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Grant / Funding

University of Florida

Bachman Strauss Center of Excellence

Torsin A Study - Dr. Robert Mckenna, Dr.Li, Dr. Shyamasri Biswas

Dr. Li

Ampicillan Trial - Dr. Rodriguez

University of Michigan

Dr. William Dauer

Cerebellothalamic Hypothesis - Dr. William Dauer

Unraveling Torsin A function and Dysfunction - Dr. William Dauer (Stanley Fahn Grant Award)

Harvard University

IPS cells as a model for DYT1 Dystonia - Dr. Nutan Sharma and Chis Bragg

Drug Discovery for Dystonia using Chemical Genomics - Dr. Chris Bragg

Duke University

Torsin A Dysfunction - Dr. Nicole Calakos

University of Tennessee

Cell Free Assay of TorsinA Activity - Dr. Rose Goodchild

Emory University

Therapeutic RNA interface for DYT1 Dystonia - Dr. Pedro Gonzalez (Cure Dystonia Initiative Grant)

University of Iowa

Therapeutic RNA interface for DYT1 Dystonia - Dr. Pedro Gonzalez (Cure Dystonia Initiative Grant)

Tyler's Hope / DMRF

BioFocus

Tyler's Hope " Season of Hope" Fellowship Program

Year

2013

2012

2010

2010

2013

2012

2009

2011

2009

2010

2009

2009

2009

2009

2013-Present


Annual Funding

Description

On September 26, 2013, Tyler’s Hope Foundation funded the opening of the Bachmann-Strauss Center for Excellence at the UF Center for Movement Disorders. Supporting scientific and clinical research for dystonia and Parkinson’s disease, the Bachmann-Strauss Center for Excellence continues to spread awareness to the general public and medical community in hopes of finding a cure.

To better understand the enhancemnet of torisinA function in vivo caused by ampicillin, researchers have investigated the structure and biophysical characterization of torsinA. Further investigation of the structure will also determine the ph and thermal stabilitiy properties of torsinA. Moving closer to the underlining cause of dystonia, this study has provided numerous oppurtunities for the pathophysiology and neural interferance of dystonia.

In 2010, UF Center for Movemet Disorders and Neurorestoration had the privelege of recruiting the country's most promising dystonia researcher, Dr. Yuqing Li to the University of Florida. After raising one million dollars, the center constructed a state-of-the-art laboratory for dystonia research.

Early onset torsional dystonia is normally caused by the deletion of glutamic acid in the DYT1 gene product, torsionA. Causing mutants in torsionA, such deffects result in a decrease torsion A function. In hopes of restoring normal cellular functionality, representative molecules such as aminopenicillin and quinolones were analyzed in EOTD patient fibroblasts for improvements in torsion A dependent secretory function. Increasing the activity of torsion A activity, ampicillin was linked to reduced behavioral defectsin knock-in mouse models. Treamtent of ampicilllin in the DYT1 gene mutation showed signs of improved motor coordination.

In 2013, Tyler’s Hope went to great means to fund the Will Dauer Grant at the University of Michigan. Investigating the essential role of torsinB, a powerful modifier for the main cause of twisting movements in torsinA dysfunction, the William Dauer grant has supported future research in DYT1 dystonia.

According to previous research, carriers of the DYT1 dystonia mutation exhibit abnormalities in the cerebellothalamocortical motor pathways. When analyzing the pathways of knock-in mice, studies showed abnormal pathways in the brainstem regions linking cerebellar and basal ganglia motor circuits. Even mice lacking abnormal motor functions showed similar abnormalities in the cerebellothalamocortical pathways. These findings link a selective brain circuit abnormality to gene carrier status and demonstrate the similar effect of DYT1 mutatnt torsion A on humans and mice.

Funded by the Stanley Fahn Grant Award, William Dauer and his research team studied the effects of DYT1 mutations on torsion A function. After using DYT1 mouse models to study dystonic symptoms, researchers were able to link early on set dystonia to specific changes in the early stage of brain development. With further investigation, Dauer and his team predicted the lack of a torsion duirng a critical "window" of time could be responsible for the apoptosis of cells in particular regions of the brain controlling movement.

The objective of this research is to establish a collection of DYT1-specific induced pluripotent stem (iPS) cells, which are stem cells derived from patient-donated somatic (skin) cells, and matched controls that will serve as a public resource for the dystonia research community. These cells, which are generated by reprogramming skin fibroblasts resemble embryonic stem cells in culture and can be differentiated into specific cell types, such as neurons, needed for research. Thus, DYT1-specific iPS cells will represent a self-renewing population of cells bearing ‘natural’ levels of the mutated target protein, torsinAΔE, capable of becoming human neurons, which are thought to be critical in developing DYT1 dystonia. This model would enable multiple dystonia research groups to conduct new studies designed to study neuron-specific defects associated with torsinAΔE.

Supported by the Dr. Edward V. Staab Memorial Grant Award, Dr. Bragg and his colleagues have managed to complete the proposed expresiion profiling primary DYT1 fibroblasts and controls. In collaboration with Dr. Laurie Ozelius (Mt. Sinai), researchers have managed to extend the expression to a second cell type known as lymphoblasts. After deep analysis and vigor determination, investigations have revealed candidate compounds which may resue the DYT1 cellular state.

In hopes to provide new oppurtunities for the treatment and cure of dystonia, The Calakos group has proposed to use the abnormal characteristics of disease-associated TorsinA to develop a high-thorough examination with high-content readouts to screen for modifiers that will reduce the abnormal protein burden. Such information will pin-point new small molecules and pathways for the correction of pathological TorsinA activity.

After studing the maintenance of cells in a developed mammal, rearchers have linked several human diseases to the degenerative nature of particular cell types in the nuclear envelope. Localizing in either the main endoplasmic reticulum or the nuclear envelope, Torsion A's nuclear envelope funciton has shown to be important for neurons. Investigating this relationshpip between Torsion A and neural functions, Goodchild and her fellow colleagues have preducted DYT1 dystonia is caused by impapiremets of the nucleanr evenop function of torsion A.

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.

In 2009, The Dystonia Medical Research Foundation and Tyler's Hope for a Dystonia Cure joined forces to launch groundbreaking medical research in hopes of discovering new drug targets. Several hundred hits for potential proteins and genes that could rescue cells from the effects fo the DYT1 dystona mutation were identified from a library of 4,500 candidates. Referred to as Phase 1, these potential proteins and genes were implemented in drug discovery programs to develop therapeutics to aleviate dystonia.

After developing an assay using the neuron-like cell line to measure the secretion of proteins upon viral 'suppression' of torsin A in Phase 1, researchers are moving on to the next step of screening the BioFocus "SilenceSelect", a library which targets the human drugable genome. In efforts to redeuce the number of hits produced by either experimental procedures or secondary effects, all targets will undergo multiple screenings as well toxicity experiments to adjust screening conditions.

At the Center’s 5th annual Think Tank (“Novel Approaches to a Cure for DYT-1 Dystonia"), Tyler's Hope graciously donated $100,000 to the establishment of the Tyler's Hope Season of Hope Fellowship Program. Providing the funds to educate and train clinical researchers, Tyler's Hope continues to support annually one of the largest fellowship programs in the world. Supporting the restoration of hope in finding a cure, the CMD Fellowship Program supports the critical need for dystonia and Parkinson’s disease specialists in the medical field.

Update / Progress

In less than a year, the opening of the Bachman-Strauss Center for Excellence has supported fundamental breakthroughs and discoveries in the pathophysiology of DYT1 dystonia and potential gene and protein targets for torsion A dysfunction.

Results from this study have shown potential breakthroughs and discoveries for the development of drugs for dystonia therapy. Pin-pointing several small molecules repsonsible for enhancing normal wild-type torsin A activity, researchers shed light for potential reduction of mutant torsin A activity in early onset dystonia.

At the University of Florida's MDC, researchers are conducting a study to look at safety and tolerability of ampicillin to improve dystonia symptoms under the clincial trial.

After crossing mice expressing the Cre recombinase under the hindbrain driver (En1) with the inducible knock-in mouse model, results showed a selectively expressed DYT1 genotype in the hindbrain and normal torsin A gene in the forebrain structures. Conducting further analysis for an overt motor behavior phenotype, researchers concluded selectively expressing the DYT1 genotype in the hindbrain structures does not recapitulate the disease manifesting state. In the near future, Dauer and his team plan to continue their preliminary studies and explore the potential unique effects that result from torsin A dysfunction in forebrain versus hindbrain structures. Using the mice neurons, researchersi n addition hope to build a cell-culture of DYT1 dystonia.

The current plan is to perform an initial analysis of DYT1 vs. control-derived neurons and publish the findings, at which point the cells will be deposited with the Coriell Institute for public distribution. The Institute has already been notified about the intent to deposit the DYT1 iPS cells.

In order to confirm such predictions, additionals steps are being made to find the best compounds needed to move forward into animal models and further pre-clincial development.

In the last phase of the project, a narrowed down selection of validated targets will be screened again by using a different assay and cell biological methods. The goal is to identify a manageable number of validated target that are likely players in the disease process. When successfully completed this will allow for identification of genes and proteins affecting torsinA function that might become targets for rational drug design. The identified targets will also enrich our knowledge about the role of torsinA in neurons and guide future research in this area.