R&D tax relief projects›Sectors›Biotechnology
Case study

R&D Tax Credits for Biotech Companies

Case study: Reducing CRISPR Off-Target Editing

An example of how Lister prepares R&D tax relief evidence for a biotech project.

Paylists’ powerful AI, Lister, reads the project data, searches published work and recommends an answer to each question below, with supporting references.

How Lister prepared these answers
  1. 01Reads project dataStages, timesheets, costs, tests and documents recorded in Paylists.
  2. 02Searches published workOpenAlex, Europe PMC, PubMed, arXiv, Crossref, OSTI, NASA NTRS, NIST and other sources.
  3. 03Recommends answersEach answer is supported by references for your team and R&D tax advisor to review.
Main question

What the R&D aim of the project is

  1. Lister recommended answer

    To develop a CRISPR editing configuration that maintains useful on-target editing while materially reducing experimentally measurable off-target cleavage.

Main question

Scientific or technological uncertainty

  1. 01

    Describe exactly which uncertainties you need to resolve

    Lister recommended answer

    Whether guide design, nuclease selection and editing conditions can achieve the required specificity without reducing on-target editing below the project's acceptance threshold.

  2. 02

    Describe what made it a project to resolve a specified uncertainty

    Lister recommended answer

    Genome-wide off-target activity was already known, but the balance between specificity and efficiency depends on the guide, nuclease, genomic locus and biological system. The required performance could not be inferred reliably from existing methods alone.

  3. 03

    Describe the steps you plan to take to resolve them

    Lister recommended answer

    Test alternative guides and nuclease configurations, measure on-target activity, perform genome-wide off-target detection, validate candidate off-target sites and repeat the selected configuration using independent biological samples.

  4. 04

    What difficulties are foreseen for the project

    Lister recommended answer

    Improving specificity may reduce editing efficiency, computational predictions may miss genuine off-target sites and biological replicates may behave differently.

  5. 05

    Information about any major changes to the aims, or new uncertainties that have been encountered, while running the project.

    Lister recommended answer

    If initial configurations reduce off-target effects but also materially reduce the intended edit, the team may need to change nuclease variants, guide sequence or delivery conditions.

  6. 06

    How the uncertainties and other challenges were overcome (or not).

    Lister recommended answer

    Configurations would be progressively eliminated where either specificity or on-target performance failed. Only replicated configurations satisfying both safeguards would support technical resolution.

Main question

An advance in science or technology

  1. 01

    A review of the current state of knowledge

    Lister recommended answer

    GUIDE-seq and related research had already shown that CRISPR can produce substantial and unpredictable off-target activity. High-fidelity nucleases were also known before the project.

  2. 02

    How the project sought an advance in a qualifying area of science or technology

    Lister recommended answer

    The project sought an experimentally demonstrated improvement in the combined specificity-efficiency envelope for the particular biological system.

Outcome

Result, conclusion and evidence

Result

The final configuration reduced detected off-target activity while maintaining the predefined on-target requirement under the tested conditions.

Conclusion

The potential advance is not CRISPR editing itself, but the demonstrated ability to achieve the required specificity and editing performance together.

Evidence still needed

Guide sequences, nuclease versions, cell model, sequencing depth, raw off-target results, biological replicates and professional interpretation.

References

Supporting references

  1. Tsai et al. (2015), GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases.

    pmc.ncbi.nlm.nih.gov ↗

  2. Kleinstiver et al. (2016), High-fidelity CRISPR-Cas9 variants with undetectable genome-wide off-targets.

    pmc.ncbi.nlm.nih.gov ↗

  3. Slaymaker et al. (2016), Rationally engineered Cas9 nucleases with improved specificity.

    pmc.ncbi.nlm.nih.gov ↗
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