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Small-Molecule PAPD5 Inhibitors Restore Telomerase Activity in Patient Stem Cells. | LitMetric

Small-Molecule PAPD5 Inhibitors Restore Telomerase Activity in Patient Stem Cells.

Cell Stem Cell

Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Stem Cell Institute, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Stem Cell Program, Boston Children's Hospital, Boston, MA, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA; Harvard Initiative in RNA Medicine, Boston, MA, USA. Electronic address:

Published: June 2020

AI Article Synopsis

  • Genetic issues that lower telomerase activity lead to serious diseases like dyskeratosis congenita (DC) and pulmonary fibrosis (PF) by preventing stem cells from replicating.
  • Researchers have discovered small-molecule inhibitors of PAPD5 that can restore telomere length and telomerase activity in lab-grown stem cells and in animal models.
  • The study highlights a specific PAPD5 inhibitor, BCH001, that has shown effectiveness in DC patient stem cells, and also a treatment (RG7834) that improved telomere length in engineered blood stem cells in mice, suggesting potential for therapies targeting aging-related diseases.

Article Abstract

Genetic lesions that reduce telomerase activity inhibit stem cell replication and cause a range of incurable diseases, including dyskeratosis congenita (DC) and pulmonary fibrosis (PF). Modalities to restore telomerase in stem cells throughout the body remain unclear. Here, we describe small-molecule PAPD5 inhibitors that demonstrate telomere restoration in vitro, in stem cell models, and in vivo. PAPD5 is a non-canonical polymerase that oligoadenylates and destabilizes telomerase RNA component (TERC). We identified BCH001, a specific PAPD5 inhibitor that restored telomerase activity and telomere length in DC patient induced pluripotent stem cells. When human blood stem cells engineered to carry DC-causing PARN mutations were xenotransplanted into immunodeficient mice, oral treatment with a repurposed PAPD5 inhibitor, the dihydroquinolizinone RG7834, rescued TERC 3' end maturation and telomere length. These findings pave the way for developing systemic telomere therapeutics to counteract stem cell exhaustion in DC, PF, and possibly other aging-related diseases.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275922PMC
http://dx.doi.org/10.1016/j.stem.2020.03.016DOI Listing

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