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Dystonia International Patient Registry (DIPR)

The Dystonia International Patient Registry (DIPR) is an observational registry of individuals who carry the DYT-1 gene. The ultimate goal of this registry is to provide the natural history of DYT-1 Dystonia worldwide. All scientific and medical investigators are encouraged to utilize the registry as a source of patients for clinical research and as a source of demographic information on the patient population.

Click here to access the registry.

Dystonia Coalition Obtains ORD Grant
Unprecedented monies to support dystonia research

The Dystonia Coalition is a collaboration of scientists, institutions, and patient organizations formed to advance the pace of clinical research for the dystonias.

In October, Officials at the Office of Rare Disorders (ORD) at the National Institutes of Health (NIH) announced the funding of a five year award for the Dystonia Coalition to advance clinical research on primary focal dystonias including cervical dystonia, spasmodic dysphonia/laryngeal dystonia, blepharospasm, and others. Leading the Coalition will be H. A. Jinnah, MD, PhD, Professor of Neurology and Human Genetics at Emory University in Atlanta, Georgia.

The $6.2 million award will allow the Dystonia Coalition to cultivate a better understanding of the primary focal dystonias and find better therapies. This includes projects to develop a better understanding of their natural history, establish instruments for monitoring symptom severity in clinical trials, and develop proper diagnostic criteria. The creation of a biorepository to store biological samples to support future research is also planned, which will make these resources available to investigators worldwide.

American Dystonia Society

Bachmann-Strauss Dystonia & Parkinson Foundation
Beat Dystonia
Benign Essential Blepharospasm Research Foundation
DySTonia, Inc.
Dystonia Medical Research Foundation
National Spasmodic Dysphonia Association
National Spasmodic Torticollis Association
Tyler's Hope for a Dystonia Cure
We Move

Awarded the Dr. Edward V. Staab Memorial Grant for 2009-2010

1. Accelerating drug discovery for dystonia using chemical genomics

David Christopher Bragg, Ph.D.

Instructor in Neurology

Harvard Medical School

Massachusetts General Hospital

2. Developing a Cell-Free Assay of TorsinA Activity

Rose Goodchild, Ph.D.

Department of Biochemistry & Cellular and Molecular Biology

University of Tennessee Knoxville

3. Treatment of Dystonias with Deep Brain Stimulation of Cerebellar Structures

Robert S. Raike, PhD

Post Doctoral Fellow

Department of Pharmacology

Emory University School of Medicine

Biofocus Drug Discovery

"Project Firesky" It is estimated that this work, in three phases, will cost between $1,500,000 to $1,750,000. Phase I is complete and Phase II is in the works. Tyler's Hope has joined forces with the DMRF to fund these drug discoveries. This is a very exciting project with a good potential to discover a drug that will treat or eliminate dystonia symptoms. Thank you to the DMRF for paving the way. We are very happy to assist financially to dicover these drugs and fund this research.

Create an rAAV-based animal model for DYT1 dystonia

Ron Mandel, University of Florida College of Medicine

Genetically modified mice are the current gold-standard to model genetic neurological disorders. Indeed, in many cases, these mouse models have been invaluable and extremely reliable. However, there are also notable failures. The most accessible example comes from inherited forms of Parkinson disease (PD). The first PD causing gene was α-synuclein (α-syn) in which point mutations at 2 different amino-acids as well as a triplication of the gene all cause familial PD. Although approximately 20 transgenic and knock-in mice harboring α-syn mutations have been created, none have pathology resembling human PD. A similar pattern is true of the PD causing genes, parkin, DJ-1, and PINK1 for which mouse models do not show PD-like pathology.

In contrast, the use of a viral vector, recombinant adeno-associated virus (rAAV) has provided the only faithful α-syn animal model available today. Certain versions of rAAV vectors (rAAV2 and rAAV5) have the fortuitous property, that, when injected in the substantia nigra of a rodent or a primate, have a relative specificity for infecting dopamine neurons. Thus, when rAAV vectors expressing the human mutated form of α-syn in the substantia nigra of rats, we observed a progressive loss of nigral neurons over approximately 8 weeks. Moreover, as an interesting control we injected the wild-type (un-mutated) of human α-syn and saw similar neuropathology. It was only later that a family with inherited PD was found to have a triplication in the α-syn gene and therefore expressed more of the protein. Another important advantage of the rAAV system is that it can also be injected in any mammalian species. To determine the fidelity of our PD model, we also injected the same α-syn vectors in the marmoset, a small new-world monkey. The nigral α-syn-induced pathology was nearly identical to that seen in the rat model. We have followed these studies with further studies that have identified proteins that interact with α-syn in the substantia nigra and have also identified alterations to the α-syn that render it non-toxic to dopamine neurons.

Based on these previously successful models based on rAAV, and the lack of useful phenotype in DYT1 mutant or knock-out mice. We propose to make 3 rAAV viruses: wild-type DYT1, mGAGDYT1, and siRNAs against rat DYT1. Pedro Gonzales-Allegre has graciously agreed to provide us with the constructs for all these proposed viruses. Because we do not know the precise anatomical location of the neuropathology in DYT1, we would propose to inject each of the viruses in different groups of rats including another control virus (green fluorescent protein, GFP) bilaterally in the striatum and globus pallidus, the cerebellum, and both areas together. This would result in 9 groups of rats (n = 8 each). Expression of the proteins takes about 2 weeks to reach a peak so we would begin behavioral testing approximately 3 weeks after vector injection and monthly thereafter. The transgenes are expressed for the life of the animal.

We would first test spontaneous behavior in a battery of tests such as gait analysis, rotorod, and the cylinder rearing test. If we see no behavioral impairments in these tests it will be possible to test the animals in drug paradigms that are known to induce dystonias in rats except that we would use regimens that are mild enough that they would not produce dystonias in normal rats. Possibilities include physostigmine treatment or repeated L-dopa treatment.

This experimental design in rats has the potential to identify the relative contribution of different anatomical structures to dystonias (basal ganglia vs. cerebellum), to help determine if there is a dominant negative effect vs. a loss of function (gagDYT1 vs. DYT1 siRNA). The performance of this experiment including analysis of the data is estimated to be 1 year.

The results of these initial studies would guide future development of the rat model. However, regardless of whether a phenotype is detected or not. It seems prudent to attempt a parallel experiment in marmosets which are available here at UF. As pointed out in your recent “think tank”, DYT1 dystonia might be a disorder only seen in primates which, among many other differences in physiology, definitely have different anatomical structures that subserve motor function. However, with regard to marmosets, we will come back to the Tyler’s Hope foundation with a detailed plan for research in marmosets.

It is worth pointing out, that if rAAV-mediated over-expression or knock-down of DYT1 causes dystonia in either rats or marmosets, it is then possible to perform experiments whereby the vector is injected in more discrete anatomical areas to potentially identify if different phenotypic forms of dystonia are mediated by different anatomical regions. This last goal would most likely best be reached by studying primates.

It was universally agreed at the “think tank” that prior to beginning drug trials or finding therapeutic avenues, a phenotypically relevant animal model was crucial. Because there has been little or no success in genetic mouse models, we believe that the viral vector approach may provide an animal model for DYT1 dystonia.

“Unraveling torsinA function and dysfunction”

Investigator: William Dauer, MD, Columbia University, New York

DYT1 dystonia is an autosomal dominant disease caused by the loss of a single amino acid in the protein torsinA. We have found that the disease mutation appears to block the normal function of torsinA. Because of this, we believe that experiments to study what happens to neurons when they lose torsinA function will provide clues regarding what goes wrong in the disease. To pursue this research goal, we propose a range of studies on the brains and cultured nerve cells from mice that either lack the torsinA protein or only make the disease form of torsinA. We also believe that learning more about the function of proteins that torsinA interacts with will yield clues to the function of torsinA, and have also proposed experiments along these lines.

Cure Dystonia Initiative Grant
“Therapeutic RNA interference for DYT1 dystonia”
Investigator: Pedro Gonzalez-Alegre, MD, University of Iowa

Pedro Gonzalez-Alegre, MD and his colleagues are using RNAi to restore human neural cells to normal by selectively silencing a gene that causes the movement disorder DYT1 dystonia. The findings also may help researchers apply RNAi to other brain diseases such as Huntington's disease.

Book The Dystonia Patient funded by Tyler's Hope

Written by the dystonia team at the University of Florida Movement Disorders Center, this book is designed as a practical and complete guide to the integrated management of the dystonia patient. It provides a current understanding of this common but often poorly appreciated condition and a framework for delivering comprehensive multi and intra-disciplinary care. Individual chapters review medical and surgical strategies, botulinum toxin therapy, and programming issues for deep brain stimulators. The remainder of the book is devoted to the important role of health professionals from various disciplines and what the physician needs to know to direct a successful long-term care team for dystonia patients. Features include:

Emphasis on a multi-disciplinary team approach to long-term management
Coverage of both adult and pediatric patients
Pearls and practical points within each chapter to guide the practitioner

Lists of resources and referral information for patients, families, and medical teams

Okun's remarkable 248 page practical guide, The Dystonia Patient, is the first book that exclusively focuses on patients diagnosed with the rare movement disorder, dystonia. It is well written, efficiently organized with plenty of gems and advice for healthcare providers, who provide direct care to this complex patient population. Most importantly, it highlights the role and application of the multidisciplinary care model for these patients; an under-emphasized care model that is intensely needed for these patients and their families. Many require assistance from a variety of health providers including the physical therapist, occupational therapist, psychologist, pain management specialists, neurosurgeons, nurse practitioners etc.

Okun has truly given much thought to the total concept of "holistic ", "gestalt" care for these patients when writing this guide. It is quite obvious that the information, provided in a positive,easy-to-read approach, has been thoroughly researched in collaboration with other healthcare providers. I highly applaud the author, a practicing physician specializing in movement disorders, for recognizing the needs and the care required by these patients.

I highly recommend this book for nursing and medical students, newly practicing neurologists including those ready to enter the arena of movement disorders. The book is an absolute necessity in the office- libraries of all those providing care to the unique Dystonia Patient, as well as organizations providing support to patients and their families. A true Gem of a Read for all !

Beka Serdans, RN, MS, NP

Founder

Care4Dystonia, Inc.

Tyler's Hope Center for Comprehansive Dystonia Care

A true Inter-Disciplinary Center for Dystonia, where all the services and resources are consolidated in one location; where bench research is immediately brought to the bedside.

The Summit

Gainesville, Florida
McKnight Brain Institute
EMail: tylershope@intermed1.com
Phone: 352-273-5550

Tyler's Hope & the McKnight Brain Institute presents: TheAnnual Think Tank on Novel Approaches to a Cure for DYT-1 Dystonia.
The Dr. Edward V. Staab Memorial Fund will award the first annual grant to the most promising project towards a Dystonia cure.