Contributions
Abstract: P1650
Type: LB Poster
Abstract Category: Late Breaking News
Many researchers have reported that epigenetics may play an important role in neurodegeneration. Several reports involved histone deacetylase (HDAC) inhibitors, but most of these compounds did not progress into clinical trials due to lack of selectivity or overt toxicity. In the recent years, other epigenetic targets have been identified, including the Lysine Specific Demethylase-1 (LSD1). LSD1 demethylates H3K4me1/2 and is a component of transcriptional repressor complexes together with CoREST, HDAC1/2 and REST/NRSF. ORYZON is pioneering the development of LSD1 inhibitors for CNS diseases and is currently testing the dual LSD1/MAO-B inhibitor ORY-2001, proposed as a novel therapeutic drug for the treatment of Alzheimer´s Disease (AD), in a Phase I clinical trial. ORY-2001 has an excellent pharmacological profile, and can be used for long term treatment. We previously reported that ORY-2001 restores cognition in SAMP-8 mice and biomarker anaysis showed that the compound induces cognition related and down-regulates neuroinflammatory genes in the hippocampus, including S100A9. S100A9 binds to and induces TLR4, and functions as an amplifier of inflammation. Up-regulation of S100A9 has been described in AD, but also in Multiple Sclerosis (MS) and in Experimental autoimmune encephalomyelitis (EAE) in mice. To assess the potential of LSD1 inhibition in MS, mice were immunized s.c. with 100 ug of MOG35-55 following a standard protocol. Animals were treated orally with 1 or 3 mg/kg ORY-2001 during two weeks following the onset of symptoms of the disease, and assessed the animals daily for signs of EAE according to the classical clinical scoring system. Treatment with ORY-2001 during the effector phase greatly inhibited the development of EAE and reduced disease incidence and severity. These data represent the first report of the benefit of epigenetic modulation of histone demethylation in an autoimmune disorder and point at a potential of ORY-2001 for the treatment of MS.
Disclosure: This study was sponsored by Oryzon Genomics S.A.
Tamara Maes, PhD: is shareholder and employee of Oryzon Genomics S.A.
Fernando Cavalcanti, PhD: is employee of Oryzon Genomics S.A.
Elena Gonzalez-Rey, PhD : is employed at the Instituto de Parasitología y Biomedicina "López-Neyra"-CSIC Granada Spain: nothing to disclose
Cristina Mascaró, PhD: is employee of Oryzon Genomics S.A.
David Rotllant, PhD: is employee of Oryzon Genomics S.A.
Carlos Buesa, PhD: is shareholder and employee of Oryzon Genomics S.A.
Abstract: P1650
Type: LB Poster
Abstract Category: Late Breaking News
Many researchers have reported that epigenetics may play an important role in neurodegeneration. Several reports involved histone deacetylase (HDAC) inhibitors, but most of these compounds did not progress into clinical trials due to lack of selectivity or overt toxicity. In the recent years, other epigenetic targets have been identified, including the Lysine Specific Demethylase-1 (LSD1). LSD1 demethylates H3K4me1/2 and is a component of transcriptional repressor complexes together with CoREST, HDAC1/2 and REST/NRSF. ORYZON is pioneering the development of LSD1 inhibitors for CNS diseases and is currently testing the dual LSD1/MAO-B inhibitor ORY-2001, proposed as a novel therapeutic drug for the treatment of Alzheimer´s Disease (AD), in a Phase I clinical trial. ORY-2001 has an excellent pharmacological profile, and can be used for long term treatment. We previously reported that ORY-2001 restores cognition in SAMP-8 mice and biomarker anaysis showed that the compound induces cognition related and down-regulates neuroinflammatory genes in the hippocampus, including S100A9. S100A9 binds to and induces TLR4, and functions as an amplifier of inflammation. Up-regulation of S100A9 has been described in AD, but also in Multiple Sclerosis (MS) and in Experimental autoimmune encephalomyelitis (EAE) in mice. To assess the potential of LSD1 inhibition in MS, mice were immunized s.c. with 100 ug of MOG35-55 following a standard protocol. Animals were treated orally with 1 or 3 mg/kg ORY-2001 during two weeks following the onset of symptoms of the disease, and assessed the animals daily for signs of EAE according to the classical clinical scoring system. Treatment with ORY-2001 during the effector phase greatly inhibited the development of EAE and reduced disease incidence and severity. These data represent the first report of the benefit of epigenetic modulation of histone demethylation in an autoimmune disorder and point at a potential of ORY-2001 for the treatment of MS.
Disclosure: This study was sponsored by Oryzon Genomics S.A.
Tamara Maes, PhD: is shareholder and employee of Oryzon Genomics S.A.
Fernando Cavalcanti, PhD: is employee of Oryzon Genomics S.A.
Elena Gonzalez-Rey, PhD : is employed at the Instituto de Parasitología y Biomedicina "López-Neyra"-CSIC Granada Spain: nothing to disclose
Cristina Mascaró, PhD: is employee of Oryzon Genomics S.A.
David Rotllant, PhD: is employee of Oryzon Genomics S.A.
Carlos Buesa, PhD: is shareholder and employee of Oryzon Genomics S.A.