Precision T cell correction platform for inborn errors of immunity
CRISPR-Cas9 gene editing is a promising tool to correct pathogenic variants for autologous cell therapies targeting inborn errors of immunity (IEI). Current strategies, such as gene knockout or cDNA knockin, address many single-gene defects but can disrupt gene expression, highlighting the need for precise correction platforms. While transplanting corrected autologous hematopoietic stem cells is a curative approach, it is unsuitable for patients with advanced disease, inflammation, or acute infections. As correcting T cells is an alternative therapeutic strategy for lymphoid IEIs, we present an efficient T cell single-nucleotide variant (SNV) correction platform based on homology-directed repair (HDR). By using STAT1 gain-of-function, cartilage hair hypoplasia, deficiency of ADA2, and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy as IEI models, we demonstrate that our platform achieves up to 80% correction, with resultant functional correction of the disease phenotype in the selected models. Furthermore, we performed safety profiling using GUIDE-seq, single-cell RNA sequencing, long-read genome sequencing, and proteomics analysis and detected no genomic, transcriptomic, or proteomic aberrations. This study establishes HDR-based SNV editing as a portable method for developing clinical autologous T cell therapies and represents a promising step toward a broad-spectrum gene correction platform for treating diverse monogenic immune disorders.
Authors
- Monika Szymańska (ORCID: https://orcid.org/0000-0003-0957-9568)
- Ganna Reint (ORCID: https://orcid.org/0000-0003-4823-5485)
- Shiva Dahal‐Koirala (ORCID: https://orcid.org/0000-0002-0165-5098)
- Timi Martelius (ORCID: https://orcid.org/0000-0002-3678-958X)
- Simon Storgård Jensen (ORCID: https://orcid.org/0000-0002-3519-4103)
- Johanna Olweus (ORCID: https://orcid.org/0000-0002-1898-3100)
- Katariina Mamia
- Karen Helene Bronken Martinsen (ORCID: https://orcid.org/0000-0001-9040-3134)
- Zhuokun Li (ORCID: https://orcid.org/0000-0001-7297-6916)
- Thea Johanne Gjerdingen
- Fred Haugen (ORCID: https://orcid.org/0000-0001-7201-7344)
- Kornel Labun (ORCID: https://orcid.org/0000-0002-1262-2611)
- Virpi Glumoff (ORCID: https://orcid.org/0000-0003-3461-6471)
- Salla Keskitalo (ORCID: https://orcid.org/0000-0001-5555-1975)
- Eivind Valen (ORCID: https://orcid.org/0000-0003-1840-6108)
- Camilla Schalin‐Jäntti (ORCID: https://orcid.org/0000-0002-2428-0161)
- Eero Tölö (ORCID: https://orcid.org/0000-0002-2773-5731)
- Martin Enge (ORCID: https://orcid.org/0000-0001-8748-8931)
- Janna Saarela (ORCID: https://orcid.org/0000-0002-0853-6219)
- Timo Hautala (ORCID: https://orcid.org/0000-0001-7889-1614)
- Emma Haapaniemi (ORCID: https://orcid.org/0000-0002-6693-8208)
- Markku Varjosalo (ORCID: https://orcid.org/0000-0002-1340-9732)
- Antti Tuhkala (ORCID: https://orcid.org/0009-0008-7956-9043)
- Carolina Wieczorek Ervik
- Pavel Kopcil
- Nail Fatkhutdinov
- Trond Melbye Michelsen
- Solrun Kolbeinsdottir (ORCID: https://orcid.org/0000-0001-7462-0278)
- Eira Leinonen
- Anna Komisarczuk
- Britt Olaug Lindestad
- Hans Christian Erichsen
Institutions
- Oslo University Hospital (NO)
- University of Helsinki (FI)
- University of Oslo (NO)
- Oulu University Hospital (FI)
- Finance Norway (NO)
- Helsinki Institute of Physics (FI)
- Helsinki University Hospital (FI)
- Karolinska Institutet (SE)
- Institute of Genetics (HU)
- Folkhälsans Forskningscentrum (FI)
- Hospital District of Helsinki and Uusimaa (FI)
- University of Bergen (NO)
Publication Details
- Journal
- Molecular Therapy
- Published
- 2025-08-12
- DOI
- https://doi.org/10.1016/j.ymthe.2025.08.018
- Citations
- 1
- Primary Topic
- Immunodeficiency and Autoimmune Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.80