Breakthroughs & Accomplishments
“Bachmann-Strauss is continuing the momentum into discovery, enabling major advances and insights that are now helping to identify new therapies.”
- Ted Dawson, MD, PhD
Research funded by The Bachmann-Strauss Dystonia & Parkinson Foundation has led to the following key scientific accomplishments:
Our early funding of the first genetically altered (“transgenic”) mouse model resulted in the groundbreaking discovery of DYT1 dystonia that showed behavioral features similar to patients with early onset dystonia.
Since that time, Bachmann-Strauss Foundation supported the development of several additional animal models that are bringing greater insight into the causes, progression and treatment of dystonia and Parkinson’s disease:
- - Two mouse models, one of L-DOPA responsive dystonia and the other of rapid onset dystonia-Parkinsonism, provided new information to characterize the link between dystonia and Parkinsonism. This research also will be useful for further study to develop new therapies.
- - Five new genes that protect dopamine neurons from dying – a hallmark trait of Parkinson’s disease – were identified in transgenic roundworm models. This is a possible step toward identifying new targets for drug development and genetic factors that make some people more susceptible to the disease.
- - A mouse model of a novel mutation in the DYTI gene, TOR1A developed by Dr. Nicole Calakos and her lab at Duke University, enables research on the role of abnormal synaptic plasticity in patients with late-onset, sporadic focal dystonia. Using cell-based protein expression assays to compare the mutant protein to normal TorsinA and the DYT1-causing form of TorsinA, Dr. Calakos’ group found that this novel mutation caused abnormalities more akin to the DYT1 mutant protein, but also with some distinctive features.
- - In 2014, a team of researchers led by neurologist William Dauer, MD, at the University of Michigan developed a new strain of mice that closely mimics the symptoms of dystonia, which include uncontrollable twisting, stiffening and spasms of muscles in the neck and limbs. A paper published in the Journal of Clinical Investigation details important new discoveries about dystonia using his mice. http://www.uofmhealth.org/news/archive/201406/dystonia
Historically, dystonia has always been considered a disorder of the basal ganglia. But recent evidence has pointed towards cerebellar circuits as well. Many researchers now believe that dystonia is caused by a disruption of a motor network that involves both the basal ganglia and cerebellum, rather than an isolated dysfunction of only one motor system. But how the motor network relates to the genes and proteins that are thought to be involved in the development of dystonia is a fertile area of research.
The Bachmann-Strauss Foundation’s annual Think Tank has provided a valuable forum for researchers to exchange ideas about where future research should be directed. Promising areas of inquiry have included:
- Understanding the cascade of chemical and electrophysiologic changes that occur as a consequence of loss of striatal dopamine in parkinsonism that can then be translated into new and more effective therapies for both Parkinson's disease and dystonia.
- Demonstrating that fast-spiking interneurons (FSIs) can exert powerful control over striatal output and may be a novel therapeutic target for the treatment of hyperkinetic movement disorders.
- Explaining how plasticity may be a driver of long-term therapeutic effects of deep brain stimulation in dystonia.
- Investigating why dysfunctional interactions between the cerebellum and the basal ganglia are a key factor in the underlying pathophysiology of rapid-onset dystonia-parkinsonism.
TorsinA is a protein that, when mutant, can cause dystonia. Major findings in this area have included:
- - Development of the antibody to torsinA, and work that helped to define the normal function of torsinA
- - Demonstrating that torsinA protects against cell death and that mutant torsinA does not, and demonstration that torsinA is present in Lewy bodies in Parkinson's disease. Lewy bodies are massive clumps of protein within cells.Determining that torsinA is a chaperone-like enzyme that normally operates on proteins within the nuclear envelope where it is located. The nuclear envelope is a two-layered membrane surrounding the nucleus of a living cell.Identifying where torsinA is located in the brain in normal rodents, in normal human controls, and in DYT1 dystonia patients.
In 2008, the Foundation launched an Anti-Dystonia Drug Discovery Program led by Ellen Hess, PhD. Her team uses behavioral and cellular pharmacology to understand the cellular mechanisms that give rise to hyperactivity. The objective of Dr. Hess’s research is to identify drugs that can either move directly into clinical trial or be put forward for product development by a biotechnological or pharmaceutical company.
In 2012, Dr. Hess reported preclinical data for the mGlu5 negative allosteric modulator (NAM) oral small molecule, dipraglurant, a compound in development by Addex Therapuetics. She plans to make drug screening more widely available to facilitate preclinical testing of other novel anti-dystonia compounds.
The Bachmann-Strauss Foundation has funded numerous studies identifying genes associated with dystonia-Parkinsonism syndrome, as well as follow up research to understand the molecular pathways that underlie the diseases. Major genetic discoveries supported by the Foundation include:
- In 1997, a research team led by Xandra O. Breakefield, PhD and Laurie Ozelius, PhD, identified and cloned the DYT1 gene responsible for early-onset dystonia. The discovery reported in Nature Genetics, set the stage for major advances in our understanding of the causes, development and treatment of a severely debilitating form of dystonia that begins in childhood.
- Researchers from London’s University College, Institute of Neurology, led by Professors Nick Wood and Kailash Bhatia, identified mutations in a gene called ANO3 as the possible cause of the most common form of dystonia affecting the neck and face (cranio-cervical dystonia). The researchers found six changes throughout the new gene, ANO3, which might be linked to dystonia. This is the first work implicating an ion channel as the cause of dystonia, and it raises the question of whether medications could be targeted at the channel to compensate for improper functioning, as well as to shed light on the cellular pathways involved in the disease as a whole.
- Discovery of a novel gene, GNAL, for primary torsion dystonia, also known as dystonia musculorum deformans, was made through the collaboration of the molecular genetic laboratory of Dr. Laurie Ozelius, Icahn School of Medicine at Mount Sinai, and a clinical research team led by Dr. Susan Bressman, MD, Director, Bachmann-Strauss Dystonia Center of Excellence and Chair, Department of Neurology, Beth Israel Medical Center, New York. These findings describe the GNAL gene as pointing to pathways in the brain’s dopamine system as the origin of pathophysiology. The research unveils a new potential therapeutic target and an opportunity for developing new treatments, as well as helping in the development of genetic tests to confirm diagnoses, identify unaffected adult carriers, and provide greater reproductive health options for affected families.
- Breaking new genetic barriers, Christine Klein, MD, University of Lubeck, Germany, is characterizing the gene TUBB4 that causes Whispering Dysphonia. This is a rare inherited disorder where an individual is able to talk normally when they’re asleep, drunk or emotional, but for the most part they are only able to whisper. The condition may be progressive and leaves the person unable to make a single sound.
- In 2014, researchers at Mount Sinai Beth Israel, including lead author Rachel Saunders-Pullman, MD, MPH, reported results of genetic screening of dystonia in the Amish-Mennonite population in the journal Movement Disorders. This population is of special interest since the THAP1 gene (also known as DYT6) was originally identified in four Amish-Mennonite families sharing the same “founder” mutation through a common ancestor. The study demonstrated that in addition to this THAP1 founder mutation, different mutations in THAP1 also cause primary dystonia in Amish-Mennonites. Also identified were mutations in the recently described GNAL gene (also known as DYT25), and in the DYT1 (TOR1A) gene. These findings emphasize the range of genetic causes of primary dystonia even within a certain ethnic group.
In Deep Brain Stimulation (DBS) therapy, a small pacemaker-like device sends electronic signals to an area in the brain that controls movement. These signals block some of the brain messages that cause disabling motor symptoms. In 1997, the Food and Drug Administration approved the use of DBS to treat essential tremor. Approval for the treatment of Parkinson’s disease (2002) and dystonia (2003) soon followed.
Although DBS does not cure either Parkinson's disease or dystonia, it can help manage some of its symptoms and subsequently improve the patient’s quality of life. While DBS is most effective in DYT1 patients, there is increased interest in the role of DBS in patients with secondary dystonia. A new collaborative research study to be undertaken in 2015 among the four Bachmann-Strauss Foundation’s Centers of Excellence will be the largest of its kind to assess responsiveness of dystonia patients to DBS.
Funds provided by The Bachmann-Strauss Foundation have supported efforts to derive iPSCs by different methods. In 2012, a special “Impact Grant” Request For Proposal (RFP) focusing on dystonia research was released by the Foundation. Following intense review, the Foundation’s Scientific Advisory Board awarded two interrelated grants. The first grant was awarded to H.A. Jinnah, MD, PhD, Professor, neurology, human genetics and pediatrics, Emory University, and the second to Cristopher Bragg, PhD, Assistant Professor of Neurology, Massachusetts General Hospital. Using newly developed technology to study neurons of different motor pathways, by taking a small skin sample from patients with dystonia, growing living fibroblasts from the skin, and then converting the fibroblasts into stem cells for making neurons. These stem cells are then used to generate a variety of different types of neurons for many different types of studies.
The goal of Dr. Jinnah’s project – the Dystonia Coalition iPS Resource - is to develop a resource for the collection of skin samples for making fibroblast cultures for dystonia, to create stem cells from these fibroblasts to share with dystonia investigators, and to examine the defects in these cells after they are converted into dopamine neurons.
Dr. Bragg’s project - Generating Isogenic Dystonia iPS Cell lines with Custom TALE Nucleases - has generated iPSCs for different genetic causes of dystonia by turning normal cells into cells with dystonia mutations with TALE nucleases. His lab is now able to create iPSCs for any genetic form of dystonia using TALE technology. Dr. Bragg is also collaborating with the Jinnah laboratory in developing and comparing the different dystonia iPSC models.
- Recognizing that collaboration is key to merging clinical and research expertise, in 2009 the Foundation established its first Center of Excellence at Mount Sinai Beth Israel in New York City. To learn more about our Centers of Excellence click here.
- Building on the success of this model, the Foundation launched three new Centers of Excellence in 2013 at: the University of Alabama at Birmingham; the University of California, San Francisco; and the University of Florida. These new centers were established with grants of $400,000 each from the Foundation and have secured matching funds to ensure that they will be self-sustaining. The centers bring together multidisciplinary teams to provide dystonia and Parkinson’s patients with complete, coordinated care in a single location.
- In 2014, the Centers each received an additional award of $75,000 to undertake a collaborative study on the responsiveness of dystonia patients to DBS. The study will characterize patients with isolated forms of dystonia and collect DNA and clinical data that will enable researchers to better predict patient outcomes for treatment with DBS.