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Abstract Details

Gene therapy in a rat model of Christianson syndrome, an epileptic encephalopathy with ataxia
Movement Disorders
Movement Disorders Posters (7:00 AM-5:00 PM)
021
The objective of this work is to optimize a gene therapeutic treatment strategy in the Wistar Furth Shaker rat, a spontaneous model of ataxia caused by Slc9a6 mutation.
Human Slc9a6 mutations cause Christianson Syndrome (CS), an epileptic encephalopathy with progressive ataxia, intellectually disability, developmental delay, and autistic features. The Shaker rat is a naturally occurring, x-linked model of Purkinje cell (PC) degeneration and consequent tremor and ataxia. We recently identified a frame-shifting mutation in Slc9a6 encoding NHE6 as causing shaker. We confirmed pathogenesis of the mutation by supplementing the missing protein through gene transfer of Slc9a6 using an Adeno-associated virus (AAV).
We generated an AAV using an L7 promoter to target expression of the wildtype Slc9a6 rat gene to PCs along with a GFP tag to track cell-type specific expression. We administered this AAV via intracerebroventricular injection at 5 weeks, prior to PC degeneration, and evaluated the molecular, cellular, and motor therapeutic effect compared to an empty vector control. In this work, we evaluate a number of AAV doses to determine the safety and efficacy of different doses.

Relatively small doses of the L7-Slc9a6-GFP AAV (2.26 x 10^12 vG copies) were sufficient to improve the motor phenotype in successfully injected rats without noticeable side effects aside following surgical recovery. However, molecular and cellular phenotypes were more pronounced than motor phenotypes with low doses. We will present data evaluating the safety and efficacy of higher doses.
AAVs are a promising candidate for treatment of the motor symptoms associated with Slc9a6 mutation. Given the relative ease of targeting different cell types through various promoters, future directions will include evaluating AAVs in treating the developmental and epileptic components of the Shaker phenotype. As rats have a more developed social repertoire than mice, this model may permit detailed dissection of social behavior in CS.
Authors/Disclosures
Collin J. Anderson, PhD
PRESENTER 		The institution of Dr. Anderson has received research support from National Ataxia Foundation. The institution of Dr. Anderson has received research support from NIH. The institution of an immediate family member of Dr. Anderson has received research support from NIH. The institution of an immediate family member of Dr. Anderson has received research support from University of Utah.
Karla P. Figueroa (University of Utah) Ms. Figueroa has nothing to disclose.
Sharan Paul, PhD (University of Utah) Dr. Paul has nothing to disclose.
No disclosure on file
Mariana Gandelman, PhD (University of Utah) Dr. Gandelman has received research support from NINDS.
Daniel R. Scoles, PhD, FÂ鶹´«Ã½Ó³»­ (University of Utah) The institution of Dr. Scoles has received research support from NIH.
Stefan M. Pulst, MD, FÂ鶹´«Ã½Ó³»­ (University of Utah) Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as a Consultant for venrock. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arrowhead. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Leverna. Dr. Pulst has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Â鶹´«Ã½Ó³»­. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Leninthal LLC. The institution of Dr. Pulst has received research support from NINDS. Dr. Pulst has received intellectual property interests from a discovery or technology relating to health care.