CHICAGO – Neurons which were grafted into the brain of a patient with Parkinson’s disease fourteen years ago have developed Lewy body pathology, the defining pathology for the disease, according to research by Jeffrey H. Kordower, PhD, and associates and published in the April 6 issue of Nature Medicine.

These findings suggest that Parkinson’s disease is an ongoing process that can affect cells grafted into the brain in the same way the disease affects host dopamine neurons in the substantia nigra of the brain, according to Kordower, who is the lead author of the study and a neuroscientist at Rush University Medical Center.

“These findings give us a bit of pause for the value of cell replacement strategy for Parkinson’s disease,” said Kordower.  “We still need to vigorously investigate this approach among the full armament of surgically-delivered Parkinson’s disease therapies. While it is not clear to us whether the same fate would befall stem cell grafts, the next generation of cell replacement procedures, this study does suggest that grafted cells can be affected by the disease process.”

The collaborative research study described in the article involves Rush, Mt. Sinai School of Medicine, New York, and the University of South Florida, Tampa, In it, individuals with Parkinson’s disease received fetal cell transplants to reverse the loss in the brain of striatal dopamine.

The individual described in this article was a woman with a 22-year history of Parkinson’s disease who underwent transplantation in 1993. After transplantation she experienced improvements in disease symptoms as measured by the Unified Parkinson Disease Rating Scale (UPDRS) and required substantially lower doses of antiparkinsonian medications. Her UPDRS scores remained improved into1997, but by 2004, she experienced progressive worsening of Parkinson’s disease symptoms. She died in 2007 and her brain and that of two other patients in the study were comprehensively processed and analyzed. She had the longest survival after transplantation that had been reported to date among this study’s participants.

Double-blind, sham-controlled studies that followed did not establish clinical benefit although significant improvement was observed in a subpopulation of patients. Post mortem studies of individuals in these studies showed a robust survival of grafted neurons, suggesting that the cells were not affected by Parkinson’s disease as Kordower explains “Because Parkinson’s disease pathology progresses over decades, we think that the individuals did not live long enough for the Parkinson’s disease pathology to develop in the grafted cells.”

Scientists have long debated whether Parkinson’s disease results from an acute insult or event, or whether it is an ongoing pathological process that continues to affect healthy neurons, according to Kordower. This research indicates that mechanisms and molecules responsible for initiating the degenerative process are still present at a late stage and are capable of affecting grafted neurons.  In addition, the processes that destroy dopamine neurons are not restricted to the midbrain.

“The findings also suggest that there may be either a pathogenic factor in the brain that affects dopamine producing neurons or a pathological process that can spread from one cellular system to another,” said Kordower.  “These findings have striking implications for understanding what causes PD and the potential for cell replacement strategies to reverse the motor symptoms.”

The study is available online at http:/www.nature.com/naturemedicine

Stem cell researchers from UCLA used a high resolution technique to examine the genome, or total DNA content, of a pair of human embryonic stem cell lines and found that while both lines could form neurons, the lines had differences in the numbers of certain genes that could control such things as individual traits and disease susceptibility. The technique used to study the genome, which contains all the genes on 46 chromosomes, is called array CGH. The use of higher resolution techniques, such as array CGH and, soon, whole genome sequencing, will enhance the ability of researchers to examine stem cell lines to determine which are best – least likely to result in diseases and other problems – to use in creating therapies for use in humans.

Array CGH provided a much better look at the gene content on the chromosomes of human embryonic stem cells, with a resolution about 100 times better than standard clinical methods. Clinical specialists commonly generate a karyotype to examine the chromosomes of cancer cells or for amniocentesis in prenatal diagnosis, which has a much lower resolution than Array CGH, said Michael Teitell, a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and the senior author of the study. Small defects that could result in big problems later on could be missed using karyotyping for stem cells.

“Basically, this study shows that the genetic makeup of individual human embryonic stem cell lines is unique in the numbers of copies of certain genes that may control traits and things like disease susceptibility,” said Teitell, who also is an associate professor of pathology and laboratory medicine and a researcher at UCLA’s Jonsson Comprehensive Cancer Center. “So, in choosing stem cell lines to use for therapeutic applications, you want to know about these differences so you don’t pick a line likely to cause problems for a patient receiving these cells.”

The study appears in the March 27, 2008 express edition of the journal Stem Cells.

Differences between individual DNA sequences provide the basis for human genetic variability. Forms of variation include single DNA base pair alterations, duplications or deletions of genes or sets of genes, and translocations, a chromosomal rearrangement in which a segment of genetic material from one chromosome becomes heritably linked to another chromosome. These changes can be benign, but they can also promote diseases such as certain cancers, or confer increased risk to other diseases, such as HIV infection or certain types of kidney ailments.

In this study, Teitell and his team sought to determine copy number variants (CNVs), or differences in the numbers of certain genes, in two embryonic stem cell lines. The CNVs provide a unique genetic fingerprint for each line, which can also indicate relatedness between any two stem cell lines. Teitell used embryonic stem cell lines that made different types of neurons and studied them with array CGH for comparison. His team found CNV differences between the two lines in at least seven different chromosome locations below the level of detection using standard karyotype studies. Such differences could impact the therapeutic utility of the lines and could have implications in disease development. More studies will be required to determine the effect of specific CNVs in controlling stem cell function and disease susceptibility, he said.

“In studying embryonic stem cell lines in the future, if we find differences in regions of the genome that we know are associated with certain undesirable traits or diseases, we would choose against using such stem cells, provided safer alternative lines are available,” Teitell said.

Large genome-wide association studies are underway in a variety of diseases to determine what genetic abnormalities might be at play. When the genetic fingerprint or predisposing genes for a certain disease is discovered, it could be used as key information in screening embryonic stem cell lines.