Abstract Details

Title An AAV Encoding Human ABCD1 Shows Dose-Responsive Expression and Function Following Spinal Cord Delivery in a Rodent Model of Adrenomyeloneuropathy

Topic Movement Disorders

Presentation(s) P1 - Poster Session 1 (9:00 AM-5:00 PM)

Poster/Presentation
Number 261

Objective The preclinical investigation of an AAV9-ABCD1 as a potential therapeutic for the treatment of Adrenomyeloneuropathy (AMN).

Background X-linked adrenoleukodystrophy (ALD) is an inherited neurodegenerative disease caused by mutations in the ABCD1 gene. Adrenomyeloneuropathy is the most frequent clinical manifestation of ALD affecting virtually all males and >80% of females. AMN is characterized by a slowly progressive spinal cord disease in adults leading to loss of mobility, incontinence, and debilitating pain. The ABCD1 gene encodes a peroxisomal membrane protein that transports very long-chain fatty acids (VLCFA) into the peroxisome. In the absence of functional ABCD1, affected cells accumulate increased VLCFA levels which can result in oxidative stress at the cellular level and inflammatory demyelination in the spinal cord.

Design/Methods An ABCD1 knockout mouse model of AMN exhibits key features of the human disease. Increased VLCFA levels and changes in mitochondrial DNA levels occur as a result of oxidative stress. We examined the ability of SBT101, a novel AAV9-hABCD1 vector, to improve the markers of AMN in the ABCD1-knockout mouse.

Results In mixed glial cultures derived from ABCD1 knockout mice, SBT101 transduction resulted in a dose-dependent lowering of VLCFA and achieved approximately wild-type levels. Following intrathecal delivery of SBT101 in adult ABCD1 knockout mice, expression levels of the hABCD1 transgene in the spinal cord were dose-dependent, lasted for 6 months, and did not result in notable spinal cord pathology. Furthermore, delivery of SBT101 improved mitochondrial DNA levels and significantly reduced VLCFA levels in the spinal cord in a dose dependent manner.

Conclusions Successful targeting of the spinal cord with SBT101 therapy was demonstrated together with dose-dependent improvement of disease markers in a mouse model of AMN. These data support further preclinical development of AAV9-ABCD1 as a potential treatment of AMN.

Authors/Disclosures
David W. Anderson, PhD (SwanBio Therapeutics Inc.) PRESENTER	Dr. Anderson has received personal compensation for serving as an employee of SwanBio Therapeutics Inc. Dr. Anderson has received personal compensation for serving as an employee of Spark Therapeutics Inc. An immediate family member of Dr. Anderson has received personal compensation for serving as an employee of GSK. An immediate family member of Dr. Anderson has received personal compensation for serving as an employee of Novartis. Dr. Anderson has stock in SwanBio Therapeutics Inc. An immediate family member of Dr. Anderson has stock in GSK. Dr. Anderson has stock in Roche . An immediate family member of Dr. Anderson has stock in Novartis.
	No disclosure on file
	No disclosure on file
Vidyullatha Vasireddy, PhD (SwanBio Therapeutics Inc.)	Dr. Vasireddy has stock in SwanBio Therapeutics.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Karen Kozarsky, PhD (SwanBio Therapeutics)	Dr. Kozarsky has received personal compensation for serving as an employee of SwanBio Therapeutics. Dr. Kozarsky has received stock or an ownership interest from SwanBio Therapeutics.

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