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bioRxiv · 10.64898/2025.12.15.694499

A Human Genetics Framework for De-risking Gene Editing Targets for Hematopoietic Cell and Gene Therapy

Dhall, A.·Pyclik, A.·Ung, M.·Etchin, J.·Keschner, Y.·Ge, H. G.·Chakraborty, T.·Lydeard, J.
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Abstract

Developing novel therapeutics requires robust early-stage target de-risking to ensure safety and efficacy. We developed a scalable proteogenomic framework integrating population-scale human genetics and plasma proteomics to identify genes tolerant of inactivation (i.e., dispensable) within hematopoietic compartments, thereby enabling safer targeted immunotherapies. Using CD33 as a validated benchmark, we observed that naturally occurring loss-of-function (LoF) variants lead to concordant RNA and protein depletion, supporting functional gene inactivation. Early clinical results from the Trem-Cel trial (NCT05945849) further provide proof of concept that deletion of dispensable antigens can enable safe and effective immunotherapy in humans. We extended this approach genome-wide in the UK Biobank and identified 237 candidate dispensable genes, filtered by plasma proteomic data and hematopoietic expression, highlighting LY75 (CD205) as a novel candidate with strong proteogenomic evidence of LoF tolerance. This work establishes a generalizable, quantitative proteogenomic framework for systematic prioritization of dispensable gene targets for editing, providing a foundation for next-generation cell and gene therapies that minimize on-target, off-tumor toxicities.

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Dhall, A., Pyclik, A., Ung, M., Etchin, J., Keschner, Y., Ge, H. G., Chakraborty, T., Lydeard, J.. 2025-12-17. A Human Genetics Framework for De-risking Gene Editing Targets for Hematopoietic Cell and Gene Therapy. https://doi.org/10.64898/2025.12.15.694499

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