Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations

Abstract

Transcription disequilibria are characteristic of many neurodegenerative diseases. The activity-evoked transcription of immediate early genes (IEGs), important for neuronal plasticity, memory and behavior, is altered in CNS diseases and governed by epigenetic modulation. KDM1A, a histone 3 lysine 4 demethylase that forms part of transcription regulation complexes, has been implicated in the control of IEG transcription. Here we report the development of vafidemstat (ORY-2001), a brain penetrant inhibitor of KDM1A and MAOB. ORY-2001 efficiently inhibits brain KDM1A at doses suitable for long term treatment, and corrects memory deficit as assessed in the novel object recognition testing in the Senescence Accelerated Mouse Prone 8 (SAMP8) model for accelerated aging and Alzheimer's disease. Comparison with a selective KDM1A or MAOB inhibitor reveals that KDM1A inhibition is key for efficacy. ORY-2001 further corrects behavior alterations including aggression and social interaction deficits in SAMP8 mice and social avoidance in the rat rearing isolation model. ORY-2001 increases the responsiveness of IEGs, induces genes required for cognitive function and reduces a neuroinflammatory signature in SAMP8 mice. Multiple genes modulated by ORY-2001 are differentially expressed in Late Onset Alzheimer's Disease. Most strikingly, the amplifier of inflammation S100A9 is highly expressed in LOAD and in the hippocampus of SAMP8 mice, and down-regulated by ORY-2001. ORY-2001 is currently in multiple Phase IIa studies.

Efficacy of vafidemstat in experimental autoimmune encephalomyelitis highlights the KDM1A/RCOR1/HDAC epigenetic axis in multiple sclerosis

“…Studies using the EAE model were performed in accordance with the institutional guidelines for the care and use of laboratory animals (European Communities Council (Table A3 in Additional File 1). This therapeutic window (once the difference in exposure by oral gavage versus drinking water is accounted for) is similar to that observed for the beneficial effects of ORY-2001 on cognition in SAMP8 mice [9]. To dissect the relative contribution of the KDM1A vs MAO-B inhibitory component, we then compared the therapeutic efficacy of ORY-2001 with that of the selective KDM1A inhibitor ORY-LSD1 (0.06 or 0.18 mg/kg in Figure A1 D in Additional File 3 and 0.09 and 0.18 mg/kg in Figure 1B) and with the selective MAO-B inhibitor rasagiline (3 mg/kg).…”

Efficacy of vafidemstat in experimental autoimmune encephalomyelitis highlights the KDM1A/RCOR1/HDAC epigenetic axis in multiple sclerosis

“…ORY-2001 treatment was effective at doses that did not significantly impact the total number of circulating lymphocytes(Table A3in Additional File 1). This therapeutic window (once the difference in exposure by oral gavage versus drinking water is accounted for) is similar to that observed for the beneficial effects of ORY-2001 on cognition in SAMP8 mice[9]. To dissect the relative contribution of the KDM1A vs MAO-B inhibitory component, we then compared the therapeutic efficacy of ORY-2001 with that of the selective KDM1A inhibitor ORY-LSD1 (0.06 or 0.18 mg/kg inFigure A1D in Additional File 3 and 0.09 and 0.18 mg/kg in…”

Anxiety, Impaired Social and Aggressive Behaviour Correlates With Cognitive Decline Accompanied by Molecular Alterations in Older SAMP8 Males

“…The Resident-Intruder (RI) test was performed in order to evaluate the aggressive behaviour exhibited by the animals as described previously [43]. Briefly, the test subjects (residents) were isolated in separate cases for 7 days prior to the performance of the test.…”