Still grafting after all these years

In November 1987, Lund scientists grafted fetal neurons into the brain of a 47-year old PD patient, launching an era of neural grafting. After some promising initial results, two negative US double blind sham surgery trials (in 2001 and 2003) brought the field to a virtual standstill. In a thoughtful look back at the past 25 years, some of the original pioneers review some lessons learned (Lancet Neurology). While the transplants undoubtedly worked in some cases––several patients live off all dopaminergic medication more than 15 years after surgery––many cases benefited little and some contracted graft-induced dyskinesias. The authors explore likely reasons for the inconsistency of results, including patient selection (i.e. age, type, stage), graft preparation, graft placement, and immunotherapy. They raise trial design issues that may have unfairly biased outcomes, such as duration of patient follow up, appropriate study end points, natural variability of the disorder, and placebo effects.

They also ponder how scientific developments since 1987 have changed the context for neural grafting. It’s a different world. 25 years later, it’s become possible (at least in theory) to bypass the practical, ethical and immunological difficulties of fetal tissue by taking ordinary skin cells from the recipient and reprogramming them to become induced pluripotent stem cells (iPSCs). The trick involves using a so called Yamanaka cocktail--named for the Japanese scientist who in 2006 discovered that by manipulating four genes, rodent skin cells could be returned to a pluripotent state. UW Madison scientists Marina E. Emborg, Su-Chun Zhang and colleagues have just reported doing this with primates. Harvesting skin cells from MPTP monkeys, the UWM team turned them into induced pluripotent stem cells, then used those iPSCs to derive neural progenitor cells, which they injected into the striatum of the monkeys’ brains. With no rejection issues, the cells continued to differentiate into neurons and other brain cells over the next six months. As they write in Cell Reports, the cells looked entirely normal. And while the grafted cells didn’t have any therapeutic effect on the parkinsonian monkeys’ symptoms, they didn’t develop into tumors. A team in Yamanaka’s institute has previously reported in JPD that they’d successfully implanted human iPSCs-derived neural progenitor cells into MPTP monkeys.

The other big change since 1987 has been the reclassification of PD as much more than a motor disease. So while once neural grafting would have been characterized as a potentially transformative (semi-curative) strategy, today figures like Roger Barker and Anders Björklund have more modest aspirations.  As they write: “Dopaminergic cell replacement will only ever work as well as the best dopaminergic agents, such as levodopa. As such, they will never be able to treat most of the non-motor features of Parkinson’s disease, many of which are non-dopaminergic in origin. Thus, cell treatments aimed at dopamine cell replacement will never be curative, in the same way that levodopa is not curative. But, if used early, they could substantially reduce the amount of medication needed by the patient and, therefore, strikingly alter the natural history of treated Parkinson’s disease.”

Barker RA, Barrett J, Mason SL, Björklund A. Fetal dopaminergic transplantation trials and the future of neural grafting in Parkinson's disease.  Lancet Neurol. 2013 Jan;12(1):84-91. doi: 10.1016/S1474-4422(12)70295-8.

Marina E. Emborg, Yan Liu, Jiajie Xi, Xiaoqing Zhang, Yingnan Yin, Jianfeng Lu, Valerie Joers, Christine Swanson, James E. Holden, Su-Chun Zhang. Induced Pluripotent Stem Cell-Derived Neural Cells Survive and Mature in the Nonhuman Primate Brain. Cell Reports, 14 March 2013