Parkinson's Biomarker Initiative Expands Genetic Study

SOURCE The Michael J. Fox Foundation

PPMI now recruiting individuals with genetic mutation linked to Gaucher disease

NEW YORK, March 24, 2015 /PRNewswire-USNewswire/ -- The Parkinson's Progression Markers Initiative (PPMI), a large-scale biomarker study sponsored by The Michael J. Fox Foundation for Parkinson's Research (MJFF), is expanding to study individuals with a mutation of the GBA (glucosidase beta acid) gene. Participants will include people with or at increased risk to develop Parkinson's disease.  Researchers hope that a greater understanding of the biology and clinical features of these participants will lead to therapies benefiting all Parkinson's patients and ultimately provide strategies to prevent disease onset.

"Insights gleaned from volunteers with genetic mutations will help speed research toward new and improved Parkinson's therapies, benefitting the greater Parkinson's community," said Ken Marek, MD, principal investigator of PPMI and president and senior scientist at the Institute for Neurodegenerative Disorders in New Haven, Connecticut. 

Mutations in the GBA gene can cause Gaucher disease, a disorder where fatty substances accumulate in body cells. First linked to Parkinson's in 2008, these genetic mutations lower levels of an enzyme that helps break down proteins and lipids. In Parkinson's disease (PD) lower levels of this enzyme are associated with aggregation of the protein alpha-synuclein, the hallmark pathology of PD.

Genetics Provides Greater Understanding of Disease

Understanding the differences among people with and without PD who carry mutations such as in the GBA gene may help researchers understand what leads to disease onset and progression. In 2014 PPMI expanded to enroll individuals with a mutation of the LRRK2 or SNCA gene, the two targets of greatest interest in Parkinson's drug development.

One key tool missing from the development pipeline is an accurate way to measure progression of Parkinson's disease: a biomarker. Biomarkers would allow researchers to quickly and objectively measure a therapy's ability to slow, halt or reverse the Parkinson's process. PPMI is studying clinical and imaging data and biological samples of people with a genetic mutation to identify biomarkers, ultimately speeding clinical trials. In addition, when a drug targeting LRRK2, SNCA or GBA is ready for clinical testing, PPMI will have assembled a group of people with these mutations who stand ready to participate in studies. 

PPMI will enroll 125 people with the GBA mutation and who have Parkinson's and 125 people with the mutation who do not have Parkinson's. These participants will be followed for five years. By collecting data and samples over time from people who have not been diagnosed with the disease but who carry an associated genetic mutation, researchers can test for characteristics that may denote greater risk of disease onset or, conversely, protection from symptoms. 

Known genetic mutations currently account for only five to 10 percent of all Parkinson's cases. The vast majority of Parkinson's cases are idiopathic, meaning researchers do not know what causes the disease. However, study of individuals carrying PD-implicated genetic mutations may reveal disease traits that apply to all PD patients. The PPMI genetic cohort will expand understanding of the pathogenesis of both genetic and idiopathic Parkinson's disease.

Interested individuals can visit www.michaeljfox.org/ppmi/genetics. Similar to the LRRK2 mutation, the GBA mutation accounts for a greater number of PD cases among certain ethnic populations and families, notably those of Ashkenazi (Eastern European) Jewish descent. PPMI is particularly interested in testing individuals of this background who have Parkinson's or a close relative with the disease. 

PPMI: The Search for Parkinson's Biomarkers

Biomarkers - such as cholesterol level for heart disease - are substances, processes or characteristics of the body that indicate disease risk, onset and/or progression. They aid in diagnosis and disease management and help researchers stratify for clinical trials and test new drugs faster by measuring biological changes rather than waiting for clinical improvement. There are no validated biomarkers for Parkinson's disease, a reality researchers are hoping to change with PPMI.

Launched in 2010, PPMI is a longitudinal clinical study that collects standardized clinical, imaging and biologic data. Now taking place at 33 clinical sites around the world, the study completed initial enrollment of 423 recently diagnosed Parkinson's patients and 196 controls in April 2013. Since then, the study has expanded to include cohorts of individuals at increased risk of developing Parkinson's disease. Risk factors under study include genetics, REM sleep behavior disorder and smell loss. (Enrollment of the smell loss cohort was completed earlier this year.)

"By studying multiple cohorts, we're covering all bases to find and validate these biomarkers," said MJFF CEO Todd Sherer, PhD. "Expanding PPMI to include another genetic cohort allows science to push forward toward better therapies for people living with Parkinson's today and for those who may be at risk in the future." 

About The Michael J. Fox Foundation for Parkinson's Research As the world's largest nonprofit funder of Parkinson's research, The Michael J. Fox Foundation is dedicated to accelerating a cure for Parkinson's disease and improved therapies for those living with the condition today. The Foundation pursues its goals through an aggressively funded, highly targeted research program coupled with active global engagement of scientists, Parkinson's patients, business leaders, clinical trial participants, donors and volunteers.  In addition to funding more than $450 million in research to date, the Foundation has fundamentally altered the trajectory of progress toward a cure. Operating at the hub of worldwide Parkinson's research, the Foundation forges groundbreaking collaborations with industry leaders, academic scientists and government research funders; increases the flow of participants into Parkinson's disease clinical trials with its online tool, Fox Trial Finder; promotes Parkinson's awareness through high-profile advocacy, events and outreach; and coordinates the grassroots involvement of thousands of Team Fox members around the world. 

 http://health.einnews.com/article/256452174/CuekJjsDjrrpx3GITo view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/parkinsons-biomarker-initiative-expands-genetic-study-300054418.html

Results announced from Phase 1 single ascending dose study of PRX002, a monoclonal antibody for the potential treatment of Parkinson's disease

Last updated: Tuesday 24 March 2015 at 2am PST

Prothena Corporation plc, a late-stage clinical biotechnology company focused on the discovery, development and commercialization of novel protein immunotherapy programs, has announced positive results from a Phase 1 single ascending dose study of PRX002, a monoclonal antibody for the potential treatment of Parkinson's disease and other related synucleinopathies. PRX002 is the focus of a worldwide collaboration between Prothena and Roche.

PRX002 was safe and well-tolerated, meeting the primary objective of the study. Further, results from this study showed that administration of PRX002 leads to mean reduction of free serum alpha-synuclein levels of up to 96%. These overall results were highly statistically significant (p<0.00001). Reduction of free serum alpha-synuclein, a protein potentially involved in the onset and progression of Parkinson's disease and the target of PRX002, was shown to be robust, rapid and dose-dependent after just a single dose.

"There is genetic and pathological evidence that supports a causal role of alpha-synuclein in Parkinson's disease," said Todd Sherer, PhD, CEO of the Michael J. Fox Foundation for Parkinson's Research. "We applaud Prothena and Roche for their pioneering work in developing a potentially disease-modifying therapy for this progressive neurodegenerative disease that affects millions worldwide."

The Phase 1 double-blind, placebo-controlled, single ascending dose study enrolled 40 healthy volunteers. All volunteers enrolled were randomized 3:1 into five escalating dose cohorts (0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg or 30 mg/kg) to receive either PRX002 or placebo. No hypersensitivity reactions or drug-related serious adverse events were reported. PRX002 demonstrated favorable pharmacokinetic properties, supporting the current dosing frequency in the on-going Phase 1 multiple ascending dose study in patients with Parkinson's disease. There were no treatment emergent adverse events (TEAEs) in greater than 10% of subjects. The only TEAEs in greater than 5% of subjects were vessel puncture site pain, headache and viral infection. All PRX002-related adverse events were mild and no dose limiting toxicities were observed.

"We are extremely pleased with the results of the Phase 1 single ascending dose study as the mean reduction of free serum alpha-synuclein of up to 96% demonstrates the pharmacodynamic effects of PRX002," commented Gene Kinney, PhD, Chief Scientific Officer and Head of Research and Development at Prothena. "Importantly and for the first time in humans, we demonstrated that this robust, rapid and dose-dependent reduction of free serum alpha-synuclein was safe and well-tolerated. Thus, this approach may translate into a clinically meaningful delay or reversal of disease progression in patients with Parkinson's disease. We look forward to building upon these data with results from the on-going, multiple ascending dose study in patients with Parkinson's disease expected in the first half of 2016, where we will also be measuring levels of PRX002 in the cerebrospinal fluid and assessing additional biochemical, imaging and clinical biomarker endpoints. Separately, we are excited to co-host a symposium with Roche on March 21 at the 12th International Conference on Alzheimer's and Parkinson's Diseases and Related Neurological Disorders (AD/PD™ 2015) to continue to raise awareness of the role of alpha-synuclein as a target for Parkinson's disease."

"The results of the PRX002 study exemplify Prothena's deep domain expertise to develop novel disease-modifying protein immunotherapies with unique specificities to their targets," stated Dale Schenk, PhD, President and Chief Executive Officer of Prothena. "Prothena's consistent ability to develop targeted potential therapeutics has resulted in a strong and promising pipeline to transform patient's lives, with NEOD001 in Phase 3 clinical studies for the treatment of AL amyloidosis, PRX002 continuing in a Phase 1 multiple ascending dose study in patients with Parkinson's disease and PRX003 ready to begin clinical studies for the treatment of psoriasis and potentially other inflammatory diseases."

In December 2013, Prothena and Roche entered into a worldwide collaboration to develop and commercialize antibodies that target alpha-synuclein, including PRX002. To date, Prothena has received $45 million of the potential $600 million in total milestones through its collaboration with Roche. Prothena has an option to co-promote PRX002 in the U.S., where the companies share all profits, as well as development and commercialization costs, on a 30/70 basis (30% Prothena and 70% Roche). Outside the U.S., Roche will have sole responsibility for developing and commercializing PRX002 and will pay Prothena up to double-digit royalties on net sales.

Adapted by MNT from original media release

http://www.medicalnewstoday.com/releases/291315.php?tw

UCSF team finds key to making neurons from stem cells

Last updated: Monday 23 March 2015 at 12am PST

Pnky, a noncoding RNA found in brain stem cells, may have a broad range of clinical applications

A research team at UC San Francisco has discovered an RNA molecule called Pnky that can be manipulated to increase the production of neurons from neural stem cells.

The research, led by neurosurgeon Daniel A. Lim, MD, PhD, and published in Cell Stem Cell, has possible applications in regenerative medicine, including treatments of such disorders as Alzheimer's disease, Parkinson's disease and traumatic brain injury, and in cancer treatment.

Pnky is one of a number of newly discovered long noncoding RNAs (lncRNAs), which are stretches of 200 or more nucleotides in the human genome that do not code for proteins, yet seem to have a biological function.

The name, pronounced "Pinky," was inspired by the popular American cartoon series Pinky and the Brain. "Pnky is encoded near a gene called 'Brain,' so it sort of suggested itself to the students in my laboratory," said Lim. Pnky also appears only to be found in the brain, he noted.

Co-first authors Alex Ramos, PhD, and Rebecca Andersen, who are students in Lim's laboratory, first studied Pnky in neural stem cells found in mouse brains, and also identified the molecule in neural stem cells of the developing human brain. They found that when Pnky was removed from stem cells in a process called knockdown, neuron production increased three to four times.

"It is remarkable that when you take Pnky away, the stem cells produce many more neurons," said Lim, an assistant professor of neurological surgery and director of restorative surgery at UCSF. "These findings suggest that Pnky, and perhaps lncRNAs in general, could eventually have important applications in regenerative medicine and cancer treatment."

Lim observed that Pnky has an intriguing possible connection with brain tumors.

Using an analytical technique called mass spectrometry, Ramos found that Pnky binds the protein PTBP1, which is also found in brain tumors and is known to be a driver of brain tumor growth. In neural stem cells, Pnky and PTBP1 appear to function together to suppress the production of neurons. "Take away one or the other and the stem cells differentiate, making more neurons," said Lim. "It is also possible that Pnky can regulate brain tumor growth, which means we may have identified a target for the treatment of brain tumors."

Lim said that the larger significance of the research is that it adds to a growing store of knowledge about lncRNAs, previously unknown sections of the genome that some biologists have referred to as the "dark matter" of the human genome.

"Recently, over fifty thousand human lncRNAs have been discovered. Thus, there may be more human lncRNAs than there are genes that code for proteins," said Lim. "It is possible that not all lncRNAs have important biological functions, but we are making a start toward learning which ones do, and if so, how they function. It's a new world of experimental biology, and the students in my lab are right there on the frontier."

Lim had particular praise for Ramos, an MD-PhD student in the UCSF Medical Scientist Training Program, and Andersen, who has a fellowship from the prestigious National Science Foundation (NSF) Graduate Research Fellowship Program. "They have been a great collaborative team and an inspiration to others in my lab," said Lim. "I think they represent the pioneering, investigative spirit of the UCSF student body. 

Adapted by MNT from original media releasehttp://www.medicalnewstoday.com/releases/291203.php?tw

Long-term effect of deep brain stimulation on pain in patients with Parkinson's disease

Immunohistochemistry for alpha-synuclein showing positive staining (brown) of an intraneural Lewy-body in the Substantia nigra in Parkinson's disease. Credit: Wikipedia

Patients with Parkinson disease who experienced pain before undergoing subthalamic nucleus deep brain stimulation (STN DBS) had that pain improved or eliminated at eight years after surgery, although the majority of patients developed new pain, mostly musculoskeletal, according to an article published online by JAMA Neurology.

Pain is a common nonmotor symptom in patients with Parkinson disease and it negatively impacts quality of life.

Beom S. Jeon, M.D., Ph.D., of the Seoul National University Hospital, Korea, and coauthors evaluated the long-term effect of STN DBS on pain in 24 patients with Parkinson disease who underwent STN DBS. Assessments of pain were conducted preoperatively and eight years after surgery.

Of the 24 patients, 16 (67 percent) experienced pain at baseline when not taking their medication and had an average pain score of 6.2, on a scale where 10 was maximal pain. All baseline pain improved or disappeared at eight years after surgery, according to the results. However, the authors discovered new pain developed in 18 of 24 patients (75 percent) during the eight-year follow-up. New pain impacted 47 body parts and the average pain score for new pain was 4.4. In most of the patients (11), new pain was musculoskeletal characterized by an aching and cramping sensation in joints or muscles, the authors note.

"We found that pain in PD [Parkinson disease] is improved by STN DBS and the beneficial effect persists after a long-term follow-up of eight years. In addition, new pain developed in most of the patients during the eight-year follow-up period. We also found that STN DBS is decidedly less effective for musculoskeletal pain and tends to increase over time. Therefore, musculoskeletal pain needs to be addressed independently," the study concludes.

In a related editorial, Richard B. Dewey, Jr., M.D., and Pravin Khemani, M.D., of the University of Texas Southwestern Medical Center, Dallas, write: "Because previous studies on pain following STN DBS for PD are of short duration, the durability of the procedure's effect on pain is not well established. The chief strength of the work by Jung and colleagues is the long follow-up period, which suggests that, although DBS may relieve pain for a time, this is not a durable effect owing to the onset of new, primarily musculoskeletal pain."

"Despite its limitations, the study by Jung and colleagues provides a novel perspective on the durability of the pain-relieving properties of STN DBS in PD. The authors direct our attention to the fact that musculoskeletal painmay emerge years after DBS, warranting individualized treatment," they continue.

"Although there is growing consensus that STN DBS decreases the level of pain in people with PD, the literature is mixed on the subtypes of pain that are responsive to DBS, and the study by Jung and colleagues shows that new pain arising years after the procedure is common. This underscores the importance of performing future trials with larger cohorts, longer observational periods and standard methods to enable effective interpretation of outcomes. For now, we have learned that STN DBS does not take the ouch out of PD in the long run," the editorial concludes.

 Explore further: Deep brain stimulation improves non motor symptoms in Parkinson's disease

More information: JAMA Neurol. Published online March 23, 2015. DOI: 10.1001/jamaneurol.2015.8 

http://health.einnews.com/article/256272340/iQ1sHtuqhTiKVA74

JAMA Neurol. Published online March 23, 2015. DOI: 10.1001/jamaneurol.2015.36

UF physician part of Parkinson’s panel at White House

In this image from an online video, Dr. Michael Okun speaks during panel discussion about Parkinson's disease at the White House on Monday.

The White House

By Christopher Curry
Staff writer

Published: Monday, March 23, 2015 at 11:50 a.m.

Last Modified: Monday, March 23, 2015 at 11:50 a.m.

A UF Health physician and researcher was part of a panel of experts who gathered at the White House Monday morning to discuss progress and challenges in the treatment of Parkinson’s disease.

“The mind-blowing changes we can see from research are really amazing,” said Dr. Michael Okun, the co-director and co-founder of the UF Health Center for Movement Disorders and Neurorestoration.

Okun, who is also the medical director of the National Parkinson Foundation, described Parkinson’s as “the most complex disease in medicine. Period.”

But he said its complexity has also led to some treatment techniques that people decades ago may not have imagined possible. He pointed to deep brain stimulation, or “pushing” electricity deep into a patient’s brain to change its circuitry and improve their condition.

Okun and other panel members said the progress to date in research and treatment could slow or stall if research funding from the National Institutes of Health is not increased.

But Panel member Dr. Caroline Tanner, the director of the Parkinson’s Disease Research, Education and Clinical Center at the San Francisco Veterans Affairs Medical Center, said the funding trend has been moving in the opposite direction, with less money available and grants more difficult to obtain.

During a morning that also included discussions featuring patients and their caregivers, Okun said Parkinson’s is a “disease that affects the family.” He said that while doctors are often the “center of the universe” in medicine, with Parkinson’s, the “patient is the sun” and everything must revolve around him or her.

The panel discussion was part of the White House’s Champions for Change for Parkinson’s Disease event. 

Okun co-founded the UF Health Center for Movement Disorders and Neurorestoration in 2002. The center has treated several thousand patients and tracks nearly all of them in “one of the largest research databases of movement disorders in the world,” according to UF Health

http://health.einnews.com/article/256280988/BAjly8NBt1QGInSC