Scientists at the Cambridge, MA, startup Sage Therapeutics have discovered an innate mechanism that indirectly influences a key receptor linked to a number of neurologic and psychiatric disorders, including Alzheimer's, schizophrenia, autism and depression.
The newly discovered natural allosteric modulator influences the N-methyl-D-aspartate (NMDA) receptor, which is known to play a role in regulating synaptic function in the central nervous system and impact human learning, memory and social behaviors.
"One of the difficulties in treating CNS disorders is that these diseases are heterogeneous," Sage CEO Jeffrey Jonas told FierceBiotechResearch in an interview, referring to the diverse nature of neuropsychiatric disorders.
Working with collaborators at Weill Cornell Medical College and Washington University School of Medicine in St. Louis, the Sage team screened a series of compounds to identify 24(S)-hydroxycholesterol (24(S)-HC), a brain-specific metabolite of cholesterol, as a potent and selective positive allosteric modulator of NMDA receptor function. In preclinical studies, treatment with Sage's SGE-301, a synthetic version of (24(S)-HC), showed a reversal in cognitive and social deficits related to the NMDA receptor in rats.
Jonas said the allosteric modulator SGE-301 essentially acts like ketamine but without the safety issues associated with it. Ketamine, an anesthetic that has been abused as the party drug known as "Special K," also works on the NMDA receptor--evidence of its effectiveness as a fast antidepressant.
The research, published Oct. 30 in the Journal of Neuroscience, advances Sage's Positive and Negative Allosteric Modulator (PANAM) platform, aimed at treating CNS and orphan diseases.
Sage is funded by Third Rock Ventures and Arch Ventures and has so far received $58 million in venture cash plus a $10 million grant from the NIH to work on fragile X syndrome.
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