Challenge
A biotechnology client focused on developing novel methods for gene therapy needed to ensure that their constructs were accurately being integrated into the correct location in the genome and not at off-target locations, a crucial factor for the safety and efficacy of gene therapies. The client was using an existing publicly-available bioinformatics pipeline that enables mapping of genomically-integrated DNA.
Action
Diamond Age (DA) Consultants collaborated closely with the client’s scientific team to develop the scientific and technical strategy. The project unfolded through several key phases:
1. Initial Assessment: DA worked with the client to understand their technical needs and then ran the client’s data through the publicly-available pipeline. The open-source tool was found to be inadequate to meet their needs as it failed to:
• Efficiently assess gene therapy constructs,
• Detect unwanted genomic rearrangements,
• Provide detailed insertion site analysis,
• Accurately multiplex company-specific barcodes, and
• Assess integration into off-target sites comprehensively, risking false negatives.
2. Customized Solution: DA engaged in weekly meetings with the client to develop a prototype that included:
• Reusing viable components of the existing pipeline while designing new functionalities,
• Implementation of novel visualizations and custom metrics specifically tailored to the
client’s requirements, and
• Integration of advanced detection capabilities for a collection of undesirable
mutations/structural rearrangements that their lab process tended to produce and that
went undetected by the open-source tool.
3. Prototyping and Testing: The prototype was rigorously tested against a dataset of known insertions to ensure accurate detection of both intended and unintended insertions.
4. Production and Implementation: DA finalized the prototype into a robust, production-grade system.
Result
These collaborative efforts led to the development of a highly customized, production-grade genomic analysis pipeline that significantly improved the client’s ability to ensure the accuracy and safety of their gene therapy constructs. Key outcomes included:
• Enhanced Precision: DA’s customized solution enables precise identification of the
location and type of genetic insertions, including complex and truncated variants.
• Reduced Risk of False Negatives: The tailored approach for detecting off-target effects
minimizes the risk of overlooking unintended genomic integrations, critical for clinical
safety.
• Client Satisfaction: The client confirmed that the data and analyses provided by the
new pipeline met all their requirements, leading to improved confidence in their gene
therapy constructs.