Deciphering the Circuits in Neuroscience Research

Craig Lindsley, Director of the Warren Center for Neuroscience Drug Discovery

With advances in research, we are increasing our understanding of how our brains work and how symptoms associated with mental health conditions develop.² Through this greater understanding of the brain, we are now in a better position to decipher the circuits that combine to affect behavior. In a step toward expanding efforts to accelerate the delivery of new treatment options to patients, Boehringer Ingelheim joined forces with the Warren Center for Neuroscience Drug Discovery (WCNDD) at Vanderbilt University, one of the world’s leading groups integrating basic neuroscience and new translational approaches in neuropsychiatric conditions.

“Vanderbilt’s vision and commitment to pioneer new approaches aligns with the work happening at Boehringer Ingelheim. We wanted to collaborate with a company that’s going to wave the flag for neuroscience and CNS disorders, sticking with programs until they show results,” says Craig Lindsley, director of the WCNDD

This commitment is even more important as the nature of neuroscience research poses unique challenges for innovators with many pharmaceutical companies exiting the field. The reality is that despite the progress of technology and increased understanding of the brain in recent decades, standard pharmacological treatment approaches for mental illness have barely changed for at least 25 years.

Trailblazing with new targets

Working together with Jeffrey Conn, WCNDD director emeritus, who established the group in 2003, Craig Lindsley set out to build a platform to explore new approaches to modulate key receptors in neuroscience. Bringing the experience gained while together working in the pharmaceutical industry, they wanted to develop the whole field of allosteric modulators of G-protein coupled receptors (GPCRs) – integral membrane proteins that convert extracellular signals into intracellular responses. The WCNDD made rapid progress in unravelling how GCPRs work at synapses, focusing specifically on metabotropic glutamate (mGlu) receptor subtypes.

A shared strategic vision

Daniel Ursu, Principal Scientist, Boehringer Ingelheim

“When your goal is to find first-in-class molecules in a particularly challenging therapeutic area, it makes sense to collaborate with the world-leading research groups in the field,” recalls Daniel Ursu, Principal Scientist, Boehringer Ingelheim. “We had a shared strategic vision to develop drugs that regulate maladaptive brain circuitry to alleviate symptoms in neuropsychiatric conditions.”

Early in 2019 the WCNDD and Boehringer Ingelheim announced their collaboration to investigate, develop and commercialize novel small molecules targeting distinct GPCRs modulating brain circuitry that is altered in neuropsychiatric conditions including schizophrenia. Current drugs for schizophrenia treat positive symptoms (such as hallucinations) but modulate dopamine globally, causing cognitive impairments. “There is a real unmet need for therapies that can treat the negative and cognitive symptoms of schizophrenia as well as the positive symptoms,” explains Lindsley. He adds, “We are working on fundamentally novel mechanisms involving metabotropic glutamate receptors that are highly localized in the brain striatum, which means you don’t get a global effect. This should improve positive and negative symptoms of schizophrenia, and we also have data showing improved cognition.”

“Allosteric modulation of GPCRs offers the possibility of achieving selectivity,” notes Ursu. “Our aim is to selectively target receptors expressed in the brain acting on specific circuits to treat specific symptoms in a particular patient population, in this case schizophrenia. This aligns well with our group’s strategy on moving towards a precision psychiatry approach for the treatment of psychiatric disorders.”

Trust and respect are driving rapid progress

Common goals, mutual trust and complementary expertise have facilitated rapid progress. “There is always a period at the start of any collaboration where people are feeling each other out and trying to work together”, Lindsley recalls. “What was key was that we both wanted to get an ideal candidate quickly.”

Henning Priepke, Senior Principal Scientist, Boehringer Ingelheim

“The experience of many of the Vanderbilt team meant they were aware of what is required for profiling compounds, including the pharmacokinetic aspects. So, in many ways, we talked the same language, which helped in being able to plan how to move forward,” explains Henning Priepke, Senior Principal Scientist, Boehringer Ingelheim.

Lindsley considers the trust and respect that was quickly established between the scientists, together with effective shared leadership, was essential in helping drive progress. Remarkably, the team only met twice before COVID-19 hit. “It’s pretty amazing how well it’s worked, despite not being able to meet in person. There’s a real diversity of thought. And that’s just what you need when you are working on these challenging targets”.

This diversity has fuelled innovative approaches to solving challenges along the way, argues Lindsley. “It’s not just the diversity of thought between industry and academics. It’s also cultural, across the mix of US and European scientific thinking. We talk and come up with solutions that combine the best of both worlds.”

“Sharing our ideas and figuring out the best approach has been great to see, and it’s helped to move things forward much more quickly,” agrees Ursu. “If we were working independently, you would never get those different ideas and concepts coming together that we have seen through our combined efforts."

The two teams working closely together have already discovered a range of novel allosteric modulators targeting selective glutamate receptors. These novel compounds have showed efficacy in preclinical behavioral models with the most promising currently being progressed towards clinical development.

Looking to the future

“This collaboration has really taken the best of both organizations and put that into a cohesive, first-in-class project team, with people committed to finding solutions to the complex challenges we are facing,” suggests Lindsley. He considers the work being done is of such high quality and scientific depth that it’s going to provide definitive answers on how best to benefit patients. “Our collaboration is so important for advancing this whole scientific field and for patients with neuropsychiatric conditions. At the end of the day, whether we are successful or not, I think the work we are doing is going to be important. It’s very exciting.”

References

1. World Health Organization Fact Sheet – Mental disorders 2019. https://www.who.int/news-room/fact-sheets/detail/mental-disorders
2. Roiser, J. What has neuroscience ever done for us? The Psychologist. 2015; 28; 284-287. Available at: https://thepsychologist.bps.org.uk/volume-28/april-2015/what-has-neuroscience-ever-done-us