Movement Disorders

Date/Time: Monday, September 11, 2023 - 4:15 PM – 5:45 PM
Track: Special Interest Group (SIG) Session
Room: Franklin Hall 3 (4th Floor)
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Chair: Erin Stimming, MD

Co-Chair: Sheng-Han Kuo, MD

Novel clinical trials targeting organelles such as lysosomes, and mitochondria have been at the center of therapeutic development of movement disorders. In addition, gene therapies have been the techniques used to deliver such targeted therapies. In this session, panelists to discuss the basic biology rationale for new therapeutic development in movement disorders and new clinical trials. This SIG seeks to educate neurologists about the most recent development of novel therapies in movement disorders.

Learning Objectives:

  • Become more knowledgeable about the gene therapies being employed to treat various neurological diseases. 
  • Be better equipped to educate their patients concerning the types of clinical trials being performed targeting mitochondria and lysosomal dysfunction.
  • Learn the potential of these strategies to treat neurological disorders.
  • Understand the risks associated with the use of gene therapies.

Mitochondrial strategies for Friedreich’s ataxia

Speaker: David Lynch, MD, PhD, FANA

Friedreich Ataxia is an autosomal recessive multisystemic degenerative disorder caused by decreased levels of the mitochondrial protein frataxin. Deficiency of frataxin in vitro leads to loss of endogenous antioxidant enzymes and the transcription factor Nrf2, accumulation of mitochondrial iron, deficiency of ATP production, abnormalities of mitochondrial biogenesis, and cell death through ferroptosis. Based on such discoveries, a variety of agents have been tested in early and later-stage clinical trials.  Nrf2 enhancers such as omaveloxolone have shown exciting results, and therapies designed to decrease ferroptosis and augment mitochondrial biogenesis have entered clinical trials.  While definitive therapy will likely require restoration of deficient frataxin, such mitochondrially targeted approaches are likely to ameliorate dysfunction to a significant degree should they prove efficacious.

Optimizing AAV gene therapies

Speaker: Beverly L. Davidson, PhD

AAVs hold promise for treating inherited and acquired CNS disorders given their ability to provide for long term expression after gene delivery to cell of the nervous system. However, there is a need to improve their targeting and the doses required for efficacy.  We will discuss the current shortcomings and the strategies being employed to improve their utilities for brain gene therapy including ways to reduce off-targeting and improve gene therapy efficiencies, and methods to provide for regulated expression for those indications where payloads need to be expressed only once, for limited time periods, or where expression levels must be managed.


Speaker: Un Jung Kang, MD

Understanding How GBA Mutations Influence Parkinson’s Disease Progression

Oral Abstract Presenter: Arnav Khera, BS

We are investigating mechanisms underlying the clinical observation that GBA mutations are associated with increased risk of developing PD, along with faster progression of motor and cognitive symptoms. Mutations in the gene glucosidase, beta acid 1 (GBA) are the strongest genetic risk factor for Parkinson's Disease (PD) and accelerate disease progression. Our prior work using a Drosophila GBA deficient model revealed altered exosomes may act as vehicles to accelerate protein aggregate spread. We are now further investigating how GBA affects neuronal endolysosomal trafficking and exosome biogenesis. To do so, we are using a Drosophila and human cell culture model. We have developed a Drosophila model of GBA deficiency (GBAdel) by deleting the Drosophila homolog of the GBA gene. We have generated human induced pluripotent stem cells (iPSCs) from fibroblasts of an individual with PD carrying the IVS2+1G>A GBA mutation (GBAIVS PD). Dopaminergic neurons were differentiated from GBAIVS PD, isogenic GBAWT PD, and age- and sex-matched healthy control iPSCs using StemCell Technologies reagents and protocols. Confirmation for differentiation was performed by IHC. We isolated neuronal EVs by size exclusion chromatography from conditioned media. Our Drosophila model has shown us that isolated exosomes from from GBAdel mutant flies have altered protein cargo, including increased levels of exosome-intrinsic proteins Rab11 and Rab7, and increased oligomerized Ref(2)p, the Drosophila ortholog for p62. Expression of wildtype dGBA1b in flight muscle or glia of GBAdel mutant flies rescued protein aggregation in the brain, and also rescued levels of exosomal Rab11, Rab 7 and Ref(2)p. Our Drosophila model supports the hypothesis that GBAdeficiency alters exosomes, which may act as a vehicle to accelerate the spread of Lewy pathology. We are now extrapolating these results to our iPSC model, by examining how GBAalters endolysosomal trafficking leading to exosome biogenesis. We have performed IHC for essential markers of the endolysosomal trafficking pathway, to analyze differences in the amount and spread of these proteins in control vs. GBA mutant neurons. By understanding how altered exosomes can be a vehicle for Lewy pathology propagation could elucidate mechanisms to halt or slow down the spread of pathogenic protein aggregation in PD.