08 Feb 2012

Although some Parkinson’s medications ease symptoms, none stop the disease in its tracks. Researchers hope to get closer to the goal of disease-modifying treatment by studying people who carry PD risk mutations in the LRRK2 gene. By assembling a genetically defined group of people at very high risk of developing Parkinson’s from several different nations, researchers expect to be able to observe presymptomatic stages of the disease and to characterize the sequential steps in its pathology. Besides refining emerging biomarkers for predicting onset and tracking progression, such data would also yield clues to the biology behind PD while fingering potential therapeutic targets, scientists said. To that end, scientists have built a consortium to study some 2,000 people worldwide who carry LRRK2 mutations. Dubbed the LRRK2 Cohort Consortium and funded by the Michael J. Fox Foundation (MJFF), the study is on track to finish recruiting participants this year, with data rolling in over the next several years.

The LRRK2 Cohort Consortium is quite similar to genetic initiatives in the Alzheimer’s disease field, such as the Dominantly Inherited Alzheimer Network (DIAN; see ARF related news story) or the Alzheimer's Prevention Initiative (API; see ARF related news story). Like these efforts, the LRRK2 Consortium aims to set the stage for clinical trials of disease-modifying treatments in early-stage or presymptomatic populations. As one of many large research initiatives in the PD field, the LRRK2 Consortium reflects a general trend in neurodegenerative research toward multicenter, cooperative observational studies. In the AD field, besides API and DIAN, these are, for example, the Alzheimer’s Disease Neuroimaging Initiative (ADNI), whose correlate in PD is the Parkinson’s Progression Markers Initiative (PPMI). Modeled after ADNI, the PPMI follows recently diagnosed PD patients to identify multiple biomarkers of disease progression. The Parkinson's Associated Risk Study (PARS) aims earlier, gathering data from the general population to look for biomarkers that precede sporadic PD.

The LRRK2 Consortium presents a unique opportunity because it allows researchers to target a high-risk population. “Because it’s a genetically defined group of individuals, it gives us the chance to study people before they get the symptoms of PD, and that allows us to look earlier in the disease process,” said Brian Fiske, who directs research programs at MJFF. At the core of the LRRK2 Cohort Consortium is a longitudinal study in the Ashkenazi Jewish population, where the G2019S LRRK2 mutation is common. This study is complemented by efforts in eight other specific populations worldwide, all of which will pool data, Fiske said.

Why LRRK2? The gene currently sits at number 4 on the PDGene Top Results. Together, its five known mutations account for up to 2 percent of all PD cases. Additionally, the G2019S mutation occurs in about 4 percent of familial cases in people of European ancestry (see, e.g., Ozelius et al., 2006). These variants confer a greatly increased risk for PD; for example, G2019S carriers face a 16-fold higher risk than the general population, roughly similar to the AD risk conferred by two copies of ApoE4. Google co-founder Sergey Brin carries the G2019S mutation (see Scientific American story).

In addition, the LRRK2 protein presents an attractive therapeutic target because it is a kinase, a type of protein that regulates the activities of other proteins. Because of the importance of kinases in cancer research, pharmaceutical companies are experienced at inhibiting these enzymes, and have expressed interest in going after LRRK2 for drug development, Fiske said. “LRRK2 is a priority target for us,” Fiske told ARF (see MJFF LRRK2 position paper).

Besides encouraging the pharmaceutical industry to invest in PD treatments, the LRRK2 Cohort Consortium will benefit basic science, said Mark Cookson at the National Institutes of Health, Bethesda, Maryland. “For those of us who run basic labs, we get up every morning and we dream that one day we’re going to have [a treatment] to put into patients…. But we know very little about the progression of these diseases. Unless people start putting together cohorts like this, we’re all going to be floundering around.” Most current knowledge of the disease comes from cross-sectional studies, which provide little insight into how the disorder progresses, Cookson added. “This effort is critical.”

Andrew Siderowf at the University of Pennsylvania, Philadelphia, who heads the PARS study, noted that the PARS, PPMI, and LRRK2 Cohort Consortium efforts all complement each other. “I think the data from the three studies can all be put together,” Siderowf said. He pointed out that, while the other initiatives focus on specific disease stages, the LRRK2 study “uses the leverage from having a known molecular abnormality to study PD across the spectrum” from presymptomatic to advanced stages. “This is a really important initiative,” he added.

Longitudinal Data: The Ashkenazi Jewish Study
The LRRK2 mutation G2019S is particularly common among Ashkenazi (i.e., Eastern European) Jews, accounting for up to 20 percent of PD cases in them. The LRRK2 Cohort Consortium includes three research groups that have been studying Ashkenazi cohorts; the principal investigators are Susan Bressman at Beth Israel Medical Center and Karen Marder at Columbia University, both in New York City, and Nir Giladi and Avi Orr-Urtreger at Tel Aviv University, Israel. Funded since 2009 (see MJFF grant), the three groups are coordinating their efforts in a five-year longitudinal study.

One goal of the Ashkenazi Jewish study is to understand the biology of LRRK2 and how it contributes to disease, Bressman said. For example, does PD due to a LRRK2 mutation differ from idiopathic PD? At the 10th International Conference on Alzheimer’s and Parkinson’s Diseases, held March 2011 in Barcelona, Spain, Bressman presented preliminary data suggesting that the two are largely the same on clinical and imaging measures. The G2019S mutation seems to cause a slightly milder, more slowly progressing form of PD than seen in sporadic cases, and with less cognitive impairment, Bressman said. But, by and large, this LRRK2 mutation leads to typical Parkinson’s pathology with Lewy bodies. “This is a terrific genetic model of idiopathic Parkinson’s disease,” Bressman concluded.

One intriguing puzzle is why G2019S mutations do not always cause disease. LRRK2 mutations are less penetrant than most mutations studied in DIAN and API, for example, making LRRK2 more of a strong risk gene than a deterministic one. The researchers will look for genetic modifiers and environmental factors that explain this reduced penetrance, Bressman said. If scientists can uncover how LRRK2 leads to disease, and why some carriers escape it, it may point the way toward novel therapeutic interventions, she speculated.

The second major goal of the Ashkenazi study is to identify risk and progression biomarkers in the LRRK2 population, and then see if the same set of markers also applies to other populations at high risk for PD, Bressman said. If so, the markers will enable investigators to select appropriate presymptomatic participants for clinical trials, as well as monitor the effects of interventions on disease progression.

Bressman told ARF that, to date, the Ashkenazi piece of the LRRK2 Cohort Consortium has identified some 150 PD patients (or “probands”) with the G2019S LRRK2 mutation. Each proband brought in family members, both non-carriers as well as carriers who do not have the disease. In addition, the researchers are enrolling non-LRRK2 PD cases and healthy controls, so Bressman expects the total number of participants to approach 700. In the coming year, the three centers (at Beth Israel, Columbia, and Tel Aviv) will finish enrolling volunteers and completing their first clinical and diagnostic evaluation. Some of the earliest-enrolled participants are already coming back for their first 15-month follow-up appointment, Bressman noted. For the most part, patients and family members have been enthusiastic about participating, Bressman added.

Participants undergo a neurological workup, as well as tests of various systems known to be disturbed in early PD, such as smell, sleep, and gait. The three sites collect biological samples including blood, urine and, in a subset of patients, cerebrospinal fluid (CSF). Bressman said that her site will use these samples to measure DNA, RNA, and gene expression. The sites are not currently measuring α-synuclein levels in the CSF, although that may come later, Bressman said. They will also perform brain scans including an ultrasound of the substantia nigra, a DaTscan (SPECT imaging that reveals the integrity of the dopamine system), and, at the Israel site, functional MRI.

LRRK2 Research Joins Forces Across the Globe
The Ashkenazi Jewish study forms part of the broader LRRK2 Cohort Consortium, which encompasses a total of 11 sites in eight countries. In 2009, the MJFF began supporting a study in Berbers, a North African indigenous population in whom the G2019S mutation accounts for up to 40 percent of all PD cases. The following year, the Foundation reached out to other international groups studying LRRK2, and now supports studies in Norway, Germany, Spain, and France, all of which have populations carrying the G2019S variant. In addition, the Consortium includes a Chinese population, where a different LRRK2 mutation, G2385R, is more common.

Sites worldwide are currently recruiting participants, Fiske told ARF. He expects that, including the Ashkenazi Jewish participants, the total initiative will eventually include 1,000 PD patients with LRRK2 mutations, 1,000 unaffected carriers of those mutations, and 1,000 other participants such as healthy controls and non-LRRK2 PD cases. Most of the sites are funded for two years, but the Foundation is considering extending some of them into longitudinal studies, if possible, Fiske added.

All sites are collecting a basic set of data that, at a minimum, includes standard clinical and diagnostic exams as well as blood and urine samples, Fiske said. Unlike in the Ashkenazi Jewish piece of the Consortium, only some sites also collect CSF and imaging data. Ken Marek at the Institute for Neurodegenerative Disorders in New Haven, Connecticut, is in charge of standardizing DaTscan protocols for the Consortium (see MJFF research grant). As is done between ADNI and DIAN, here, too, data collection has been standardized across sites and matches protocols used by PPMI. That way, data from the Consortium can inform PPMI efforts and vice versa, Fiske said. Investigators enter all data into a shared database at the University of Rochester, and store biological samples in various repositories: Coriell Institute for Medical Research in Camden, New Jersey, for the North American sites; BioRep in Milan, Italy, for Europe; and at other repositories elsewhere. The ultimate goal is to make the data and samples available to all scientists studying PD, Fiske said, in the same way that PPMI data is open-access.

Plumbing the Mysteries of LRRK2
The LRRK2 Cohort Consortium is but one piece of a broader LRRK2 strategy that MJFF is pursuing, Fiske emphasized. The Foundation is developing research tools such as LRRK2 antibodies and animal models that they plan to make freely available to investigators. MJFF also supports a LRRK2 Biology Consortium consisting of more than 30 laboratories that investigate the basic biology of the protein, trying to figure out what it is doing in cells and how it might affect PD pathology. People with PD-linked LRRK2 mutations show no specific LRRK2 neuropathology, only what is seen in idiopathic PD, Fiske noted. “It’s possible LRRK2 plays some kind of upstream role that might link a number of different PD pathways together,” Fiske speculated.

The goal of a LRRK2-based therapy would be to halt disease progression, rather than treat symptoms, Fiske pointed out. To translate treatments to the clinic, “You need to not only know the biology, but also have the right model systems to test drugs. You need an engaged patient population and know how to target them, and what kind of things you would want to measure in those individuals,” Fiske said. “We’ve taken a multipronged approach to try to tackle all of these different things in parallel.” He hopes these initiatives will lead to clinical trials in early-stage or presymptomatic PD populations before too long. Both DIAN and API, which got started in 2008 and 2009, respectively, are aiming to offer their participants a first clinical trial before 2012 is out.—Madolyn Bowman Rogers.

More Than a LRRK: PD Field Thinks Big With Genetic Cohort

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