Novel Therapy Development for Dystonia

Dystonia is a movement disorder characterized by involuntary repetitive, sustained muscle contractions, or postures. About 300,000 to 500,000 individuals, including military and veteran populations, suffer from dystonia in the US. DYT1 dystonia is the most common type among the genetic dystonia as an early-onset hyperkinetic movement abnormality.

This type of dystonia is prevalent in ages from 5 to 28 years old. The symptoms of DYT1 dystonia start from limbs and then remain segmental or become generalized with cervical muscle involvement. Patients usually are severely disabled and limit to wheelchairs. The DYT1 dystonia is an autosomal dominant disease showing variability in phenotype with low penetrance (30%-40%) possibly caused by additional genetic mutations and/or environmental variations.

The individuals affected by DYT1 dystonia share the same genetic mutation located in exon 5 of DYT1 gene, leading to a loss of an amino acid residue for a protein called torsinA. This type of mutation occurs in 50-60% of non-Jewish patients and more than 90% of Ashkenazi Jewish patients. DYT6 is another form of generalized, early-onset dystonia. Unlike DYT1 dystonia, DYT6 dystonia symptoms appear with a slower progression and frequently involve the cervical and cranial muscles. In addition, DYT6 does not respond well to deep brain stimulation (DBS) in the brain. In DYT6, the causative gene is THAP domain-containing apoptosis-associated protein 1 (THAP1). The THAP1 is a small DNA binding protein. There are commonalities between DYT1 dystonia and DYT6 dystonia. Thap1 appears to regulate the activities of torsinA. Furthermore, brain imaging studies show that a certain connection in the brain influences penetrance in both DYT1 and DYT6 dystonia.

The current treatments for dystonia have variable success rates among individuals and even in the same person over time. We aim to develop and validate a novel virus-based treatment strategy based on the role of this brain connection in influencing the penetrance and dystonia severity. We plan to use an overt dystonia
mouse model (Dlx-CKO mice) to test the hypothesis that Purkinje cell-specific viral expression of DREADD (designer receptors exclusively activated by designer drugs) molecules will alter this connection and improve motor performance and dystonia in an overt dystonia mouse models. It should be noted that although we are using the Dlx-CKO mice that were developed using conditional knockout of torsinA, this overt dystonia mouse model should have a broad representation of other types of dystonias as well because knockout of torsinA in Dlx5/6-positive neurons does not occur in humans. Cerebellar stimulation has been used in treating dystonia patients in the past with mixed success. The advantage of using the DREADD approach is that it not only can stimulate neuronal activity; it can also silence the neuronal activity.

Furthermore, it can manipulate specific types of neurons or over multiple brain regions or anatomic locations, all depends on the specific gene instructions used that are available to the scientists.
Viral therapies recently reached a milestone when the FDA approved Novartis’ Zolgensma in May 2019 for the treatment of children with spinal muscular atrophy (SMA). The therapy approved is to introduce
the missing gene that can help in the production of the protein that is otherwise missing in patients with SMA. As clinical efficacy of virus-based vectors becomes more established, there is an expectation that
applications of these vectors will extend to other neurological indications, including dystonia. The successful completion of the proposed experiments will pave the way for the future development and
implementation of virus-based treatment for DYT1, DYT6, and other dystonias. This may include testing in a larger animal model that is closer to human patients, applying for IND, and starting phase 1 trial in patients.