On Target: Drug Discovery Efforts Pursue New & Improved Treatment

This article originally appeared in the Dystonia Dialogue.

Drug discovery and development efforts are an important part of the Dystonia Medical Research Foundation’s (DMRF) multi-faceted science strategy. “The dystonia community cannot wait for pharmaceutical and biotech companies to necessarily get interested in dystonia on their own,” explains Jan Teller, MA, PhD, DMRF’s Chief Scientific Advisor. “DMRF has a responsibility to encourage and support drug discovery efforts while we work constantly to engage pharma and industry partners.”

In late 2018, DMRF organized a workshop entitled “Targeted Drug Discovery for Dystonia” in Chicago. Meeting participants included seasoned dystonia investigators and non-dystonia experts experienced in protein-based drug discovery. The workshop was co-chaired by Christian Schlieker, PhD of Yale School of Medicine and Thomas Schwartz, PhD of Massachusetts Institute of Technology, whose recent work is discussed later in this article. The goal of the meeting was to summarize and discuss recent efforts to identify drug targets for dystonia, with special emphasis on DYT1 dystonia because it is among the best understood dystonias at this time.

A drug target is a molecule in the body, often a protein, that is essential in a disease process and that can be manipulated by a drug to correct or interrupt this process. Identifying drug targets for dystonia is critical to developing new medications and/or identifying existing drugs that may be effective.

A clear take away from the drug discovery meeting,” says Dr. Teller, “was that we need extensive mechanistic studies in order to understand the biology of dystonia if we are to approach drug development in a thoughtful and responsible way.”

Pushing Aside the Side Effects
Anticholinergic drugs, such as trihexyphenidyl (Artane®), can be effective at controlling dystonia symptoms but are not a viable treatment for many patients because the side effects can be unbearable: memory difficulties, sedation, even hallucinations. These unwanted effects occur because anticholinergic drugs act on many receptors in the brain, not only the receptors associated with dystonia symptoms. If the drugs acted more precisely, and targeted only the receptors associated with dystonia, this would avoid the unwanted side effects.

Dr. Teller explains: “There is a lot of interest in making existing drugs ‘cleaner’ and less prone to producing side effects. This has significant advantages over designing new drugs, in terms of time and cost. DMRF has supported numerous research teams pursing this.”

Ellen Hess, PhD of Emory University is a past DMRF grant recipient. She is leading an investigation funded through the Department of Defense (DOD) Peer Reviewed Medical Research Program to better understand how medications to treat dystonia work in the brain and how to improve them. She and her team found that trihexyphenidyl corrects an imbalance of dopamine, a neurotransmitter in the brain critical for normal movement. This restoration of normal dopamine processing reduces dystonia symptoms. The discovery provides clues about which receptors are important for treating dystonia. The scope of the DOD grant includes outreach to pharmaceutical companies and academic institutions that possess compounds not yet on the market that target the helpful receptors for possible development into commercially available medications.

Dr. Hess recently received a grant from the DMRF to detect abnormal patterns of brain activity associated with dystonia, and that work is ongoing.

Additional investigators who are making important discoveries related to anticholinergic drugs and receptors include DMRF grant recipients Antonio Pisani, MD, PhD of University of Rome Tor Vergata (whose work is discussed below), and P. Jeffrey Conn, PhD of Vanderbilt Center for Neuroscience Drug Discovery. A member of Dr. Conn’s team, Mark Moehle, PhD, recipient of the DMRF’s Mahlon DeLong Young Investigator Award, presented on their work at the recent DMRF drug discovery workshop.

The Dopamine Enigma
Individuals with dystonia vary in their response to oral medications. And it is not clear why. For example, dopa-responsive dystonia is an inherited movement disorder in which the body cannot properly process dopamine, a neurotransmitter critical for coordinating normal movement. Levodopa, an oral medication that boosts dopamine, can dramatically reduce dystonia symptoms. However, levodopa produces inconsistent results in other types of dystonia, for example, DYT1 and other inherited dystonias. Furthermore, some dystonia patients respond to dopamine-blocking drugs, such as tetrabenazine, rather than dopamine-boosting drugs.

A newly published study led by DMRF grant recipient and former member of the Medical & Scientific Advisory Council Antonio Pisani, MD, PhD of University of Rome Tor Vergata offers new insights into the role of dopamine in DYT1 dystonia. It may explain why DYT1 dystonia patients vary in their response to dopamine-boosting medications such as levodopa. The work of Dr. Pisani and his group highlight the role of RGS9-2, a protein that regulates dopamine signaling in the striatum, part of the basal ganglia in the brain. The researchers have shown that activating RGS9-2 may potentially correct the dopamine imbalance in the brain associated with dystonia and other movement disorders.

Dr. Pisani’s work is revealing important information about dopamine receptors. The dopamine receptor DRD2 regulates the synthesis, storage, and release of dopamine. Lower levels of DRD2 can slow down dopamine production and activity, leading to neurologic effects. DRD2 receptor levels are lower in DYT1 dystonia as well as in animal models of the disorder. Notably, the majority of current antipsychotic drugs, which can trigger movement disorders, also target the DRD2 receptor. RGS9-2 belongs to specific molecular machinery associated with the DRD2 receptor. Dr. Pisani and his group discovered that lower levels of the DRD2 receptor correspond with reduction in RGS9-2 protein. These changes have direct negative consequences for neurophysiological function of striatal neurons and control of movement. The researchers were able to reverse these negative consequences by experimentally increasing the level of RGS9-2, which restored the levels of DRD2 and its normal function. The dopamine imbalance was corrected by influencing the DRD2 receptors, by increasing RGS9-2 levels. The results from this study shed new light on the role of  dopamine signaling in DYT1 dystonia, and suggest the RGS9-2 protein could be an important therapeutic target for dystonia.

Starting from Scratch
Oral medications currently available to treat dystonia are used off-label, which means they are not specifically approved by the US Food & Drug Administration for dystonia. Doctors are permitted to prescribe them based on clinical experience. At the moment, there are no oral medications intentionally designed or developed to treat dystonia. However, work by Thomas Schwartz, PhD of Massachusetts Institute of Technology could ultimately help pave the way toward custom-made dystonia medications.

Dr. Schwartz received a DMRF research grant several years ago to take on one of dystonia research’s most pressing challenges: solving the structure of TorsinA, the protein responsible for causing DYT1 dystonia when it becomes dysfunctional due to genetic changes. The function of a protein is determined by its shape, so solving TorsinA’s structure is critical to understanding its role in cells and the processes that fail when the protein does not function properly. Using sophisticated X-ray crystallography techniques, Dr. Schwartz successfully solved the structures of both normal and mutated TorsinA—a critical, fundamental step toward therapies that correct dystonia at the source of the problem. Dr. Schwartz revealed that the disease mutation causes subtle surface changes on the protein that could potentially be repaired by an appropriate drug. Dr. Schwartz previously established
that TorsinA can only function when activated by associated proteins, LAP1 and LULL1, which opens up additional potential opportunities to manipulate TorsinA for therapeutic purposes.

Dr. Schwartz recently received a large grant from the Department of Defense (DOD) to build upon the work funded by DMRF and screen for drugs that may act on TorsinA. This work represents the latest steps toward truly novel therapeutic approaches to dystonia.

Next Steps
“These projects are true drug discovery attempts but also, inevitably, expand our fundamental knowledge about dystonia, something companies rarely, if at all, do,” says Dr. Teller. Continuing to understand the fundamental causes of dystonia is essential to identifying dystonia drug targets and the future of treatment.

Dr. Teller continues: “Something we can do right away is to encourage and intensify information exchange and collaboration among investigators. Sharing information and organizing more frequent meetings will undoubtedly speed up the process of acquiring knowledge and conscientiously proceeding to drug development. DMRF can play a significant role in this area.”


The Dystonia Medical Research Foundation is a 501(c)(3) non-profit organization dedicated to advancing research for improved dystonia treatments and ultimately a cure, promoting awareness, and supporting the well-being of affected individuals and families.