Reducing Immune Reactions in Gene Therapy with Engineered Nucleases
Author Information
Author(s): Raghavan Rumya, Friedrich Mirco J., King Indigo, Chau-Duy-Tam Vo Samuel, Strebinger Daniel, Lash Blake, Kilian Michael, Platten Michael, Macrae Rhiannon K., Song Yifan, Nivon Lucas, Zhang Feng
Primary Institution: Broad Institute of MIT and Harvard
Hypothesis
Can we engineer nucleases to reduce their immunogenicity while maintaining their activity for gene therapy?
Conclusion
The engineered SaCas9 and AsCas12a variants show reduced immunogenicity and maintain their gene editing efficiency.
Supporting Evidence
- Engineered variants of SaCas9 and AsCas12a showed significantly reduced T cell responses compared to wild-type.
- Immunogenicity was assessed using PBMCs from healthy donors, showing reduced recognition of engineered peptides.
- SaCas9.Redi variants maintained editing efficiency comparable to wild-type in vivo.
Takeaway
Scientists made changes to certain proteins used in gene therapy so that our bodies don't react to them as much, while still keeping them effective.
Methodology
The study involved computational modeling and experimental validation of engineered nucleases to assess their immunogenicity and editing efficiency.
Potential Biases
Potential bias in the selection of epitopes and the specific HLA backgrounds tested.
Limitations
The study primarily focused on reducing cellular immunogenicity and did not extensively address humoral immunity.
Participant Demographics
Healthy human donors were used for PBMCs in the immunogenicity assays.
Statistical Information
P-Value
<0.0001
Statistical Significance
p<0.0001
Digital Object Identifier (DOI)
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