Contributions
Abstract: P656
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: Lysine specific demethylase 1 and histone deacetylase (HDAC) 1 and 2 are histone modifying proteins involved in transcription regulation. ORY-2001, a clinical stage LSD1/MAO-B inhibitor, reduces the clinical score in a mouse model of experimental autoinmune encephalomyelitis (EAE) at doses ranging from 0.05 to 3 mg/kg. ORY-2001 reduced lymphocyte egress and infiltration of immune cells in the spinal cord, preventing demyelination. Importantly, the therapeutic effects of ORY-2001 could be achieved at doses that do not significantly affect hematology, a common side effect in multiple sclerosis (MS) drugs, and in absence of gastro-intestinal toxicity. Interestingly, several FDA-approved drugs for MS including S1P receptor modulators and fumarates, were reported to target HDAC complexes in addition to their primary targets.
Objectives: To compare the mechanism of action of ORY-2001 and fingolimod in the effector phase of the EAE model.
Methods: Mice were immunized with MOG34-55 and treated orally during 2 weeks following onset of symptoms with 0.5 mg/kg ORY-2001 or 1 mg/kg fingolimod / day. The clinical score was assessed daily and animals were sacrificed on D17 after immunization (maximum clinical score). Spleen and lymph nodes were harvested for cell count and cytokine analysis; medulla and brain were used for gene expression (GE), cytokine and morphological analysis.
Results: ORY-2001 and fingolimod reduced the clinical score in the model, but ORY-2001 was more effective (60 vs 22% reduction) and/or acted faster under the described test conditions. Both compounds induced IL2 and MOG-induced cell proliferation; and increased anti-inflammatory cytokines (IL-4 and IL-10) and chemokines (IP-10 and MCP1). ORY-2001 and fingolimod increased cellularity in lymph nodes but only ORY-2001 increased it in spleen and modulated the B cell compartment, reducing the IgG2a/IgG1 ratio. GE profiling confirmed that
a) ORY-2001 reduced S100a9 expression in the spinal cord;
b) considerable overlap exists between the GE profiles of ORY-2001 and fingolimod;
c) ORY-2001 but not fingolimod induced Transthyretin (Ttr), a gene potently downregulated in a progressive EAE model; and lowered the demyelination marker Cystatin F, elevated in MS.
Conclusion: ORY-2001, a novel epigenetic drug finalizing a Phase I clinical trial, is a compound with distinct immune modulatory and expression profile, to be evaluated in clinical trials in multiple sclerosis.
Disclosure:
Tamara Maes is executive director and shareholder of Oryzon Genomics S.A. and member of the ADDF Scientific Review Board
Fernando Cavalcanti is employee of Oryzon Genomics S.A.
Elena Gonzalez-Rey has nothing to disclose.
Manuel Delgado has nothing to disclose.
Michelo Lufino is employee of Oryzon Genomics S.A.
Jordi Xaus is employee of Oryzon Genomics S.A.
Cristina Mascaró is employee of Oryzon Genomics S.A.
Carlos Buesa is executive director and shareholder of Oryzon Genomics S.A.
This work was financed by Oryzon Genomics S.A. and co-funded by Eurostars grant E!9683/CIIP-20152001 and Spanish grant RTC-2016-4955-1
Abstract: P656
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: Lysine specific demethylase 1 and histone deacetylase (HDAC) 1 and 2 are histone modifying proteins involved in transcription regulation. ORY-2001, a clinical stage LSD1/MAO-B inhibitor, reduces the clinical score in a mouse model of experimental autoinmune encephalomyelitis (EAE) at doses ranging from 0.05 to 3 mg/kg. ORY-2001 reduced lymphocyte egress and infiltration of immune cells in the spinal cord, preventing demyelination. Importantly, the therapeutic effects of ORY-2001 could be achieved at doses that do not significantly affect hematology, a common side effect in multiple sclerosis (MS) drugs, and in absence of gastro-intestinal toxicity. Interestingly, several FDA-approved drugs for MS including S1P receptor modulators and fumarates, were reported to target HDAC complexes in addition to their primary targets.
Objectives: To compare the mechanism of action of ORY-2001 and fingolimod in the effector phase of the EAE model.
Methods: Mice were immunized with MOG34-55 and treated orally during 2 weeks following onset of symptoms with 0.5 mg/kg ORY-2001 or 1 mg/kg fingolimod / day. The clinical score was assessed daily and animals were sacrificed on D17 after immunization (maximum clinical score). Spleen and lymph nodes were harvested for cell count and cytokine analysis; medulla and brain were used for gene expression (GE), cytokine and morphological analysis.
Results: ORY-2001 and fingolimod reduced the clinical score in the model, but ORY-2001 was more effective (60 vs 22% reduction) and/or acted faster under the described test conditions. Both compounds induced IL2 and MOG-induced cell proliferation; and increased anti-inflammatory cytokines (IL-4 and IL-10) and chemokines (IP-10 and MCP1). ORY-2001 and fingolimod increased cellularity in lymph nodes but only ORY-2001 increased it in spleen and modulated the B cell compartment, reducing the IgG2a/IgG1 ratio. GE profiling confirmed that
a) ORY-2001 reduced S100a9 expression in the spinal cord;
b) considerable overlap exists between the GE profiles of ORY-2001 and fingolimod;
c) ORY-2001 but not fingolimod induced Transthyretin (Ttr), a gene potently downregulated in a progressive EAE model; and lowered the demyelination marker Cystatin F, elevated in MS.
Conclusion: ORY-2001, a novel epigenetic drug finalizing a Phase I clinical trial, is a compound with distinct immune modulatory and expression profile, to be evaluated in clinical trials in multiple sclerosis.
Disclosure:
Tamara Maes is executive director and shareholder of Oryzon Genomics S.A. and member of the ADDF Scientific Review Board
Fernando Cavalcanti is employee of Oryzon Genomics S.A.
Elena Gonzalez-Rey has nothing to disclose.
Manuel Delgado has nothing to disclose.
Michelo Lufino is employee of Oryzon Genomics S.A.
Jordi Xaus is employee of Oryzon Genomics S.A.
Cristina Mascaró is employee of Oryzon Genomics S.A.
Carlos Buesa is executive director and shareholder of Oryzon Genomics S.A.
This work was financed by Oryzon Genomics S.A. and co-funded by Eurostars grant E!9683/CIIP-20152001 and Spanish grant RTC-2016-4955-1