PROGRAMS - Schizophrenia and Calcineurin
Schizophrenia is a devastating psychiatric disease that affects 2-3 million individuals in the United States and approximately 1% of the population worldwide. It is characterized by "positive symptoms" such as delusions and hallucinations, "negative symptoms" including blunted emotions and social isolation, and cognitive deficits including impairments in attention and working memory. While currently available therapies for schizophrenia show effectiveness in some patients, many patients remain refractory to treatment and many more suffer significant side effects. In addition, treatments have historically been ineffective at treating the negative symptoms and cognitive impairments, characteristic of the disease. Given the high incidence and severity of this illness and the lack of ideal therapies, there is a tremendous need for new treatments for schizophrenia.
Calcineurin is a serine/threonine protein phosphatase that is highly expressed in the mammalian brain and is involved in multiple neuronal functions. The laboratories of Dr. Susumu Tonegawa at MIT and Dr. Maria Karayiorgou at Columbia University Medical Center (formerly at The Rockefeller University) have obtained behavioral and genetic evidence suggesting that calcineurin dysfunction contributes to schizophrenia pathogenesis. These findings raise the exciting possibility that the calcineurin pathway could provide novel and effective therapeutic targets for this disease. We are leveraging our unique access to schizophrenia animal models and cutting-edge genomics-based and neurophysiologic research capabilities to better understand the role of calcineurin dysfunction in schizophrenia. This research is now generating small molecule modulators of the calcineurin pathway which we hope will yield novel treatments for schizophrenia characterized by improved cognitive function, improved effects on negative symptoms and reduced side effects.
Furthermore, our powerful mechanism-based approach and unique models permit us to validate other potential therapeutic targets for psychiatric disorders and assess their efficacy at an early stage of development.
5-HT2C agonists and schizophrenia
Serotonin (5-HT) receptors can be divided into 14 subtypes, the majority of which are G protein-coupled receptors (GPCRs). Modulation of serotonin receptor signaling has emerged as a promising new therapeutic approach for schizophrenia. In particular, the activation of 5-HT2C receptors in the brain has been validated as an approach for treatment of schizophrenia in a number of preclinical studies, and 5-HT2C agonists have shown efficacy in a variety of preclinical models predictive of antipsychotic efficacy. These studies indicate that 5-HT2C agonists have potential to provide effective treatment for psychosis without inducing the undesired side effects of current antipsychotic medicines. We are currently advancing our novel indole-based series of 5-HT2C agonists to create safer, more effective treatments for schizophrenia.
5-HT6 antagonists for cognitive impairment
associated with schizophrenia (CIAS)
Another promising serotonergic target is the 5-HT6 receptor, which is highly expressed in brain regions associated with learning and memory. 5-HT6 antagonists increase central cholinergic and glutamatergic neurotransmission and have yielded pro-cognitive effects in a variety of preclinical models, including efficacy in tests of attention and working memory. 5-HT6 antagonists thus have exciting potential to effectively treat the cognitive deficits associated with schizophrenia. Our series of antagonists have demonstrated potent 5-HT6 receptor antagonism, excellent selectivity over other serotonin receptor family members and positive effects in multiple animal models of cognition. We are currently developing our novel 5-HT6 antagonists for the treatment of CIAS.
Cognitive impairment has become widely recognized among psychiatrists as a core component of schizophrenia, and many believe that treatment of CIAS is one of the greatest unmet needs in this disease. Impairments in cognition are a chronic feature of schizophrenia and these deficits, which include attention, speed of processing, memory, executive functioning and reasoning, severely impact the ability of patients to function in their daily lives.
