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.