1/ Thrilled to share an advancement in gene therapy from my PhD in @NatureComms! We've developed a new approach to reduce immune responses while maintaining efficiency—paving the way for safer, more effective therapies. Big thanks to @zhangf & @mircoscopy!

RT @zhangf: Congratulations to @rumya_r @mircoscopy @DStrebinger @blake_lash @cyrusbiotech and colleagues on an exciting study combining AI….

RT @broadinstitute: Nucleases, core components of CRISPR-based genome-editing therapies, can stimulate unwanted immune responses. Scientist….

8/8 This interdisciplinary work wouldn't have been possible without @zhangf, @mircoscopy, Indigo King, Samuel Vo, @DStrebinger, @BlakeLash1, Michael Killian, @yfsong, @lucas_nivon, Rhiannon Macrae, @cyrusbiotech and the entire team at @broadinstitute!

7/8 This study highlights how structural biology and immunology converge to create tailored solutions in medicine. By designing proteins that “fly under the radar” of the immune system, we’re improving safety and accessibility of cutting-edge treatments and transforming medicine.

6/8 This work represents a significant step closer to making CRISPR therapies safe and effective for more patients! Importantly, it provides a framework for engineering other minimally immunogenic proteins for safer, more versatile therapies across disease applications.

5/8 In vivo, these Redi variants performed exceptionally. SaCas9.Redi.1 editing of PCSK9 not only matched wild-type efficiency but also reduced immune responses significantly. PCSK9 is one of many clinical targets and this approach opens doors for repeated dosing in gene therapy!

4/8 The result? The engineered "Redi" (REDuced Immunogenicity) variants of SaCas9 and AsCas12a dramatically reduced recognition by T cells and cytokine production, while maintaining wild-type levels of activity and specificity. A key milestone for safer therapeutic use.

3/8 Using MHC-associated peptide proteomics (MAPPs) with @AbzenaGroup we identified the specific immunogenic "hotspots" on SaCas9 and AsCas12a. Then, we used computational modeling with @cyrusbiotech to design mutations that reduce MHC binding and evade immune detection.

2/8 The problem? Most CRISPR systems, like SaCas9 and AsCas12a, come from bacteria, and many people’s immune systems recognize these proteins. This limits their use, especially in repeated treatments. We set out to address this with precision engineering.

RT @FrangiehChris: Really exciting work on structural studies and engineering of a non-LTR retrotransposon with @maxewilkinson Rhi Macrae a….