Parkinson’s-like symptoms.
From five of 10 monkeys, rhesus iPSC (RhiPSC) lines were first established, then transformed into dopaminergic neuron precursor cells.
The Parkinson’s model was created by infusing a neurotoxin into the 10 older monkeys. All monkeys developed a slowness of movement (bradykinesia), posture and gait imbalances, tremors, and motor skills impairments. Positron emission tomography (PET) scans of the brain monitored dopaminergic activity, which was decreased. Symptoms persisted from one to three years before transplant.
“We evaluated through observation and clinical tests how the animals walk, how they grab pieces of food, how they interact with people — and also with PET imaging, we measured dopamine production,” said Emborg.
Guided by real-time MRI, the dopamine-producing neurons were injected into the area in the monkey’s brain where neurons are damaged (the striatum). Five monkeys received an autologous transplant (with cells from their bodies), while the remaining five received allogenic transplants.
After a few months, animals with autologous transplants showed recovery, whereas allogenic monkeys did not. In autologous recipients, the amount, speed, and fluidity of movement increased, along with the ability to walk and hold treats. Climbing in the cage was a slow and strenuous task for monkeys treated with allogenic stem cells, but greatly improved in animals treated with autologous stem cells, as was the hunched posture.
“The autologous animals started to move more,” Emborg said. “Where before they needed to grab the cage to stand up, they started moving much more fluidly and grabbing food much faster and easier.”
PET scans found significant increases in dopamine levels in autologous monkeys, while allogenic animals had small nonsignificant increases. Moreover, the team measured the autologous graft volume, but they detected no graft volumes in allogenic animals.
An examination of brain tissue found allogenic transplanted cells had a clear surrounding boundary. In contrast, autologous grafts had merged with host tissues, showing substantial numbers of grafted dopaminergic neurons and longer nerve fibers (axons) intermingled with surrounding cells.
“They could grow freely and extend far out within the striatum,” said first author Yunlong Tao, PhD. “In the allogenic monkeys, where the grafts are treated as foreign cells by the immune system, they are attacked to stop the spread of the axons.”
Besides motor deficits, the Parkinson’s induced monkeys displayed signs of mood disorders, with symptoms that resembled depression and anxiety, such as pacing, disinterest in others and their favorite treats. While these symptoms remained unchanged or worsened in allogenic monkeys, they lessened after autologous transplants grew into tissue.
“Although Parkinson’s is typically classified as a movement disorder, anxiety and depression are typical, too,” added Emborg. “In the autologous animals, we saw extension of axons from the graft into areas that have to do with what’s called the emotional brain.”
“The study was aimed at mimicking future clinical application by using older rhesus monkeys and performing transplantation years after the onset of [Parkinson’s disease],” the researchers wrote. “Here we show that over a 2-year period…, [Parkinson’s disease] monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs.”
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