Summary: Grafting neurons derived from a monkey’s own stem cells reversed the debilitating and mental health symptoms associated with Parkinson’s disease. The treatment shows promise for alleviating the symptoms of Parkinson’s in humans.
Source: University of Wisconsin-Madison
Grafting neurons grown from monkeys’ own cells into their brains relieved the debilitating movement and depression symptoms associated with Parkinson’s disease, researchers at the University of Wisconsin-Madison reported today.
In a study published in the journal Nature Medicine, the UW team describes its success with neurons made from induced pluripotent stem cells from the monkeys’ own bodies. This approach avoided complications with the primates’ immune systems and takes an important step toward a treatment for millions of human Parkinson’s patients.
“This result in primates is extremely powerful, particularly for translating our discoveries to the clinic,” says UW-Madison neuroscientist Su-Chun Zhang, whose Waisman Center lab grew the brain cells.
Parkinson’s disease damages neurons in the brain that produce dopamine, a brain chemical that transmits signals between nerve cells. The disrupted signals make it progressively harder to coordinate muscles for even simple movements and cause rigidity, slowness and tremors that are the disease’s hallmark symptoms. Patients — especially those in earlier stages of Parkinson’s — are typically treated with drugs like L-DOPA to increase dopamine production.
“Those drugs work well for many patients, but the effect doesn’t last,” says Marina Emborg, a Parkinson’s researcher at UW-Madison’s Wisconsin National Primate Research Center. “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.”
Scientists have tried with some success to treat later-stage Parkinson’s in patients by implanting cells from fetal tissue, but research and outcomes were limited by the availability of useful cells and interference from patients’ immune systems. Zhang’s lab has spent years learning how to dial donor cells from a patient back into a stem cell state, in which they have the power to grow into nearly any kind of cell in the body, and then redirect that development to create neurons.
“The idea is very simple,” Zhang says. “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.”
The application was less simple. More than a decade in the works, the new study began in earnest with a dozen rhesus monkeys several years ago. A neurotoxin was administered — a common practice for inducing Parkinson’s-like damage for research — and Emborg’s lab evaluated the monkeys monthly to assess the progression of symptoms.
“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,” Emborg says. (PET is positron emission tomography, a type of medical imaging.) “We wanted symptoms that resemble a mature stage of the disease.”
Guided by real-time MRI that can be used during procedures and was developed at UW-Madison by biomedical engineer Walter Block during the course of the Parkinson’s study, the researchers injected millions of dopamine-producing neurons and supporting cells into each monkey’s brain in an area called the striatum, which is depleted of dopamine as a consequence of the ravaging effects of Parkinson’s in neurons.
Half the monkeys received a graft made from their own induced pluripotent stem cells (called an autologous transplant). Half received cells from other monkeys (an allogenic transplant). And that made all the difference.
Within six months, the monkeys that got grafts of their own cells were making significant improvements. Within a year, their dopamine levels had doubled and tripled.
“The autologous animals started to move more,” Emborg says. “Where before they needed to grab the cage to stand up, they started moving much more fluidly and grabbing food much faster and easier.”
The monkeys who received allogenic cells showed no such lasting boost in dopamine or improvement in muscle strength or control, and the physical differences in the brains were stark. The axons — the extensions of nerve cells that reach out to carry electrical impulses to other cells — of the autologous grafts were long and intermingled with the surrounding tissue.
“They could grow freely and extend far out within the striatum,” says Yunlong Tao, a scientist in Zhang’s lab and first author of the study. “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.”
The missing connections leave the allogenic graft walled off from the rest of the brain, denying them opportunities to renew contacts with systems beyond muscle management.
“Although Parkinson’s is typically classified as a movement disorder, anxiety and depression are typical, too,” Emborg says. “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.”
Symptoms that resemble depression and anxiety — pacing, disinterest in others and even in favorite treats — abated after the autologous grafts grew in. The allogenic monkeys’ symptoms remained unchanged or worsened.
The results are promising enough that Zhang hopes to begin work on applications for human patients soon. In particular, Zhang says, the work Tao did in the new study to help measure the relationship between symptom improvement, graft size and resulting dopamine production gives the researchers a predictive tool for developing effective human grafts.
Funding: This research was supported by grants from the National Institutes of Health (NS076352, NS096282, NS086604, U54 HD090256 and P51OD011106), the National Medical Research Council of Singapore, the Dr. Ralph & Marian Falk Medical Research Trust and UW-Madison.
Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys
Degeneration of dopamine (DA) neurons in the midbrain underlies the pathogenesis of Parkinson’s disease (PD). Supplement of DA via L-DOPA alleviates motor symptoms but does not prevent the progressive loss of DA neurons.
A large body of experimental studies, including those in nonhuman primates, demonstrates that transplantation of fetal mesencephalic tissues improves motor symptoms in animals, which culminated in open-label and double-blinded clinical trials of fetal tissue transplantation for PD.
Unfortunately, the outcomes are mixed, primarily due to the undefined and unstandardized donor tissues. Generation of induced pluripotent stem cells enables standardized and autologous transplantation therapy for PD. However, its efficacy, especially in primates, remains unclear.
Here we show that over a 2-year period without immunosuppression, PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs. These behavioral improvements were accompanied by robust grafts with extensive DA neuron axon growth as well as strong DA activity in positron emission tomography (PET).
Mathematical modeling reveals correlations between the number of surviving DA neurons with PET signal intensity and behavior recovery regardless autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number.