Lentivirus-mediated gene therapy corrects ribosomal biogenesis and shows promise for Diamond Blackfan anemia

• DOI: 10.1172/jci.insight.171650
• Publication Date: 2024-05-21T18:00:31Z
• Authors: Yari Giménez; Manuel Palacios; Rebeca Sánchez-Do...; Christiane Zorbas; Jorge Peral; Alexander Puzik; Laura Ugalde; Omaira Alberquilla; Mariela Villanueva; Paula Río; Eva Gálvez; Lydie Da Costa; Marion Strullu; Albert Catala; Anna Ruiz-Llobet; Jose Carlos Segovia; Julián Sevilla; Brigitte Strahm; Charlotte M. Niem...; Cristina Beléndez; Thierry Leblanc; Denis L.J. Lafont...; Juan Bueren; Susana Navarro
• Keywords: Diamond–Blackfan anemia; ribosome biogenesis

This study lays the groundwork for future lentivirus-mediated gene therapy in patients with Diamond Blackfan anemia (DBA) caused by mutations ribosomal protein S19 (RPS19), showing evidence of a new safe and effective therapy. The data show that, unlike Fanconi (FA), hematopoietic stem cell (HSC) reservoir DBA was not significantly reduced, suggesting that collection these cells should constitute remarkable restriction Subsequently, 2 clinically applicable lentiviral vectors were developed. In former vector, PGK.CoRPS19 LV, codon-optimized version RPS19 driven phosphoglycerate kinase promoter (PGK) already used different trials, including FA latter one, EF1α.CoRPS19 expression elongation factor alpha short promoter, EF1α(s). Preclinical experiments showed transduction patient CD34+ LV restored erythroid differentiation, demonstrated long-term repopulating properties corrected cells, providing improved maturation. Concomitantly, restoration biogenesis verified using potentially novel method to patients' blood based on RNA methylation analyses. Finally, vivo safety studies proviral insertion site analyses nontoxic.