Published on: July 4, 2012 on the SCIENCE DAILY website

Researchers have taken a step towards personalized medicine in Parkinson's disease patients by studying the signs of the disease in cells derived from the patients and examining the response of the cells to drug treatments. The study was funded by the National Institutes of Medicine (NIH).

The researchers collected skin cells from patients who genetically inherited various forms of Parkinson's disease, and reprogrammed them into nerve cells. They found that nerve cells derived from patients with special types of Parkinson's disease showed similar signs of vulnerability and distress, especially damage to the mitochondria - the cells' respiratory organelles and the cells' energy producers. At the same time, the response of the cells to different treatments depended on the type of disease that each of the Parkinson's patients had. .

The results were published in SCIENCE TRANSLATIONAL MEDICINE.

"These findings open up new possibilities for clinical trials in Parkinson's disease, which cell reprogramming method can be used to identify which patients will have the best chances of responding to a particular treatment," says Dr. Margaret Sutherland, program director at the US National Institute of Neurological Disorders and Stroke (NINDS) belonging to to the NIH.

A group of researchers conducted the study with initial funding from the NINDS. The group is led by Dr. Ole Isaacson, professor of neurology at McLean Hospital and Harvard Medical School in Boston.

The group's initial goal was to transform the skin cells into pluripotent stem cells (stem cells that can become any type of cell depending on the stimulation they receive) - IPS cells, these are mature cells that have been reprogrammed to behave like embryonic stem cells. The group's researchers used a combination of growth conditions with growth-stimulating molecules to direct IPS cells to become neurons, including the type that is damaged and dies in Parkinson's disease patients.

Parkinson's disease affects several areas of the brain, including the movement control area in the brain called SUBSTANIA NIGRA -SN. There the disease destroys nerve cells that produce the chemical dopamine. Losing these nerve cells causes uncontrollable tremors, slow movements, muscle stiffness and other symptoms. Medication can help control the symptoms, but there is no treatment that slows or stops the disease.

Most cases of Parkinson's disease are sporadic, meaning without a known cause, but the hereditary part has an important component. There are 17 regions of the genome with common variations that affect the risk of developing Parkinson's disease. Researchers have also identified 9 genes that, when mutated, can cause the disease.

Dr. Isaacson and his researchers extracted IPS cells from five people with different forms of hereditary Parkinson's disease. Focusing on the hereditary forms rather than the sporadic ones, they estimated, would give them a better chance of finding trends in the development of the disease and response to treatments. Three of the five had mutations in a gene called LRRK2, while the other two who were siblings had mutations in the PINK1 gene. The researchers also derived IPS cells from two siblings of the two sick siblings, who had no mutations and were healthy.

Because previous studies have shown that Parkinson's disease is involved in mitochondrial dysfunction, they looked for signs of dysfunctional mitochondria in the patients' neurons. Mitochondria turn sugar and oxygen into cellular energy. The researchers found that the rate of oxygen consumption was lower in patient cells with the LRRK2 mutation and higher in cells with the PINK1 mutation. The researchers also found a high sensitivity to oxidative stress. This is a destructive process that in theory can be treated with antioxidants.

In the next step, the researchers examined whether nerve cells derived from patients and healthy patients are sensitive to toxins, including those that act on the mitochondria. Nerve cells derived from patients were more sensitive - damage and death after exposure to mitochondrial toxins.

In the next step, the researchers tried to save the cells that were exposed to mitochondrial toxins with various substances that showed promising potential in animal experiments in Parkinson's disease models, including the antioxidant coenzyme Q10 and the immunosuppressant RAPAMYCIN. All nerve cells, even if they carried a mutation in the LRRK2 gene or in the PINK1 gene, showed a beneficial response to coenzyme Q10. In contrast, the nerve cells derived from the patients differed in their response to RAPANYCIN. The drug worked to prevent nerve cell damage with a mutation in the LRRK2 gene, but it did not protect nerve cells with a mutation in the PINK1 gene. These results suggest that IPS cell technology may help define patient subgroups for clinical trials. To date, clinical trials have not been divided into subgroups and treatments against subgroups of patients or certain forms of disease have not been tested, because there were a small number of clues that would cause the research to concentrate in the direction of individual treatment.

Although the current research focused on hereditary forms of Parkinson's disease, IPS cell technology can help define disease mechanisms and the most promising treatments for sporadic Parkinson's disease patients as well. The NINDS group of researchers studying IPS cells for Parkinson's disease is only one of 3 groups funded by NINDS. One group focuses on the development of IPS cells for Huntington's disease and the other focuses on ALS and frontotemporal dementia.

The Huntington group recently reported successful derivation of IPS cells and patient-derived IPS neurons. Cells from both early stage disease patients and late stage disease patients showed severe damage in physiology, metabolism and cell survival compared to cells from healthy volunteers. These results were reported in the June 28, 2012 issue of CELL STEM CELL. This group of researchers is led by Dr. Leslie Thompson, professor of psychiatry and human behavior at the University of California, Irvine.

Skin cells and IPS cell cultures, developed in the group are available to researchers in both academia and the pharmaceutical industry through NINDS through the Human Cell Culture Repository at the Curiel Institute. To date, NINDS has distributed over 200 cell cultures worldwide.

The IPS cell group for Parkinson's disease is mainly funded by grants from the NINDS (NS070276, NS0708338). The 3 research groups were established in 2009 with more than 11 million dollars in grants from the NINDS, which was made possible by the recovery law. Funding for groups was recently renewed until the end of 2013 through public-private cooperation. The goals for the future are to increase the number of cell cultures, IPS cells and to increase the variety of mutations shown, and to attach biological tags to some of them. This will allow researchers to see when the cells have transformed into specific neurons. NINDS is funding the next phase in conjunction with the Michael J. Fox Foundation and the Parkinson's Disease Foundation, the ALS Association, the Frontotemporal Degeneration Association, the CHDIF Foundation, the American Huntington's Disease Society, the Hereditary Disease Foundation and the California Institute for Regenerative Medicine.

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2. The HD iPSC Consortium. Induced Pluripotent Stem Cells from Patients with Huntington's Disease Show CAG-Repeat-Expansion-Associated Phenotypes. Cell Stem Cell, 2012; IT HURTS: 10.1016 / j.stem.2012.04.027

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