New Dystonia Drug Candidates Discovered

Several research teams reported major advances in the development of new drugs to treat movement disorders including dystonia. In one of the preclinical studies, investigators have identified several compounds that retain the beneficial effects of anticholinergic drugs like Artane® while eliminating side effects. Another research group successfully corrected dystonic brain abnormalities in mice with a Food & Drug Administration (FDA)-approved antiviral drug. These studies represent remarkable leaps forward in the effort to develop novel dystonia treatments.

“The dystonia community, patients and researchers, have been waiting for these kinds of studies for years. And it took years to get to this point! Enormous research and organizational efforts were required to achieve these scientific feats,” explained Dr. Jan Teller, Chief Scientific Advisor to the Dystonia Medical Research Foundation (DMRF).

Next Generation Anticholinergics

P. Jeffrey Conn, PhD and colleagues have worked for years in pursuit of dystonia-specific drugs.

A research team from Vanderbilt University School of Medicine led by past DMRF Medical & Scientific Advisory Council (MSAC) member Dr. P. Jeffrey Conn and colleagues Drs. Aaron Bender and Jerri Rook have discovered and extensively characterized new compounds that reduce parkinsonism and dystonia in mice by targeting specific cholinergic receptors.

Many drugs work by acting on receptors, which are cellular proteins that receive information from outside the cell. Drugs binding to receptors may either activate or inhibit them, and this affects various cellular processes. Sometimes a drug acts to prevent other molecules, like neurotransmitters, from binding to that receptor.

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, including memory difficulties, sedation, or even hallucinations, can be unbearable. These unwanted effects occur because existing anticholinergic drugs act on many receptors in the brain, not only the receptors associated with dystonia symptoms one would want to target. If the drugs acted more precisely, and targeted only the receptors associated with dystonia, this would eliminate the side effects.

The Vanderbilt research team first identified such specific receptors and then synthesized novel compounds that specifically reduced dystonic symptoms in dystonia mouse models. Three of these compounds have been thoroughly tested and characterized making them prime candidates for further drug development and clinical testing.

In a subsequent paper, the team describes a discovery of another highly selective preclinical drug candidate for the treatment of dystonia and other movement disorders. These discoveries represent many years of research and are major advances in the exploration of more potent and specific anticholinergic drugs that reduce motor symptoms in dystonia and other movement disorders.

“Most dystonia patients are familiar with often terrible side effects of anticholinergics. Finding drug candidates that target specific cholinergic receptor subtypes without affecting others has been a true Holy Grail for pharmacologists. After many years of hard work, the Vanderbilt team led by Dr. Jeff Conn, finally delivered. We can only hope that these drug candidates will ultimately be as effective in the clinic as they are in the lab,” said Dr. Teller.

Current MSAC member and past grant recipient Dr. Ellen Hess of Emory University School of Medicine and Dr. Mark Moehle, a past recipient of the DMRF’s prestigious Mahlon DeLong Young Investigator Award, currently at the University of Florida, Gainesville, also participated in these studies.

Antiviral Drug Corrects Dystonic Brain Abnormalities

Nicole Calakos, MD, PhD and her team identified a promising new drug for dystonia that is already FDA-approved.

A team of researchers from Duke University led by past DMRF grant recipient and current member of the MSAC, Dr. Nicole Calakos discovered that an existing FDA-approved drug corrects dystonia-specific brain changes in a mouse model of DYT-TOR1A dystonia.

DYT-TOR1A dystonia is a genetic dystonia that typically begins in childhood and progresses to generalized symptoms. Screening a library of drugs by using an assay they developed, the researchers found that the HIV antiviral drug ritonavir was among 18 compounds shown to have a specific and robust effect. Ritonavir belongs to a class of drugs called protease inhibitors and is used in combination with other drugs to treat HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome). Ritonavir corrected abnormal TorsinA migration in the dystonic mouse neurons. Critically, ritonavir corrected the striatal cholinergic physiology disrupted in dystonia through a unique mechanism that is different from the mechanism that slows HIV infection. In the dystonia models, ritonavir acts on pathways related to cell stress response, in which TorsinA appears to play a critical role.

The results of this study provide strong preclinical support to further explore ritonavir and other analogous protease inhibitors for dystonia.

Dr. Teller said, “The Duke team led by Dr. Nicole Calakos achieved something quite astonishing. Many groups try to ‘repurpose’ existing drugs, to see if already approved and safe medications can be used for different indications. This can be a very chaotic process. The Duke team used a beautiful, systematic approach. They not only identified a promising drug for dystonia but, equally importantly, showed that its beneficial effects are inherently linked to a biological process compromised in DYT-TorsinA and other dystonias.”

Moving Forward

Drug discovery and development efforts are a critical part of DMRF’s multi-faceted science strategy. The Vanderbilt and Duke studies described above were supported in part by major funding from the Department of Defense (DoD) Peer Reviewed Medical Research Program, which began offering funding to dystonia investigators in 2010 at the urging of the Dystonia Advocacy Network led by DMRF. To date, the DoD has awarded more than $23 million to dystonia researchers.

“Congratulations to everyone involved in these spectacular research achievements,” said DMRF President Art Kessler. “We look forward to future updates with hope and enthusiasm.”

“It is powerful to see our legislative advocacy efforts in support of federal research funding lead directly to groundbreaking scientific discovery,” said Carole Rawson, Chair of the Dystonia Advocacy Network and DMRF’s Vice President of Public Policy. “I want to thank our volunteer advocates who work every year to keep dystonia in the DoD Peer Reviewed Medical Research Program. This could not have happened without you.”

Individuals and families affected by dystonia can play a critical role in accelerating new scientific discoveries by advocating for increased federal funding for dystonia researchers through the DoD Peer Reviewed Medical Research Program and the National Institutes of Health. Click here to learn more about joining the Dystonia Advocacy Network.


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.