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The cellular/molecular mechanism of CREB-dependent long-term synaptic plasticity is thought to underlie long-term memory formation and other aspects of brain plasticity. Accordingly, Dart NeuroScience is developing modulators of the CREB pathway for the treatment of neurocognitive disorders arising from psychiatric illness (schizophrenia, depression, post traumatic stress syndrome), neurodevelopmental disorders (intellectual disability, autism spectrum disorder, Fragile X) and to facilitate rehabilitation after brain injury (stroke, traumatic brain injury). Individuals whose cognitive deficits and memory loss place them in a transitional position on the continuum between normal aging and dementia, such as those with Mild Cognitive Impairment (MCI), also may benefit from this new class of memory enhancer. One or more of these disorders may be studied in clinical proof of concept trials conducted later in development.

PDE4

HT-0712 is an inhibitor of phosphodiesterase 4 (PDE4). PDE4 catabolizes cyclic AMP, elevated levels of which lead to activation of CREB. Phase 1 studies have shown HT-0712 to be well-tolerated in young and elderly subjects. A Phase 2a study, carried out for 28 days in elderly subjects with age-associated memory impairment (AAMI), also showed HT-0712 (i) to be well-tolerated, (ii) to have no effects on measures of short-term (working) memory, (iii) to have no effects on passive EEG measures and (iv) to have a statistically significant effect at one dose on long-term memory of word list recall. Phase 1 studies have begun with a PDE4 BackUp compound.

MAO-B

MAO-B is an outer mitochondrial membrane flavoenzyme involved in catabolism of neurotransmitters and exogenous amines. MAO-B predominates in the human brain and is responsible for the breakdown of dopamine, a neurotransmitter important for memory formation. Selective inhibition of MAO-B results in elevations of dopamine and thereby may enhance memory formation. Clinical studies of an in-house Lead Compound, HT-3951, currently are underway, and a back up compound has been identified.