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 then, Bachmann-Strauss funded studies on transgenic mice and on the roundworm C elegans have shed light on the pathophysiology of DYT1 dystonia, abnormalities in the brain that may result in dystonia, and the impact of proteins.
- In addition, two mouse models, one of L-DOPA responsive dystonia and the other of rapid onset dystonia-Parkinsonism, provide new information to characterize the link between dystonia and Parkinsonism. This research will also 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 recently 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.
Evidence has been found that dysfunction in the cerebellum may play a role in dystonia, and that two areas of the brain – the basal ganglia and the cerebellum – interact in the expression of dystonic movement. Previous theory held that dystonia was caused by a malfunction in the basal ganglia alone.
- TorsinA is a protein that, when mutant, can cause dystonia. Major findings in this area include:
- - Development of the antibody to torsinA, and work that helped to define the normal function of torsinA.
- - Demonstration 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.
- - Determination 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.
- - Determining where torsinA is located in the brain in normal rodents, in normal human controls, and in DYT1 dystonia patients.
Discovery of compounds and genes shown to suppress the harmful stress associated with the misfolding of proteins within cells have led to a licensing agreement with a biotech company to explore drug development for treating dystonia, Parkinson’s disease and other neurological disorders.
Identification of genes associated with dystonia-Parkinsonism syndrome, and follow up research to understand the molecular pathways that underlie this disease.
- Development of the concept that low frequency Deep Brain Stimulation (DBS) surgery can help alleviate symptoms in DYT1 patients.
- Study of the role of DBS in patients with secondary dystonia.
Ellen Hess Continues to Break New Ground
No cure for dystonia exists, effective screening and treatment for dystonia helps to lessen the symptoms of muscle spasms, pain, and awkward postures. The goal is to improve the quality of life and functioning of patients with the fewest side effects possible. The Bachmann-Strauss Scientific Advisory Board has announced that the Foundation will continue to fund the Anti-Dystonia Drug Discovery Program, headed by Ellen Hess, PhD, Professor, Department of Pharmacology, Emory University School of Medicine. "My general goal is to understand the pathomechanisms of dystonia by examining the underlying anatomical, physiological and biochemical substrates of the disorder by creating and manipulating mouse models. This strategy allows us to induce or ameliorate motor dysfunction in the context of an intact nervous system revealing potential targets for therapeutics," explained Dr. Hess.
For example, her team is currently using behavioral and cellular pharmacology to understand the cellular mechanisms that give rise to hyperactivity. Continuing her Bachmann-Strauss funded research studies, 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. The drug screening protocol created in the first phase of her research has transitioned to the testing of new compounds to alleviate dystonia symptoms in mice.
Looking ahead, the Anti-Dystonia Drug Discovery Program plans to make drug screening more widely available to facilitate preclinical testing of novel anti-dystonia compounds.
Using explicit criteria and a stringent scientific review process, The Bachmann-Strauss Dystonia & Parkinson Foundation encourages research designed to transform the care and treatment of dystonia and Parkinson’s disease. For 2012, a one-time special 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. The Board believes these gifted researchers have the potential to develop bold new directions in dystonia treatment.
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 begin to examine the defects in these cells after they are converted into dopamine neurons.
Using newly developed technology to study neurons of different motor pathways, Dr. Jinnah explained that this technology involves 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 can be used to generate a variety of different types of neurons. Thus, it becomes possible to have an unlimited quantity of different types of neurons for many different types of studies. As these cells are made from skins samples of dystonia patients, they will contain the genetic defects responsible for the disorder.
Dr. Bragg’s project - Generating Isogenic Dystonia iPS Cell lines with Custom TALE Nucleases - will generate iPSCs to different genetic causes of dystonia by turning normal cells into cells with dystonia mutations with TALE nucleases. Essentially they will be able to create iPSCs to any genetic form of dystonia using TALE technology. Dr. Bragg will also collaborate with the Jinnah laboratory in developing and comparing the different dystonia iPSC models. Directly comparing TALE nuclease -generated iPSC lines to ones generated by reprogramming patient fibroblasts can provide a lot of useful information.
The funds provided by The Bachmann-Strauss Foundation will support efforts to derive iPSCs by different methods. The work will take place over the next two years and will proceed in parallel with Dr. Jinnah’s lab. Dr. Bragg, explained, “Once our labs have derived iPSC models, it will be highly useful for us to coordinate functional analyses of the different models within the same assays, i.e., Dr. Jinnah’s group could potentially differentiate all lines in the same platform and characterize morphologic features, while our group could perform transcriptional profiling on all lines.”
In seeking proposals from extraordinary researchers like Drs. Jinnah and Bragg with the potential for innovative approaches in previously unexplored areas, the Scientific Advisory Board looks for projects that will lead to new tools or new directions for future treatments in dystonia and Parkinson’s disease.