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Part 2 of a 4-Part Series on the History of the DMRF Research Support
Why Does the DMRF Fund Basic Research?
How Studying Drug Targets Led to More Effective Dystonia Treatments
The founding of the Dystonia Medical Research Foundation in 1976 came at a time when the study of movement disorders was transitioning from a loosely defined area to a recognized neurological subspecialty. Then, as now, the DMRF funded research related to drug targets, which are molecules in the body, usually proteins or nucleic acids, that are essential in a disease process and can be
manipulated by a drug to correct or interrupt their function.
Christian Schlieker, PhD, (third from left) at the Yale School of Medicine with his team of researchers at the Schlieker lab. Dr. Schlieker is working on a DMRF-funded research project to identify the genetic networks involved in DYT-TOR1A dystonia. The study will explore disease-causing gene networks that could become novel drug targets.
Identifying drug targets for dystonia has been critical to developing new medications and/or existing drugs that may be effective. This process takes time, and ongoing funding for basic research is essential to ensuring that the pace of discovery doesn’t slow down.
1970s–1980s: Early Dystonia Research Trials and Treatments
Hyder A. (Buz) Jinnah, MD, PhD, from the Emory University School of Medicine and member of the DMRF Medical and Scientific Advisory Council (MSAC), noted that early trials for dystonia treatments often involved medications already approved for other disorders.
“The initial attempts were mainly trial and error and not always based on a specific drug target,” Dr. Jinnah explained. “As you can imagine, there were a lot of trials that did not work out, and this trial-and-error process was very frustrating to patients.”
The first brain region linked to dystonia was the basal ganglia. This finding led many investigators to consider focusing on drugs that were known to affect neural signaling in the basal ganglia, like dopamine. There were numerous trials of drugs that either suppressed or amplified dopamine signaling. These early trials discovered one population of dystonia patients had a dramatic response to levodopa. It was called dopa-responsive dystonia (a term that was coined in 1988, which refers to a group of inherited dystonias that improve dramatically with levodopa). Children with profoundly disabling dystonia were able to get out of their wheelchairs and walk normally, and physicians still use levodopa treatment for this form of dystonia. In other patient populations, dopamine related drugs seemed to have at least some benefit, although not as dramatic as with dopa-responsive dystonia.
Dr. Jinnah added that the study of neurotransmitters has had a big impact on the approach to treating many neurological disorders, including dystonia. “The basic idea was that if brain regions used neurotransmitters to communicate, then we might be able to modify this communication by using drugs that influence this neural signaling,” he said. “This is the concept that drove early trials of dopamine-related drugs.”
Another basal ganglia neurotransmitter was acetylcholine, leading to trials of anti-cholinergic drugs, which block the neurotransmitter acetylcholine. In 1986, Robert E. Burke, MD; Stanley Fahn, MD; and CD Marsden, MD published the results of a clinical trial in the Neurology journal which found that high-dosage trihexyphenidyl therapy (known by the brand name Artane) is effective in the management of torsion dystonia. While these drugs seemed to be beneficial, they had a lot of side effects, limiting their popularity. Dr. Jinnah noted that there are companies currently working to develop newer anti-cholinergics with fewer side effects. Botulinum toxins (BONT) also target neural signaling; but instead of targeting signaling in the brain, they target signaling at the neuromuscular junction. “Botulinum toxins were already known to produce muscle weakness, so the idea was that this ability to cause weakness might be used to advantage in disorders where muscle pulling was too strong,” said Dr. Jinnah. “They were basically diluted out and given in such small amounts that they can suppress over-active muscles, like in dystonia.”
Health Canada approved Botox® for the treatment of blepharospasm in 1990, and for cervical dystonia in 2000. There are now brands of BoNT approved in Canada for the treatment of dystonia, with several companies now working to improve them by making their effects last longer.
1990s: The Role of Genetics in Target Driven Research
By the 1990s, genetic discoveries began broadening scientists’ understanding of certain types of dystonia. For example, dopa-responsive dystonia had been clinically described and defined by Masaya Segawa, MD, PhD, by the mid-1970s, but it wasn’t until 1994 that a research team led by Hiroshi Ichinose, PhD, identified mutations in the DYT5 gene (specifically the GCH1 gene) that were associated with this form of dystonia.
According to Christian Schlieker, PhD, from the Yale School of Medicine whose research is currently funded by the DMRF, the identification of the DYT1 gene by Xandra Breakefield, PhD and Laurie Ozelius, PhD in the late 1990s was a breakthrough in the modern era of target-driven dystonia research.
“DYT1 represents a common inherited form of dystonia, and its discovery was a true landmark for the field,” explained Dr. Schlieker. “Now a clearly defined disease-causing allele could be linked to a condition that had previously been clinically recognized but biologically ill-defined. This finding fundamentally shifted dystonia research from symptom-based descriptions toward a mechanistic, molecular framework.”
Dr. Schlieker added that the identification of the DYT1 mutation catalyzed efforts by many researchers, including those funded by the DMRF, to define the underlying defect at the protein level. These studies revealed that TorsinA—a protein crucial for neuron development—is a highly unusual AAA+ ATPase (a large superfamily of motor proteins) and that the disease mutation disrupts its activation mechanism.
“This insight reframed dystonia as a disorder of specific molecular pathways, highlighting concrete targets for therapeutic intervention,” Dr. Schlieker said.
Building on the success of DYT1, advances in sequencing technologies rapidly expanded the catalog of dystoniaassociated genes. This genetic framework fundamentally changed how scientists think about drug targets—from attempting to broadly modulate neural circuits to identifying disease-relevant proteins, pathways, and functional networks. Together, this growing genetic insight provides a foundation for understanding disease etiology at a systems level and for developing targeted, mechanism-based therapeutic strategies.
These genetic discoveries provided a new way to think aboutdrug targets. Instead of focusing on signaling mechanisms in brain regions thought to cause dystonia, it became possible to focus on mechanisms related to dystonia genes. With more than 200 genes now linked to dystonia, this means hundreds of new mechanistic targets.
“There has been increasing effort to group these mechanisms into shared pathways,” said Dr. Jinnah. “By targeting shared pathways, we target a group of dystonias, rather than targeting one at a time.”
Research That Builds on Past Discoveries
Finding the gene linked to a genetic disorder is the very first step toward unraveling the mechanism, which is why basic research investigates the pathways and functions the affectedgene is involved in.
“In my view, we still do not understand how TorsinA actually functions. Thus, a targeted drug does not yet exist,” said Thomas Schwartz, PhD, of the Massachusetts Institute of Technology, who unraveled the structure of TorsinA, which was a big step forward in dystonia drug development. “Any basic science work needs long-term funding. Torsin biology remains the area that promises to eventually open a path to a specific cure for dystonia. It has proven difficult to pinpoint its function, for multiple reasons, but the general lack of funding is a big factor.”
Dr. Jinnah noted that current research often builds upon past discoveries. “There are ongoing efforts underway to develop better botulinum toxins, better anti-cholinergics, and better dopamine-related drugs,” he said. “A new target has been muscles themselves. One company has begun to test a drug that inhibits muscle contraction for disorders of muscle overactivity, including dystonia. The overall idea is similar to botulinum toxins, but the mechanistic target is totally different rather than targeting the neuromuscular junction, the new drug targets the muscle contraction mechanism directly.”
Scientists frequently use findings from one disorder to treat another. For example, about 30% of people with Parkinson'sdisease (PD) also have dystonia. Sometimes the dystonia presents first, and sometimes PD is the initial diagnosis. Medications that might help address the dystonia in PD may be valuable to try in individuals with dystonia who do not have Parkinson’s disease. Epilepsy is another disorder that has led to new trials in dystonia.
“Epilepsy is a disorder of neuronal excitability, and there has been lots of interest in neuronal excitability in dystonia,” said Dr. Jinnah. “This physiological mechanism led to trials of drugs that suppress neuronal excitability in dystonia, such as drugs that inhibit signaling by glutamate, one of the brain’s major excitatory neurotransmitters.”
2000s and Beyond: Areas of Emerging Research
Dr. Schlieker noted that one particularly exciting direction in the field of dystonia research is the discovery of defects in nuclear pore assembly and function.
“These defects arise either from Torsin dysfunction, as in DYT1 dystonia, or from mutations in core components of the nuclear pore complex itself,” said Dr. Schlieker. “Importantly, this connection was established through independent studies performed in entirely different dystonia model systems and through patient sequencing efforts, including work by Michael Zech (also a member of the DMRF MSAC) and colleagues. The convergence of evidence from multiple independently operating laboratories underscored the robustness of this finding and highlighted nuclear pore biology as a promising new class of drug targets.”
Dr. Schlieker’s research team has been studying nuclear pores, which are large, complex protein channels that perforate the cell’s nuclear envelope, acting as the essential gateways for regulating traffic of molecules like RNA and proteins between the nucleus and the cytoplasm, ensuring proper cell function and gene regulation. The researchers found that misassembled nuclear pores are detrimental to neuronal protein homeostasis, which is needed to maintain healthy neuronal function, and manages protein transport to specific sites like synapses, where they are vital for learning and memory.
“This unexpected insight prompted the development of biomarkers that allow these defects to be detected and quantified,” he explained. “These tools are now being used by our laboratory and others to support drug discovery efforts and to systematically characterize dystonia-related cellular defects across experimental models. The progression from initial gene discovery to mechanistic understanding and biomarker development depended heavily on longterm, sustained funding, illustrating how such investment is essential for translating fundamental discoveries into actionable therapeutic strategies.”
The Importance of Long-Term Funding for Research
Dr. Schwartz has observed that foundations can be most impactful if they fund high-risk projects and novel ideas. For example in the United States, “federal agencies are notoriously risk averse and tend to fund the continuation of established programs,” he said. “DMRF funding has helped researchers get ‘a foot in the door’, and then use data obtained through such funds to hopefully compete successfully for federal grants.” This has included funding from the Department of Defense (DoD) through its Congressionally Directed Medical Research Programs (CDMRP), specifically the Peer Reviewed Medical Research Program (PRMRP).
Dr. Jinnah noted that most grants from governmental agencies like the National Institutes of Health (NIH) have a time limit, usually three to five years. Although it is sometimes possible to get these grants renewed for a second or even third term to extend their life, reviewers are often more interested in something new, which makes it difficult to do studies that take a long time. The DMRF serves as the administrative center for the Dystonia Coalition (DC), which is a collaboration of medical researchers and patient advocacy groups. Since its launch in 2009, the Dystonia Coalition has engaged over 40 clinical centers in North America, Australia, Europe, and Asia, and was able to obtain long-term funding for dystonia research to advance the field of study. “One example might be “natural history” studies that track evolution of a disorder over time,” said Dr. Jinnah. “These types of studies can take many years to get a full picture of a disorder, especially when it begins in childhood and progresses over decades. The Dystonia Coalition got NIH funding for nearly 15 years, so it was possible to conduct a series of natural history studies for all the most common types of dystonia, like cervical dystonia, blepharospasm, and laryngeal dystonia. We now have much better insight into what we can tell patients about the risk of getting worse over time for these conditions.
“The DMRF plays an integral role in so many aspects of keeping research in dystonia moving forward,” explained Dr. Jinnah. “This includes supporting focused dystonia ‘think tanks’ addressing important topics in the field, by bringing people together to share ideas, talk about what’s new, and talk openly about what is really important. The DMRF also sometimes plays an important role in taking the risk to support some very novel “outside the box” ideas that often get unfairly criticized by those who prefer more traditional lines of thinking. Finally, the DMRF plays a key role finding and supporting young investigators who can carry the research into the future.”
For Dr. Schlieker, and for that of many investigators across the field, the DMRF has played a pivotal role in sustaining momentum in dystonia research.
“Because dystonia is a comparatively rare disorder with a smaller research community than many major neurodegenerative diseases, generating the depth of preliminary data needed to compete successfully for large public grants often requires an additional layer of early support, and the DMRF has consistently filled this critical gap,” he said.
“For my laboratory and trainees, DMRF funding has repeatedly served as essential seed support—enabling us to test high-risk, high-reward ideas, generate proof-of concept data, and refine experimental strategies that later became competitive for larger, multi-year awards from the NIH and the Department of Defense. In this way, DMRF funding directly accelerates the pace of discovery by allowing promising projects to move forward rather than stall at an early stage.
“At present, our work focuses on identifying new drug targets through genetic screening approaches and advancing early-stage drug discovery efforts. Neither of these research directions would have been possible without initial DMRF support. More broadly, by strategically investing in early hypothesis-driven research, DMRF enables the field to move more rapidly from genetic insight to actionable therapeutic targets, ultimately shortening the timeline from discovery to potential treatments for patients.”
Thank you to DMRF for permission to adapt and share for our Canadian audience. DMRF Canada shares the mission and works in partnership with DMRF in the the United States to fund the best and most relevant dystonia research worldwide, including in Canada.
Source: DMRF Dystonia Dialogue Summer 2025 Vol 49. No 1