B5 - Neurologic Diseases (excluding Ophthalmic and Auditory Diseases)
37: Extracellular Vesicles as the Underlying Mechanism for Cross-Correction with rAAV-Based Gene Therapy for GM3 Synthase Deficiency
Type: Oral Abstract Session
Presentation Details
Session Title: Neurologic Diseases I
GM3 synthase deficiency (GM3SD) is a neurodevelopmental disorder caused by a loss-of-function mutation in the ST3GAL5 gene. ST3GAL5 encodes for GM3 synthase and loss of this enzyme results in perturbation of the ganglioside biosynthesis pathway. These gangliosides are important for cell-signaling pathways and dysfunction leads to various neurological deficits, including brain atrophy and cognitive issues. These biochemical and physiological phenotypes are observed in GM3SD mouse models. Treatment with recombinant adeno-associated viral vectors (rAAV) packaging an ST3GAL5 expression cassette was able to reverse these effects. Not only was the rAAV able to reverse disease phenotypes, but widespread correction of gangliosides across the cortex suggests that some brain structures may be cross-corrected by a mechanism that extends beyond the direct effects of the transduced cells. We hypothesize that cross-correction is possible through the use of extracellular vesicles (EVs) as trafficking vehicles for gangliosides across cells. Based on preliminary data from transwell assays, we show that gangliosides can be trafficked between cells without direct cell-to-cell contact. We also show that ST3GAL5 expression is linked to EV biogenesis. These results strongly suggest that EVs are associated with the correction of ST3GAL5 in GM3SD model systems. Thus, GM3SD presents a valuable opportunity to explore cross-correction mechanisms associated with rAAV treatments in the brain. Ongoing investigations into EVs as a part of this mechanism is expected to reveal new methods for increasing rAAV efficiency for the treatment of GM3SD and other disorders. G.G. and P.T. are corresponding authors.
Sophia Liu1, Jonathan Valeros2, Max Zinter3, Travis Thomson3, Jessica Spinelli2, Guangping Gao1,4, Phillip Wl Tai1,4
1Horae Gene Therapy Center, UMass Chan Medical School, Worcester, MA,2Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA,3Department of Neurobiology, UMass Chan Medical School, Worcester, MA,4Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA"
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