Novartis Lab Notebook

A quarterly compendium of scientific research publications

Novartis R&D is made up of thousands of researchers, scientists, and clinicians across the globe who are dedicated to reimagining what’s possible in drug discovery and development. They work tirelessly to fuel the company’s innovation engine, exploring the mechanisms of disease, refining methods for developing medicines and conducting clinical trials, and advancing new technologies to change the future of medical care. 

As they strive to bring the next generation of therapeutic options to patients around the world, our researchers look forward to sharing their discoveries with the broader scientific community. They publish hundreds of papers each year in scientific journals, to advance our collective knowledge as we seek to improve human health, together. 

Each quarter, we’ll highlight some of these peer-reviewed papers in the Novartis Lab Notebook. In this, our first edition, we feature:

• New approaches to improve the stability, safety, and effectiveness of biotherapeutics 
• Discoveries that may fuel further drug development for rare viral infections and inflammatory diseases
• An academic and industry collaboration offering a new, data-driven approach to classifying multiple sclerosis progression
• And more from our labs…

Using AI to reclassify multiple sclerosis progression

New research published in Nature Medicine uses a probabilistic machine learning model to examine how disease progression is classified in multiple sclerosis. The work, which was conducted by researchers from Novartis and the Big Data Institute (BDI) at University of Oxford, in collaboration with other academic and industry experts, suggests that MS is more accurately viewed as an early- to advanced-stage spectrum of disease rather than as distinct sub-types, which is how the disease is currently delineated. This data-driven understanding of the disease could potentially help improve disease management and make drug discovery and clinical trials more efficient and precise. Learn more in this BDI news story.

Regulating the NLRP3 inflammasome

Research in Cell Chemical Biology led by Novartis scientists in Biomedical Research explores degradation of the kinase NEK7 as a potential approach to treating diseases driven by the NLRP3 inflammasome—a multiprotein complex that when hyperactivated has been linked to numerous inflammatory diseases. The publication describes the discovery of an investigational molecular glue degrader targeting NEK7, and reveals context- and species-specific insights about NEK7’s role in modulating the NLRP3 inflammasome.  

Exploring lung tissue regeneration using 3D organoids

The efficient exchange of oxygen and carbon dioxide is a fundamental function of the lung. The alveolar epithelium is a thin layer of cells integral to this process. Damage there can lead to fibrosis and chronic pulmonary diseases, making regeneration of this tissue a major goal in pulmonary biology. To this end, Novartis researchers used a complex, multicellular, 3D organoid culture derived from mouse cells to identify a small molecule that facilitated regeneration of alveolar type 1 (AT1) cells. They then used single-cell RNA sequencing (scRNA-seq) to identify the likely target of the molecule. Their work, published in Communications Biology, underscores the potential of using multicellular cultures coupled with scRNA-seq to trace mechanisms-of-action for early drug discovery.  

Fueling advances in Nipah virus drug discovery

To date, there are no approved treatments for Nipah virus (NiV), which although rare, can cause a zoonotically-transmitted viral infection with high mortality rates. Novartis researchers and collaborators from Emory University School of Medicine recently published findings in Nature Communications that may enable breakthroughs in the development of direct-acting antiviral medicines for NiV and other related henipaviruses. They used high-resolution microscopy known as cryo-EM and developed new, high-throughput biochemical assays to analyze the NiV polymerase, revealing new insights on structural variation, enzyme conformation and activity – findings that could help accelerate the discovery of antiviral drug candidates. 

Understanding the role of Kdm2a in male infertility 

Researchers from Novartis and the Friedrich Mieschler Institute for Biomedical Research studied knockout models of the gene Kdm2a in mice to better understand its role in spermatogenesis, the cellular differentiation process required for male fertility. They found that the histone demethylase produced by Kdm2a plays a critical and previously unrecognized role in the coordination of gene expression programs during spermatogonial differentiation and meiosis—repressing that differentiation and leading to progressive loss of male germ cell development and infertility. Their full findings are published in Nature Communications. 

Models for predicting long-term stability of biopharmaceuticals

Two papers published in Scientific Reports offer new approaches for predicting long-term stability of biopharmaceuticals, which is pivotal for effective and patient-friendly administration of these therapies. One, led by a team from Novartis Technical Research and Development, demonstrated that long-term stability predictions for biologics—specifically unwanted protein aggregation, which can compromise the stability, safety and effectiveness of these therapies—can be effectively assessed using a first-order kinetic model. The work could help shape best practices for implementing new ICH standardization guidelines on stability modeling for biologics. The second paper, which was conducted in collaboration with University of Ljubljana, described a predictive AI and molecular dynamics platform designed to model protein aggregation of monoclonal antibodies in biopharmaceutical formulations. 

Complete knockout of SLC30A8 reduces T2D risk

Genetic association studies have demonstrated that partial loss of function of the SLC30A8 gene provides some protection against type 2 diabetes (T2D) in humans. To determine how complete loss of SLC30A8 function might impact T2D risk, a team led by researchers from Novartis, Columbia University Irving Medical Center, and the Center for Non-Communicable Diseases in Karachi, Pakistan searched the Pakistan Genome Resource biobank for examples of human SLC30A8 ‘knockouts’ – individuals for whom both copies of the gene are non-functioning. Their research identified 18 such cases and showed that complete loss of SLC30A8 function proportionally reduced T2D risk, suggesting that SLC30A8 knockdown could potentially be a safe and effective therapeutic approach for T2D treatment. Their study appears in Diabetologia.