Ataluren improves hematopoietic and pancreatic disorders in Shwachman-Diamond syndrome patients: a compassionate program case-series

Valentino Bezzerri, Anna Pegoraro, Anca Manuela Hristodor, Genevieve M. Crane, Ilaria Meneghelli, Cecilia Brignole, Christian Boni, Elena Baldisseri, Antonio Vella, Giacomo Menichetti, Roberto Valli, Giovanni Porta, Giovanna D’Amico, Cristina Tecchio, Alice Parisi, Giuseppe Lippi, Angela Mercuri, Simone Cesaro, Seth J. Corey and Marco Cipolli ()
Additional contact information
Valentino Bezzerri: Azienda Ospedaliera Universitaria Integrata
Anna Pegoraro: Azienda Ospedaliera Universitaria Integrata
Anca Manuela Hristodor: Azienda Ospedaliera Universitaria Integrata
Genevieve M. Crane: Cleveland Clinic
Ilaria Meneghelli: Azienda Ospedaliera Universitaria Integrata
Cecilia Brignole: Azienda Ospedaliera Universitaria Integrata
Christian Boni: Azienda Ospedaliera Universitaria Integrata
Elena Baldisseri: Azienda Ospedaliera Universitaria Integrata
Antonio Vella: Azienda Ospedaliera Universitaria Integrata
Giacomo Menichetti: Azienda Ospedaliera Universitaria Integrata
Roberto Valli: Universita’ degli Studi dell’Insubria
Giovanni Porta: Universita’ degli Studi dell’Insubria
Giovanna D’Amico: Fondazione IRCCS San Gerardo dei Tintori
Cristina Tecchio: University of Verona
Alice Parisi: University of Verona
Giuseppe Lippi: University of Verona
Angela Mercuri: Azienda Ospedaliera Universitaria Integrata
Simone Cesaro: Azienda Ospedaliera Universitaria Integrata
Seth J. Corey: Cleveland Clinic
Marco Cipolli: Azienda Ospedaliera Universitaria Integrata

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Shwachman-Diamond syndrome (SDS) is characterized by exocrine pancreatic insufficiency, neutropenia, and a high risk of myeloid malignancy. Most patients with SDS harbor nonsense mutations in Shwachman-Bodian-Diamond syndrome gene (SBDS), which encodes a ribosome assembly factor. We investigated the translational read-through effect of ataluren in three patients with SDS undergoing a compassionate use program for twelve months. The primary and secondary endpoints were restoring SBDS protein levels in hematopoietic cells and improving myelopoiesis, respectively. SBDS synthesis increased in hematopoietic cells, whereas the bone marrow showed improved cellularity with the maturation of myeloid progenitors. In parallel, absolute neutrophil count was improved in two out of three patients, whereas platelet count increased in all recruited patients. Ataluren treatment normalized mTOR phosphorylation in peripheral blood monocytes and lymphocytes, suggesting a reduction of ribosomal stress. The exocrine pancreatic function also improved. Although the reduced sample size may represent a major limitation of this work, our findings strongly encourages the further clinical development of ataluren to treat SDS.

Date: 2025
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DOI: 10.1038/s41467-025-63137-3

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