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MSKCC researchers use hESCs to treat Parkinsonís disease in animal models
NEW YORKóScientists have been chasing the potential of human pluripotent stem cells (PSCs) as applications in regenerative medicine for nearly two decades, but for various reasons, the effective use of PSCs as cell therapies has yet to be realized. Now, with a recent study published in Nature, scientists at Memorial Sloan-Kettering Cancer Center (MSKCC) say they have used human embryonic stem cells (hESCs) to successfully treat Parkinson's disease in mice and ratsóthe first step in developing an approach to treating the debilitating disease in humans.
"The key novel finding is that our group found a way a new way to generate human dopamine nerve cells from embryonic stem cells and that those cells release dopamine, survive well in multiple animal models of Parkinson's disease and improve the animal's function," explains Lorenz Studer, lead author of the paper and a stem cell biologist at MSKCC. "This is very exciting, as many groups have tried to do this for more than 10 years."
The method devised by Studer and his colleagues uses dopamine to help control muscle movement, as the brain's dopamine-producing cells are slowly destroyed in Parkinson's disease patients. While other researchers have had some success in making dopamine-like cells, those cells typically perform poorly after transplantation, Studer notes. There are also considerable safety concerns for PSCs, as well as the potential for the growth of tumor-like structures.
"In contrast, the new method described in our Nature paper has overcome this problem and yields cells that perform extremely well after transplantation (i.e., efficiently "cure" the animal of its symptoms)," he says. "In addition to being very efficacious, the cells generated with the new methods are also very safe with no evidence of any type of overgrowth."
In previous research efforts, scientists added two specialized proteinsóthe floor-plate (FP) marker FOXA2 and the roof-plate marker LMX1Aóto turn hESCs into dopamine-producing nerve cells. Now, by adding a third substanceóCHIR99021, a potent GSK3B inhibitor known to strongly activate WNT signalingóStuder and his colleagues say they were able to activate a vital biological pathway in the hESC cells, making human dopamine cells with greater function.
The MSKCC team gave animals six injections of more than 1 million cells each to parts of the brain affected by Parkinson's disease in mouse, rat and monkey models. The team observed that neurons survived, forming new connections and restoring lost movement.
MSKCC's strategy suggests that past failures were due to incomplete specification, rather than a specific vulnerability of the cells.
"We think that our new study removes the main bottleneck in the field that prevented us from developing embryonic stem cell based cell therapy for treating Parkinson's disease patients," says Studer. "We are now moving to a phase where we will produce such cells under clinical grade conditions and pushing towards the potential translation of these findings."
The study, "Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease," was published online on Nov. 6 in Nature.