SARM1 Deletion Prevents Degeneration of Peripheral and ...€¦ · SARM1 Deletion Prevents...
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SARM1 Deletion Prevents Degeneration of Peripheral and Central Axons Raul Krauss*, Thomas Engber, Rajesh Devraj, Todd Bosanac, Robert Hughes Disarm Therapeutics, Cambridge, Massachusetts, USA 3. SARM1 Loss of Function Protects in Axotomy and Chemical Injury Models in vitro *** p < 0.001 **** p < 0.0001 Axotomy 4. cADPR is a Proximal Biomarker of SARM1 Activation after Axonal Injury in vitro Conclusions 8. SARM1 Genetic Deletion Prevents Increase of cADPR and Plasma NF-L in CIPN Model ** p < 0.01 7. SARM1 Genetic Deletion Prevents Increase of cADPR and Plasma NF-L in Sciatic Nerve Transection Model 9. SARM1 Genetic Deletion Prevents Increase of cADPR and Plasma NF-L in Optic Nerve Crush Model SARM1 genetic deletion protects axons from traumatic and chemical nerve damage in vitro and in vivo cADPR is a proximal biomarker of SARM1 enzymatic activity in vitro and in vivo NF-L, a prognostic biomarker of neurodegeneration increasingly used in the clinic, is released in blood following CNS, ocular, and PNS axonal degeneration in a SARM1-dependent manner Disarm is developing small-molecule SARM1 inhibitors as potentially disease- modifying therapeutics for patients with central and peripheral nervous system diseases such as multiple sclerosis and CIPN 6. cADPR and NF-L Increase after Peripheral and Central Nerve Injury in vivo Sciatic Nerve Axotomy Axotomy Chemical Injury Optic Nerve Crush NF-L Biomarker cADPR Biomarker SARM1 Pathway NF-L Biomarker cADPR Biomarker NAM + ADPR/cADPR Chemical Injury 5. NF-L is a Biomarker of Axonal Degeneration in vitro Axotomy, paclitaxel and vincristine cause a SARM1- dependent axonal injury in primary mouse DRG neurons WT 25 µm Untreated SARM1 KO WT Vincristine SARM1 KO WT Paclitaxel 25 µm *** p < 0.001 WT SARM1 KO **** p < 0.0001 Axotomy NF-L Biomarker cADPR Biomarker ** p < 0.01 ** p < 0.01 Axonal degeneration causes disability and disease progression in chronic and acute diseases of the central, ocular, and peripheral nervous systems such as multiple sclerosis, amyotrophic lateral sclerosis, glaucoma, and peripheral neuropathies. Although substantial evidence indicates that these neurological diseases are primarily the result of damage to axons, there are currently no therapies to prevent axonal degeneration. SARM1 has been identified as the central mediator of a cell-autonomous program of axonal degeneration and loss of axonal function. A variety of genetic, immune, metabolic insults, and injuries activate SARM1 enzymatic function, which directly leads to axonal degeneration. SARM1 is therefore an attractive target for development of a novel class of potentially disease- modifying therapeutics for central, ocular, and peripheral neurological diseases characterized by axonopathy. Disarm is developing small-molecule inhibitors of SARM1 to reproduce the axonal protective phenotype seen with SARM1 genetic deletion. We have established SARM1-dependent peripheral and central axonal disease models to assess in vivo PK/PD of therapeutic candidates. We discovered that cADPR is a proximal biomarker of SARM1 activity in vitro and in vivo. We also established that neurofilament light chain (NF-L), an axon-specific cytoskeletal protein released when axons degenerate, is a CSF and blood biomarker of SARM1-dependent CNS and PNS axonal degeneration. Blood NF-L is increasingly being used as a clinical biomarker of central and peripheral neurodegeneration to measure disease progression and disease- modifying therapy effectiveness. Disarm is developing two small-molecule inhibitors in parallel, one for central axonopathies, including multiple sclerosis, and one for peripheral axonopathies such as chemotherapy- induced peripheral neuropathy. 1. SARM1 Drives Rapid NAD + Loss Leading to a Bioenergetic Crisis and Axonal Degeneration 2. SARM1 - The Central Driver of Axonal Degeneration in Neurological Diseases
Transcript of SARM1 Deletion Prevents Degeneration of Peripheral and ...€¦ · SARM1 Deletion Prevents...
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SARM1 Deletion Prevents Degeneration of Peripheral and Central AxonsRaul Krauss*, Thomas Engber, Rajesh Devraj, Todd Bosanac, Robert HughesDisarm Therapeutics, Cambridge, Massachusetts, USA
3. SARM1 Loss of Function Protects in Axotomy and Chemical Injury Models in vitro
*** p < 0.001 **** p < 0.0001
Axotomy
4. cADPR is a Proximal Biomarker of SARM1 Activation after Axonal Injury in vitro
Conclusions
8. SARM1 Genetic Deletion Prevents Increase of cADPR and Plasma NF-L in CIPN Model
** p < 0.01
7. SARM1 Genetic Deletion Prevents Increase of cADPR and Plasma NF-L in Sciatic Nerve Transection Model
9. SARM1 Genetic Deletion Prevents Increase of cADPR and Plasma NF-L in Optic Nerve Crush Model
SARM1 genetic deletion protects axons from traumatic and chemical nerve damage in vitro and in vivo
cADPR is a proximal biomarker of SARM1 enzymatic activity in vitro and in vivo NF-L, a prognostic biomarker of neurodegeneration increasingly used in the
clinic, is released in blood following CNS, ocular, and PNS axonal degeneration in a SARM1-dependent manner
Disarm is developing small-molecule SARM1 inhibitors as potentially disease-modifying therapeutics for patients with central and peripheral nervous system diseases such as multiple sclerosis and CIPN
6. cADPR and NF-L Increase after Peripheral and Central Nerve Injury in vivo
Sciatic Nerve Axotomy
Axotomy Chemical Injury
Optic Nerve Crush
NF-L BiomarkercADPR BiomarkerSARM1 Pathway
NF-L BiomarkercADPR Biomarker
NAM + ADPR/cADPR
Chemical Injury
5. NF-L is a Biomarker of Axonal Degeneration in vitro
Axotomy, paclitaxel and vincristine cause a SARM1- dependent axonal injury in primary mouse DRG neurons
WT
25 µm
Untreated
SARM1 KOWT
Vincristine
SARM1 KOWT
Paclitaxel
25 µm
*** p < 0.001
WT SARM1 KO
**** p < 0.0001
Axotomy NF-L BiomarkercADPR Biomarker
** p < 0.01
** p < 0.01
Axonal degeneration causes disability and disease progression in chronic andacute diseases of the central, ocular, and peripheral nervous systems such asmultiple sclerosis, amyotrophic lateral sclerosis, glaucoma, and peripheralneuropathies. Although substantial evidence indicates that theseneurological diseases are primarily the result of damage to axons, there arecurrently no therapies to prevent axonal degeneration.SARM1 has been identified as the central mediator of a cell-autonomousprogram of axonal degeneration and loss of axonal function. A variety ofgenetic, immune, metabolic insults, and injuries activate SARM1 enzymaticfunction, which directly leads to axonal degeneration. SARM1 is therefore anattractive target for development of a novel class of potentially disease-modifying therapeutics for central, ocular, and peripheral neurologicaldiseases characterized by axonopathy.Disarm is developing small-molecule inhibitors of SARM1 to reproduce theaxonal protective phenotype seen with SARM1 genetic deletion. We haveestablished SARM1-dependent peripheral and central axonal disease modelsto assess in vivo PK/PD of therapeutic candidates. We discovered that cADPRis a proximal biomarker of SARM1 activity in vitro and in vivo. We alsoestablished that neurofilament light chain (NF-L), an axon-specificcytoskeletal protein released when axons degenerate, is a CSF and bloodbiomarker of SARM1-dependent CNS and PNS axonal degeneration. BloodNF-L is increasingly being used as a clinical biomarker of central andperipheral neurodegeneration to measure disease progression and disease-modifying therapy effectiveness. Disarm is developing two small-moleculeinhibitors in parallel, one for central axonopathies, including multiplesclerosis, and one for peripheral axonopathies such as chemotherapy-induced peripheral neuropathy.
1. SARM1 Drives Rapid NAD+ Loss Leading to a Bioenergetic Crisis and Axonal Degeneration
2. SARM1 - The Central Driver of Axonal Degeneration in Neurological Diseases
SARM1 Deletion Prevents Degeneration of Peripheral and Central Axons�Raul Krauss*, Thomas Engber, Rajesh Devraj, Todd Bosanac, Robert Hughes�Disarm Therapeutics, Cambridge, Massachusetts, USA
