David Gray, CSO of Inscopix talks to Lu Rahman about the company’s understanding of the neuroscience market and its quest to improve technologies for neuroscientists to enable multimodal research.
Inscopix is a neurotechnology company focused on understanding the function of the brain to better address the tremendous need for improved treatments of brain and nervous system disorders. The company’s platform is based on its miniature microscope (miniscope) technology that enables real-time visualisation of brain circuit activity. Inscopix has created a data-driven and AI-based analysis platform that allows scientists to study the interactions between hundreds to thousands of brain cells and their correlation to real-time behaviour in freely-moving animals.
“With more than 1 billion people suffering from neurological disorders, brain- related diseases are the most significant healthcare problem in the world, impacting almost one in six of the world’s population,” says David Gray, CSO, Inscopix. “Furthermore, diseases affecting the central nervous system (CNS), such as depression and Alzheimer’s disease, are a major and unfortunately growing socioeconomic burden worldwide, which will continue to plague society until there are more effective treatments.
For decades, a parade of literally hundreds of drugs have been predicted to treat these diseases after they’ve shown efficacy in traditional preclinical disease models; however, these treatments very rarely have improved outcomes for patients in Phase II and III human clinical trials. These failures, coming very late in the research and development process, represent a staggering loss in terms of time and capital, and tremendous disappointment for patients and their families.”
Gray says that the root cause behind a majority of these failures is that scientists had selected or prioritised the wrong therapeutic hypothesis during the early preclinical stages of R&D. “The brain is the most complex organ in the body and also the most difficult to study directly. Traditional techniques used to evaluate the potential of new therapeutic ideas have remained surprisingly unchanged over the past decades, despite the many failures,” he says. “It is now known that many CNS diseases and disease symptoms manifest at the mesoscale level, where the activity of hundreds or thousands of cells coordinate their activities in what is known as the neural circuit. Traditional imaging techniques leave a crucial gap in studying the brain at this intermediate level in that they either study single neurons one at a time, or they provide averaged signals from millions of cells in larger portions of the brain.”
Gray explains that over the last decade, there have been significant advances in the technology scientists have at their disposal to interrogate the brain’s inner workings. “Understanding the brain at the functional neurocircuit level in both health and disease can provide key insights for developing effective precision therapeutics,” he adds.
Focus on opportunities
“We now know that the neural circuit, groups of neurons that are connected to and communicate with each other, is the level where many diseases are expressed. Neural circuits work together to initiate and regulate behaviours – from memory to movement and everything in between,” Gray explains. “Fortunately, many fundamentally important circuits are conserved across species – from mice to humans – which means that preclinical insights from studying neural circuits are highly informative for understanding the human brain.”
Similar to how deeper understanding of cancer has enabled drugs that are more precise and effective, new techniques like direct in-brain imaging in behaving animals via miniature head-mounted microsopes the miniscope are giving neuroscience researchers the ability to directly see and understand brain activity, and thereby identify and evaluate targeted interventions that can correct dysfunctional circuitry.
“Targeting the most effective therapeutic strategies early in the discovery process by advancing drugs that cause functional recovery at the circuit level is an approach that promises to deliver increased success in clinical development and ultimately more effective medicines for patients,” Gray adds.
Until recently, decoding the complexities of brain function at a detailed level was largely beyond the available tools. Several important technological advances are changing this. “Optical imaging of brain activity with single cell resolution, targeted optogenetic manipulation of brain circuits, high resolution and high content spatial biology techniques, and precision gene manipulation techniques are all providing unprecedented access and insight into the details of the preclinical brain,” says Gray. “While each of these technologies are impressive in their own right, it is the co-analysis of data coming from multiple simultaneous techniques, which is enabled by powerful computing resources and AI techniques, that is finally allowing researchers to truly understand brain function.”
“We are incredibly fortunate to work closely with some of the leading scientists in the field of neuroscience,” says Gray. “By working closely with collaborators, the field has progressed significantly, and we are closer than ever to discovering treatment options that provide clinically-meaningful improvements.”
One recurring barrier to deep collaborative neuroscience research, says Gray, is a lack of flexible and effective data sharing and analysis tools. “Frequently, researchers will create data sets and highly customised and experiment- specific analysis algorithms that end up siloed within their labs, resulting in data that can only be analysed and interpreted by their creators. It has been historically very challenging to re-visit and combine previously collected data sets or leverage new analytical advances from other researchers. This becomes a significant barrier in efficient collaboration, especially when it comes to multi-modal and multi-lab analytic concepts,” he adds.
Gray believes that to form seamless partnerships locally and globally, scientists need easy ways to share, organise, standardise and analyse data sets. “This will be crucial as newer techniques in both academic and biopharma labs generate richer data sets and want to conduct large-scale, multi-modal drug discovery research,” he says.
“Over my 20 years in the biopharma industry, there has not been a reliable way to visualise the detailed neuronal mechanisms within the brain and their link to the dysfunctionality which underpin neurological and psychiatric diseases,” says Gray. “The field has used the best techniques available, but the relative lack of new treatments despite tremendous investment stands as strong proof of the inadequacy of the traditional approaches.” According to Gray the industry has become proficient at identifying high quality compounds via predictive preclinical selectivity, metabolic, and safety profiling that translates into humans; however, the best and safest molecules are of little use when applied to the wrong therapeutic target.
“At Inscopix we will continue to improve our core technologies for neuroscientists, making them even more powerful and easier to use and enabling facile multimodal research. We will partner closely with biopharmaceutical companies who want to apply these tools in a therapeutic setting, and we will continue to leverage our own technology and our novel insights into the activity of specific circuits to pursue several novel therapeutic discovery programs internally,” he says.
The company has launched platforms that will improve complex data analysis and sharing workflows and added another dimension to how brain vascular dynamics and behaviour can be studied. “We will use these tools to advance our own focused pipeline of treatments for neuro-related diseases. With a modern, neurocircuitry-focused approach to selecting research targets, we are working to bring more effective medicines to patients who are counting on the neuroscience research community to deliver treatment breakthroughs,” Gray reveals.
Volume 23 – Issue 4, Fall 2022
David Gray, PhD, is Chief Scientific Officer of Inscopix, where he heads Inscopix’ drug discovery and development programs for neuro-related diseases. Dr Gray was previously VP at Cerevel Therapeutics, responsible for the development of late-stage clinical programs for Alzheimer’s disease and Parkinson’s disease.