MSKCC researchers use hESCs to treat Parkinson’s disease in animal models

Scientific team says it had found a way a new way to generate human dopamine nerve cells from embryonic stem cells that not only release dopamine but also survive well in multiple animal models

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NEW YORK—Scientists have been chasing the potential of humanpluripotent stem cells (PSCs) as applications in regenerative medicine for nearlytwo decades, but for various reasons, the effective use of PSCs as celltherapies has yet to be realized. Now, with a recent study published in Nature, scientists at MemorialSloan-Kettering Cancer Center (MSKCC) say they have used human embryonic stemcells (hESCs) to successfully treat Parkinson's disease in mice and rats—thefirst step in developing an approach to treating the debilitating disease inhumans.
"The key novel finding is that our group found a way a newway to generate human dopamine nerve cells from embryonic stem cells and thatthose cells release dopamine, survive well in multiple animal models ofParkinson'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 veryexciting, as many groups have tried to do this for more than 10 years."
The method devised by Studer and his colleagues usesdopamine to help control muscle movement, as the brain's dopamine-producingcells are slowly destroyed in Parkinson's disease patients. While otherresearchers have had some success in making dopamine-like cells, those cellstypically perform poorly after transplantation, Studer notes. There are alsoconsiderable safety concerns for PSCs, as well as the potential for the growthof tumor-like structures.
"In contrast, the new method described in our Nature paper has overcome this problemand yields cells that perform extremely well after transplantation (i.e.,efficiently "cure" the animal of its symptoms)," he says. "In addition to beingvery efficacious, the cells generated with the new methods are also very safewith no evidence of any type of overgrowth."
In previous research efforts, scientists added twospecialized proteins—the floor-plate (FP) marker FOXA2 and the roof-platemarker LMX1A—to turn hESCs into dopamine-producing nerve cells. Now, by addinga third substance—CHIR99021, a potent GSK3B inhibitor known to stronglyactivate WNT signaling—Studer and his colleagues say they were able to activatea vital biological pathway in the hESC cells, making human dopamine cells withgreater function.
The MSKCC team gave animals six injections of more than 1million cells each to parts of the brain affected by Parkinson's disease inmouse, rat and monkey models. The team observed that neurons survived, formingnew connections and restoring lost movement.
MSKCC's strategy suggests that past failures were due toincomplete specification, rather than a specific vulnerability of the cells.
"We think that our new study removes the main bottleneck inthe field that prevented us from developing embryonic stem cell based celltherapy for treating Parkinson's disease patients," says Studer. "We are nowmoving to a phase where we will produce such cells under clinical gradeconditions and pushing towards the potential translation of these findings."
The study, "Dopamine neurons derived from human ES cellsefficiently engraft in animal models of Parkinson's disease," was publishedonline on Nov. 6 in Nature.

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