From Molecular Insights to Patient Stratification

On October 5-6, 2021, the Forum on Neuroscience and Nervous System Disorders will host a virtual public workshop that brings together experts and key stakeholders from academia, industry, government, philanthropic foundations, and disease-focused non-profit organizations to discuss new genetic and neuroscience technologies and explore how these discoveries can be used to elucidate disease mechanisms and to advance the development of biomarkers and targeted therapies for patients with neurological and psychiatric disorders.

Invited presentations and discussions will be designed to:

• Explore the critical need for ancestral diversity and inclusion of individuals with severe or less common disorders—in genetics and the biological specimens needed to follow up on genetics—to advance both scientific analyses and global health equity/precision medicine.
• Examine the use of genetics and other technologies to facilitate identification of genetic variation, understand the effects of both common and rare variants on disease relevant function, and gain insights into disease mechanisms and molecular pathways in order to identify biomarkers that enable patient stratification to advance therapeutic development.
• Highlight lessons learned from recent advances in disorders associated with rare, penetrant genetic variants, and explore how resulting lessons can be applied to more common neuropsychiatric disorders.
• Explore challenges and promising approaches to nominating and validating stratification, disease progression, and treatment biomarkers.
• Explore challenges of designing innovative clinical trials that are based on deep mechanistic understanding of diseases and coupled with target engagement strategies in patients.
• Discuss a conceptual structure and opportunities to enable advanced technologies and computational approaches to be used more broadly, effectively, and rationally for new disorders, including considering data sharing and stakeholder engagement.

Workshop Background

Significant progress has been seen recently in developing therapies for rare monogenetic disorders such as spinal muscular atrophy and Dravet syndrome. In this domain there is strong collaboration and interest across the R&D landscape, from academia to biopharma and venture capital. Significant progress has also been seen in fields such as cardiovascular medicine and cancer in improving patient stratification and developing targeted drugs based on genetic findings. In contrast, progress continues to lag for neuropsychiatric disorders where critical challenges include insufficient mechanistic insights and a lack of biomarkers that can be used to stratify patients within broad symptom-based diagnostic categories. In addition, minority populations have been largely excluded or underrepresented in genetic studies and clinical trials, which has been an obstacle in development of appropriate treatments for diverse populations.

In the past several years, there have been important advances in genetic and neuroscience technologies and approaches that have great potential for improving mechanistic understanding of neuropsychiatric diseases and support the development of biomarkers. These include mechanistic and translational studies in patient-derived cells and tissues (iPS derived neurons, glia, organoids); high throughput means to analyze combinations of genetic variants; and other tools and computational approaches, including those developed as part of the BRAIN Initiative. Alongside these technical advances, it will be critical to increase the ancestral diversity in emerging precision medicine for neuropsychiatric disorders. The time is ripe to explore how these technologies and approaches can be used in the development of biomarkers for patient stratification, with the ultimate goal of advancing translational efforts and clinical development for rare and common brain disorders.