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

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.