Ataluren improves hematopoietic and pancreatic disorders in Shwachman-Diamond syndrome patients: a compassionate program case-series
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.
Authors
- Antonio Vella (ORCID: https://orcid.org/0000-0001-9598-2673)
- Cecilia Brignole
- Simone Cesaro (ORCID: https://orcid.org/0000-0002-8698-9547)
- Valentino Bezzerri (ORCID: https://orcid.org/0000-0002-6849-4487)
- Giacomo Menichetti
- Giovanni Porta (ORCID: https://orcid.org/0000-0001-5260-2415)
- Seth J. Corey (ORCID: https://orcid.org/0000-0002-3575-6401)
- Marco Cipolli (ORCID: https://orcid.org/0000-0001-5652-7248)
- Anca Manuela Hristodor
- Ilaria Meneghelli
- Anna Pegoraro (ORCID: https://orcid.org/0000-0002-5937-378X)
- Cristina Tecchio (ORCID: https://orcid.org/0000-0002-4001-1607)
- Genevieve M. Crane (ORCID: https://orcid.org/0000-0001-9274-0214)
- Elena Baldisseri (ORCID: https://orcid.org/0000-0002-9143-8205)
- Giuseppe Lippi (ORCID: https://orcid.org/0000-0001-9523-9054)
- Christian Boni (ORCID: https://orcid.org/0000-0002-9982-4100)
- Roberto Valli
- Angela Mercuri
- Giovanna D’Amico (ORCID: https://orcid.org/0000-0001-7809-7269)
- Alice Parisi
Institutions
- University of Insubria (IT)
- University of Verona (IT)
- Cleveland Clinic (US)
- Azienda Ospedaliera Universitaria Integrata Verona (IT)
- Azienda Ospedaliera San Gerardo (IT)
- Link Campus University (IT)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-02
- DOI
- https://doi.org/10.1038/s41467-025-63137-3
- Citations
- 1
- Primary Topic
- Blood disorders and treatments
- Type
- article
- Field-Weighted Citation Impact
- 1.82
Funders
- PTC Therapeutics
- Fondazione Telethon
- Università degli Studi di Pavia
- Istituto Oncologico Veneto
- National Institutes of Health