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Sarm1 Haploinsufficiency and Low Expression Levels after Antisense Oligonucleotides Delays Programmed Axon Degeneration

45 Pages Posted: 16 Mar 2021 Publication Status: Published

See all articles by Stacey Anne Gould

Stacey Anne Gould

University of Cambridge - Department of Clinical Neurosciences

Jonathan Gilley

University of Cambridge - Department of Clinical Neurosciences

Karen Ling

Ionis Pharmaceuticals - Neuroscience Drug Discovery

Payman Jaffar-Nejad

Ionis Pharmaceuticals - Neuroscience Drug Discovery

Frank Ringo

Ionis Pharmaceuticals - Neuroscience Drug Discovery

Michael Coleman

University of Cambridge - Department of Clinical Neurosciences

More...

Abstract

Activation of pro-degenerative protein SARM1 in response to diverse physical and disease-relevant injuries causes programmed axon degeneration. Original studies indicated substantially decreased levels of SARM1 were required for neuroprotection. However, we demonstrate that lowering SARM1 levels by 50% in Sarm1 haploinsufficient mice delays programmed axon degeneration in vivo, after sciatic nerve transection, in vitro in response to diverse traumatic, neurotoxic, and genetic triggers of SARM1 activation, and partially prevents neurite outgrowth defects in mice lacking pro-survival factor NMNAT2. We also demonstrate the capacity for Sarm1 antisense oligonucleotides to decrease SARM1 levels by more than 50% which delays or prevents programmed axon degeneration in vitro. Combining Sarm1 haploinsufficiency with antisense oligonucleotides further decreases SARM1 levels and prolongs protection after neurotoxic injury. These data demonstrate that axon protection occurs in a Sarm1 gene-dose responsive manner and that SARM1 lowering agents have therapeutic potential. Thus, antisense oligonucleotide targeting of Sarm1 is a promising therapeutic strategy.

Suggested Citation

Gould, Stacey Anne and Gilley, Jonathan and Ling, Karen and Jaffar-Nejad, Payman and Ringo, Frank and Coleman, Michael, Sarm1 Haploinsufficiency and Low Expression Levels after Antisense Oligonucleotides Delays Programmed Axon Degeneration. Available at SSRN: https://ssrn.com/abstract=3806068 or http://dx.doi.org/10.2139/ssrn.3806068
This version of the paper has not been formally peer reviewed.

Stacey Anne Gould

University of Cambridge - Department of Clinical Neurosciences

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Jonathan Gilley

University of Cambridge - Department of Clinical Neurosciences

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Karen Ling

Ionis Pharmaceuticals - Neuroscience Drug Discovery

Payman Jaffar-Nejad

Ionis Pharmaceuticals - Neuroscience Drug Discovery ( email )

United States

Frank Ringo

Ionis Pharmaceuticals - Neuroscience Drug Discovery ( email )

United States

Michael Coleman (Contact Author)

University of Cambridge - Department of Clinical Neurosciences ( email )

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

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