LSD1

LSD1 is expressed in many tissues of the human body, from the embryonic process to adult life. One of the tissues where LSD1 plays a more important role is the brain. It intervenes in the first stages of life helping the neuronal division in order to ensure that all neurons that will be needed later in adult life are produced. After birth, multiplication is substantially reduced and neurons differentiate, travel to their target sites and establish the myriad of connections that will ensure the correct functionality of the various brain areas. LSD1 plays an important role in this process. In several neurological and psychiatric diseases, deregulation of the activity of LSD1 can occur.

In several animal models of Alzheimer’s and Huntington’s disease, and of schizophrenia and psychosis, LSD1 inhibition results in an improvement of learning or memory. Oryzon's clinical stage LSD1 inhibitor vafidemstat reduces pathologically aggressive behavior and increases sociability in animal models. LSD1 inhibition also produces axonal and synaptic branching of prefrontal cortex neurons, and improves the ability of neurons to connect with neighboring neurons. 

SETD1A is a histone methyl transferase that catalyzes methylation of histone 3 lysine 4, a “writer” with the opposite enzymatic activity of LSD1. Loss of function mutations in the SETD1a/Compass complex have been associated with schizophrenia and neurodevelopmental disorders. In SETD1A +/- mice, inhibition of LSD1 restores transcriptional imbalances and results in the restoration of normality at neuronal, anatomical and functional level. 

In animal models, the effect of mutations in genes or inhibition of signaling pathways associated with autism spectrum disorders or other neurodevelopmental diseases can be restored by LSD1 inhibition. Patients with mutations in genes from these pathways are therefore candidates for personalized medicine approach and treatment with vafidemstat, our LSD1 inhibitor in clinical development for CNS diseases.

Finally, LSD1 is involved in inflammatory processes, and our LSD1 inhibitors have been shown to reduce inflammation and clinical signs in preclinical models of multiple sclerosis. Inflammation is a pathophysiological process that has been shown to play a role in CNS diseases such as multiple sclerosis or Alzheimer's disease as well as in psychiatric diseases.