Restless Legs Syndrome Foundation Blog

By Stefan Clemens, PhD, HdR, Chair, Research Committee, RLS Foundation Scientific and Medical Advisory Board

The RLS Foundation’s Research Grant Program is a return-on-investment initiative; member contributions lead to advances in the understanding of RLS and to potential improvements in treatment options. The RLS Foundation established the Research Grant Program in 1997 under the leadership of Bob Waterman (Board of Directors member with two terms as Board Chair, 1995–2005 and 2011–2019). The idea was to award small research grants seed funding to provide the critical data necessary to secure additional research grants from national and international agencies.

The first research grant was awarded in 1999. Since then, an average of about two projects per year have been funded. To date, 48 grants have been supported by the RLS Foundation, totaling nearly $2 million in research funding. These 48 projects were carried out by 41 clinicians and researchers. Their findings have led to over 25 publications in a wide range of neurological and neurobiological journals and books. More importantly, the seed-funding grants provided by the RLS Foundation have led to over $10 million in additional grant support from other sources, thereby further strengthening research in the field of RLS.

Research grant applications are first reviewed by the RLS Foundation’s Scientific and Medical Advisory Board (SMAB); details about its members can be found at www.rls.org/SMAB. The SMAB consists of both clinicians and basic science researchers who are responsible for monitoring RLS medical and scientific research issues and bringing their respective expertise to the grant review sessions. In addition to reviewing research grant applications, the SMAB reviews all Foundation publications and advises the RLS Foundation’s Board of Directors on issues of medical or scientific interest and importance. A group of external specialists approved by the SMAB has agreed to serve as grant reviewers to strengthen the rigor of the research supported by the RLS Foundation and to provide additional guidance. Research grant proposals that receive a favorable decision by the SMAB are then presented to the RLS Foundation’s Board of Directors for funding consideration.

Since its inception, the grant program has focused on specific areas of study: genetics, epidemiology, iron regulation, neurophysiology, the development of novel treatment options and RLS animal models. Based on the findings of research in these areas, the SMAB recently developed new guidelines and funding priorities for future grant proposals that are summarized here:

Brain Iron Homeostasis: RLS is regularly associated with changes in brain iron function.

• Research Target: Elucidate the biological factors that contribute to RLS-relevant alterations in iron homeostasis in the nervous system.

Genetic/Epigenetic Factors: Multiple studies have underscored the role of specific genetic and epigenetic factors in the development of RLS. Genetic factors refer to factors that stem from familial heredity or gene mutations; epigenetic factors refer to changes in a person’s genome as a function of, for example, exposure to environmental factors.

• Research Target: Identify genetic and epigenetic factors and their interactions in RLS patients and develop animal models in which these interactions can be better explored in mechanistic detail.

Comorbidities: RLS is often associated with a wide range of other neurological and non-neurological diseases. What is the impact of RLS on other ailments such as cardiovascular disease, sleep apnea or Parkinson’s disease?

• Research Target: Identify any possible causal links between RLS and these other diseases.

Neurobiological Interactions: A variety of signaling molecules have been identified in the nervous system that are changed with RLS. It is often unclear, however, if the changes in these signaling molecules are themselves causing RLS symptoms or if they are a result of other changes.

• Research Target: Identify RLS-relevant neurotransmitters and neural pathways that may be implicated in RLS.

Therapeutics, Pharmacological Treatments and Therapeutic Responsiveness: A wide range of medications is used to treat RLS, and many of these compounds can lead to unwanted side effects, such as tolerance or augmentation.

• Research Target: Explain the pharmacology of existing RLS medications, develop novel approaches that show better efficacy or fewer side effects, and generally advance knowledge toward development of better treatments of RLS.

Nonpharmacological Treatments: In addition to current pharmacological treatment options, RLS patients may find benefit from nonpharmacological approaches. These include, but are not limited to: transcranial or spinal magnetic or electric stimulation; transcranial direct current stimulation; cognitive behavioral therapy; and intermittent compression of the lower limbs.

• Research Target: Describe the mechanisms in nonpharmacological treatments that lead to the improvement of RLS symptoms.

Novel Diagnostic Markers: Identifying RLS relies on the subjective feedback of a patient to their clinician.

• Research Target: Develop better assessment techniques or devices that will provide improved outcome measures for clinical research.

The RLS Foundation plans to open a new series of biannual calls for submissions of research grant applications with rotating main themes, in which submissions will be prioritized around the above-listed research areas. The RLS Foundation will also be seeking grant submissions from specialists in these respective areas, to increase the scientific depth and widen the breadth in RLS-related research. Additionally, the RLS Foundation has set aside funds for one predoctoral or postdoctoral fellowship grant per year to attract promising young investigators to the field. To contribute directly to that fund, go to www.rls.org/AllenFund.

These changes to the RLS Foundation’s Research Grant Program will improve our understanding of RLS in the clinic, spearhead new approaches and treatments in the lab, identify new and emerging drugs and technologies, and improve patient outcomes by engaging an increasing number of clinicians and researchers dedicated to finding a cure for RLS.

Yuqing Li, PhD, 2015 RLS Foundation Grant Recipient, Awarded NIH Funding

The National Advisory Neurological Disorders and Stroke Council (NANDSC), a division of the National Institutes of Health (NIH), awarded a grant to Yuqing Li, PhD, a professor of Neurology and Neuroscience at the University of Florida. Dr. Li and his team will further investigate the genetic mechanisms that are involved in the development of restless legs syndrome.

Dr. Li will build on his previous research concerning the role of the MEIS1 gene in RLS, which was made possible with an RLS Foundation grant he received in 2015. Li’s work involved exploration of an animal model in which he and his team performed a detailed analysis of MEIS1 mutant mice to determine whether they showed RLS symptoms. They also examined the brain’s dopamine system to identify areas affected by the MEIS1 mutation.

“I want to take this opportunity to express my gratitude for the Foundation grant in 2015,” said Li, who published three papers on MEIS1. “The funding allowed us to collect the necessary preliminary data to apply for this NIH grant.”

Li says the Foundation grant allowed him to identify changes in the dopamine and cholinergic systems in the brains of the mutant animals, which suggests that they could be important in causing RLS.

“With the NIH grant award, we are going to develop animal models with MEIS1 altered only in dopaminergic or cholinergic systems,” said Li. “This will allow us to determine the relative importance of the two systems in causing the RLS. We may find out that both systems are important, or one is crucial and leads to the changes in the other. This kind of knowledge will allow us to have a better understanding of how RLS can develop in patients and develop better-targeted therapies for RLS patients.”

The support of the Foundation members has led to the funding of 48 grants totaling over $1.8 million in funding. “The RLS Foundation is excited by the news of this NIH award to Dr. Li. This study will help to expand our knowledge and understanding of the disease leading to development of targeted therapies and, hopefully, a cure,” said Dzienkowski, RLS Foundation executive director. To support the RLS Foundation Research Grant Program go to www.rls.org/donate.

New Study Funded by RLS Foundation

By Kris Schanilec

The RLS Foundation has awarded a grant of $36,398 to Sergi Ferré, MD, PhD, of the National Institute on Drug Abuse, for a study to explore how opioid medications work in the brain to relieve RLS symptoms. This research builds on several Foundation-funded studies previously conducted by Dr. Ferré, who is a member of the RLS Foundation Scientific and Medical Advisory Board.

“Dopamine agonists, alpha-2 delta agents and opioids are highly effective in treating RLS,” says Christopher J. Earley, MB, ChB, PhD, FRCPI, chair of the Scientific and Medical Advisory Board. “Dr. Ferré’s grant is the first to try and understand the biologic elements that may be common to these three classes of drugs that makes them so effective in treating RLS, thus opening the door for future drug development.”

Opioid medications act on three types of opioid receptors in the brain. One of these – the mu opioid receptor – is the target of the opioid medications, such as methadone, that are a very effective treatment for severe RLS when used in low total daily doses. RLS is a neurological disease that has a distinctly different underlying neuropathology than that associated with typical pain syndromes. Clinical experience among experts who use opioids to treat severe RLS has not shown the degree of drug misuse, dependency or addiction that is commonly associated with opioid use to treat chronic pain.*

In the current study, “Elucidating the mechanisms of the therapeutic effects of opioids in RLS,” Dr. Ferré’s team aims to identify the locations of mu opioid receptors involved in improving RLS symptoms with opioids. With this information, they hope to determine if specific opioid medications could selectively act on these mu opioid receptors, reducing the risk of unwanted side effects.

In previous studies funded by the RLS Foundation, Dr. Ferré’s laboratory developed an animal model for RLS using a brain iron-deficient rodent that models the brain iron deficiency that is characteristic of RLS in humans. Their model combines two techniques, optogenetics and microdialysis, to trigger and measure the release of glutamate from brain cells in live animals. The researchers used this model to confirm that brain iron deficiency increases the release of glutamate in the brain area known as striatum; other studies have reported increased glutamate in the RLS brain.

Dr. Ferré’s team also validated that several RLS drugs – the dopaminergic drugs pramipexole and ropinirole, and the alpha- 2-delta ligand gabapentin – work by counteracting this high release of glutamate. In addition, the researchers pinpointed a subtype of receptor in the brain – the dopamine D4 receptor – as a main target for the effects of the dopaminergic drugs in the striatum, and therefore, as a new target for drug development.

In a more recent study, Dr. Ferré’s laboratory reported that low levels of receptors of the neurochemical adenosine are responsible for the high levels of glutamate released in the striatum. This finding has led to exploration of drugs that increase adenosine levels in the brain – for example, dipyridamole – as a new treatment approach for RLS. According to Dr. Ferré, the reduced levels of adenosine receptors (specifically, the adenosine A1 receptors) may be the underlying cause of not only restless legs, but also the state of enhanced wakefulness (hyperarousal) experienced by people who have RLS.

In the current study, the researchers will focus on a specific neuron in the striatum, the cholinergic interneuron, which releases the neurotransmitter acetylcholine and has a high number of both adenosine A1 receptors and mu opioid receptors. The researchers hypothesize that in RLS, there are fewer adenosine A1 receptors in these cholinergic interneurons, which therefore become overactive and release more acetylcholine. The researchers also hypothesize that opioids should be able to counteract this by activating mu opioid receptors in the cholinergic interneurons. Dr, Ferré’s team will use its animal model to explore these questions.

“If the results of the study confirm our hypotheses, we will have probably found the main mechanism of the therapeutic effect of opioids in RLS,” says Dr. Ferré. “Those results would then stimulate the search for opioids with a preferential efficacy for the mu opioid receptors localized in the striatum, in the cholinergic interneurons, which should be absent of unwanted side effects.”

The RLS Foundation is grateful for the generosity of individuals whose financial gifts make this work possible, says Executive Director Karla Dzienkowski. “The Foundation’s research grant program is dedicated to find better treatments and, ultimately, a cure for RLS. This study will help us to understand why opioid medications are effective at relieving severe, unrelenting symptoms of restless legs syndrome, which will lead to an improved quality of life for people with RLS,” Dzienkowski says.

*If opioid therapy is a treatment option to manage your RLS symptoms, your healthcare provider will work closely with you to find the dose that manages your symptoms while minimizing side effects of therapy.

The RLS Foundation has awarded a $22,100 grant to John Winkelman, MD, PhD, of Harvard Medical School and Massachusetts General Hospital to continue his study on the long-term use of opioids to treat RLS. Dr. Winkelman received a grant from the Foundation in 2017 to support the first stage of this research.

“The funding extension will help the researchers obtain valuable information from long-term follow-up of patients,” says Karla Dzienkowski, executive director of the Foundation. “This is the first study in which patients with RLS who use opioids are monitored over time to evaluate the effectiveness and tolerability of this treatment long-term, and by far the largest observational study of such patients.”

Opioids are an established, highly effective treatment option for people with severe RLS when other therapies have failed. However, concrete data is lacking on long-term use of these medications for RLS. By gathering data over time, Dr. Winkelman’s team will evaluate the effectiveness, tolerability and safety of opioids for treating RLS, and aim to further understand how factors such as behavior and mood may influence opioid effectiveness and safety.

This much-needed data will help physicians and patients make more informed treatment decisions, especially in the face of increasingly strict opioid regulations limiting access at the state and federal levels.

Over the past year, Dr. Winkelman’s team has created a national registry of patients who take opioid medications for RLS. As of December, the researchers had enrolled 360 participants – far surpassing their goal of 200. Participants complete a phone interview and an online survey covering a range of topics related to their RLS symptoms, treatment, medical history, habits and behaviors. They then complete follow-up surveys every six months. All stored information is confidential and anonymous.

The study will remain open to new participants until approximately late June. Enrollment is limited to individuals who have a diagnosis of RLS, are taking an opioid medication to treat their RLS symptoms, and have previously taken or are currently taking a dopamine agonist for RLS treatment. For information about participating, see rls.org.

Please note that no consultation, advice about clinical care, or medication is provided through this study.