Cell Atlases: An Engine For Drug Discovery

Understanding Available Resources

Begin by exploring what single-cell data is already available in your therapeutic area. Some fields, like immuno-oncology, have abundant public datasets rich with relevant metadata, while others, such as metabolic diseases, may have limited data availability.

• Survey data on Human Cell Atlas (HCA),Nygen Database, and CellxGene and identify existing data that can accelerate your research without the immediate need for new data generation.

This step saves time and resources by leveraging publicly available information and helps you pinpoint specific areas where additional data is needed.

Investing in Single-Cell Technologies

After identifying gaps in the existing data landscape, the next step is to generate proprietary single-cell data tailored to your specific needs. This creates a unique data asset within your organization, enhancing your competitive edge in drug discovery.

• Choosing the Right Technology

Selecting the appropriate single-cell sequencing technology is crucial. Consider factors such as throughput, cost, sensitivity, and compatibility with your sample types. Options to consider include 10x Genomics, offers high-throughput single-cell sequencing solutions suitable for large-scale projects. Parse Biosciences - provides scalable and flexible single-cell sequencing kits ideal for various sample types, and Fluidigm C1 System- enables precise single-cell capture and preparation, beneficial for specific applications. Research each platform to determine which aligns best with your project's requirements. Consult with technology providers and consider conducting pilot studies to assess performance.

• Operational Considerations

Generating and analyzing single-cell data can be challenging due to costs and technical requirements.

• In-House vs. Outsourcing: Decide whether to build in-house capabilities or outsource data generation and analysis.
• In-House Analysis: Requires investment in equipment and recruitment of skilled bioinformaticians.
• Outsourcing: Collaborate with external facilities or partners to reduce overhead costs and access specialized expertise.

Academic sequencing facilities can provide could provide the initial outsourced support without significant overheads. Consider partnering with organizations that offer support in data generation and analysis. Nygen would be happy to assist you with our partner facilities across Europe, which can streamline the process and help overcome resource limitations.

Advanced Data Analysis and Interpretation

With your cell atlas in place, focus on extracting actionable insights to drive drug discovery. Utilize machine learning (ML) and deep learning (DL) models to analyze complex datasets and uncover patterns.

Querying the Atlas

Develop methods to effectively query your cell atlas:

• Target Identification: Analyze gene expression profiles to identify potential drug targets based on gene durability and relevance to disease pathways.
• Safety Assessment: Predict potential toxicity and cross-tissue effects to prioritize targets with minimal adverse effects.

Leveraging Analytics Platforms

Advanced analytics platforms can facilitate this process by providing tools for data analysis, visualization, and predictive modeling without the need for extensive in-house bioinformatics expertise. Platforms like CyteType offer capabilities to query and analyze your cell atlas, supporting target identification and validation through advanced computational methods.

Regulatory Compliance and Ethical Considerations

• It's important to ensure that public data being consumed has complete freedom to operate. Polluting intellectual property should be avoided. Nygen performs thorough due diligence on data provenance.
• It's also important to make sure that the data has been processed and integrated with tools that give full freedom to operate. Nygen uses permissive Free and Open Source Software (FOSS) tools in data processing.
• The data gathered needs ethical compliance and permissions from human subjects.

Successes in Drug Discovery

1. AstraZeneca's Lung Cell Atlas for Respiratory Diseases

Overview:

AstraZeneca collaborated with academic institutions and research organizations to develop a comprehensive cell atlas of the human lung. This initiative aimed to map the diverse cell types and states within healthy and diseased lung tissue, providing valuable insights into respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD).

Application in Drug Discovery:

• Target Identification:
• By analyzing single-cell RNA sequencing data from lung tissues, researchers identified key cells and pathways involved in the inflammatory processes of asthma and COPD.
• Thymic stromal lymphopoietin (TSLP), a cytokine produced by airway epithelial cells, was identified as a crucial mediator in initiating allergic inflammation.
• Drug Development:
• AstraZeneca, in partnership with Amgen, developed Tezepelumab, a monoclonal antibody that inhibits TSLP.
• Clinical trials demonstrated that Tezepelumab significantly reduced asthma exacerbations in patients with severe, uncontrolled asthma.
• Personalized Medicine:
• The lung cell atlas enabled the identification of biomarkers for patient stratification, allowing for more targeted and effective therapeutic interventions.

Regulatory Milestones

Tezepelumab received Breakthrough Therapy Designation from the FDA and was approved for use in patients with severe asthma.

Advancement in Understanding

The cell atlas provided deeper insights into lung biology and disease mechanisms, facilitating the discovery of additional therapeutic targets.

2. Kidney Precision Medicine Project (KPMP) for Renal Diseases

Overview:

The Kidney Precision Medicine Project (KPMP) is an initiative funded by the National Institutes of Health (NIH) that aims to create a detailed cellular atlas of the human kidney. The project focuses on understanding the cellular and molecular alterations in acute kidney injury (AKI) and chronic kidney disease (CKD).

Application in Drug Discovery:

• Pathophysiological Insights:
• Cellular Mapping:
  • Single-cell transcriptomic analyses identify specific kidney cell types affected in AKI and CKD.
• Pathway Identification:
  • The atlas uncovers dysregulated pathways and novel cellular interactions contributing to disease progression.
• Target and Biomarker Discovery:
• Therapeutic Targets:
  • Identification of novel targets allows for the development of drugs aimed at specific cell types or pathways.
• Biomarkers:
  • Early detection biomarkers facilitate timely intervention and improve patient outcomes.

Enhanced Drug Development

Pharmaceutical companies can utilize the kidney cell atlas to develop targeted therapies that may halt or reverse kidney damage.

Clinical Applications

Personalized treatment strategies can be devised based on a patient's unique cellular profile.