Correcting inborn errors of immunity: From viral mediated gene addition to gene editing

• Published in: Seminars in immunology 2023-03, Vol.66, p.101731, Article 101731
• Main Authors: Castiello, Maria Carmina, Ferrari, Samuele, Villa, Anna
• Format: Article
• Language: English
• Subjects: CRISPR/Cas9; Gene editing; Gene Editing - methods; Gene therapy; Genetic Therapy - methods; Genetic Vectors - genetics; Hematopoietic Stem Cell Transplantation; Humans; Inborn errors of immunity; Lentiviral vectors; Primary immunodeficiency; Retroviral vectors
• ISSN: 1044-5323; 1096-3618; 1096-3618
• DOI: 10.1016/j.smim.2023.101731

Allogeneic hematopoietic stem cell transplantation is an effective treatment to cure inborn errors of immunity. Remarkable progress has been achieved thanks to the development and optimization of effective combination of advanced conditioning regimens and use of immunoablative/suppressive agents preventing rejection as well as graft versus host disease. Despite these tremendous advances, autologous hematopoietic stem/progenitor cell therapy based on ex vivo gene addition exploiting integrating γ-retro- or lenti-viral vectors, has demonstrated to be an innovative and safe therapeutic strategy providing proof of correction without the complications of the allogeneic approach. The recent advent of targeted gene editing able to precisely correct genomic variants in an intended locus of the genome, by introducing deletions, insertions, nucleotide substitutions or introducing a corrective cassette, is emerging in the clinical setting, further extending the therapeutic armamentarium and offering a cure to inherited immune defects not approachable by conventional gene addition. In this review, we will analyze the current state-of-the art of conventional gene therapy and innovative protocols of genome editing in various primary immunodeficiencies, describing preclinical models and clinical data obtained from different trials, highlighting potential advantages and limits of gene correction. •Gene therapies for inborn errors of immunity achieved remarkable safety and efficacy results.•Genome editing is a promising therapy for inborn errors of immunity.•New safety issues need to be addressed for appropriate risk/benefit assessments.•Sustainability and accessibility of these therapies are current issues.