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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Aging / drug effects
-
Aging / psychology
-
Alzheimer Disease / drug therapy
-
Alzheimer Disease / psychology
-
Animals
-
Behavior, Animal / drug effects
-
Brain / drug effects
-
Brain / physiopathology
-
Disease Models, Animal
-
Enzyme Inhibitors / chemistry
-
Enzyme Inhibitors / pharmacokinetics
-
Enzyme Inhibitors / pharmacology*
-
Epigenesis, Genetic / drug effects
-
Female
-
Gene Expression / drug effects
-
Hippocampus / drug effects
-
Hippocampus / metabolism
-
Histone Demethylases / antagonists & inhibitors*
-
Humans
-
Male
-
Memory Disorders / drug therapy*
-
Mice
-
Mice, Inbred C57BL
-
Mice, Mutant Strains
-
Monoamine Oxidase Inhibitors / chemistry
-
Monoamine Oxidase Inhibitors / pharmacokinetics
-
Monoamine Oxidase Inhibitors / pharmacology*
-
Oxadiazoles / chemistry
-
Oxadiazoles / pharmacokinetics
-
Oxadiazoles / pharmacology*
-
Rats
-
Rats, Sprague-Dawley
Substances
-
Enzyme Inhibitors
-
Monoamine Oxidase Inhibitors
-
Oxadiazoles
-
Histone Demethylases
-
KDM1A protein, rat
-
KDM1a protein, mouse
-
KDM1A protein, human
-
vafidemstat
Grants and funding
None of the authors was a direct beneficiary but the studies were funded by Oryzon Genomics S.A. (
https://www.oryzon.com) and co-funded by grants or loans to [1] Oryzon Genomics S.A., Cornellá de Llobregat, Spain or [2] Fundació Bosch i Gimpera, Universitat de Barcelona, Barcelona, Spain or [3] Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain: [1] CEN-20081013 and CEN-20101023 of the CENIT program of CDTI, Spanish Ministry of Industry, Tourism and Commerce (
https://www.cdti.es/); by grant [1] RD08-2-0014 of CIDEM, Generalitat de Catalunya (
https://www.accio.gencat.cat/); by grants [1] 20100902VEN and 20150202 of the Alzheimer’s Drug Discovery Foundation (
www.alzdiscovery.org); by [1] FP7 grant 278871 of the European Union (
https://ec.europa.eu/research/fp7/index_en.cfm); and by [1, 2, 3] RTC-2015-3898-1 and [1, 2] RTC-2016-4955-1 of the RETOS program of CDTI, Spanish Ministry of Science, Innovation and Universities (
https://www.cdti.es/).