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

Neha Nagpal; Jianing Wang; Jing Zeng; Emily Lo; Diane H Moon; Kevin Luk; Roman O Braun; Lauri M Burroughs; Sioban B Keel; Christopher Reilly; R Coleman Lindsley; Scot A Wolfe; Albert K Tai; Patrick Cahan; Daniel E Bauer; Yick W Fong; Suneet Agarwal

doi:10.1016/j.stem.2020.03.016

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

Cell Stem Cell. 2020 Jun 4;26(6):896-909.e8. doi: 10.1016/j.stem.2020.03.016. Epub 2020 Apr 21.

Authors

Neha Nagpal¹, Jianing Wang², Jing Zeng³, Emily Lo⁴, Diane H Moon¹, Kevin Luk⁵, Roman O Braun¹, Lauri M Burroughs⁶, Sioban B Keel⁷, Christopher Reilly⁸, R Coleman Lindsley⁸, Scot A Wolfe⁵, Albert K Tai⁹, Patrick Cahan⁴, Daniel E Bauer³, Yick W Fong², Suneet Agarwal¹⁰

Affiliations

¹ 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.
² Harvard Stem Cell Institute, Boston, MA, USA; Brigham Regenerative Medicine Center, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
³ 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; Broad Institute, Boston, MA, USA.
⁴ Department of Biomedical Engineering and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Department of Molecular, Cell and Cancer Biology, Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, USA.
⁶ Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Seattle Children's Hospital, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA.
⁷ Division of Hematology, Department of Medicine, University of Washington, Seattle, WA, USA.
⁸ Department of Medical Oncology, Division of Hematological Malignancies, Dana-Farber Cancer Institute, Boston, MA, USA.
⁹ Department of Immunology, Tufts University School of Medicine, Boston, MA, USA.
¹⁰ 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: suneet.agarwal@childrens.harvard.edu.

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.

Keywords: PAPD5; PARN; RG7834; TENT4B; TERC; dihydroquinolizinone; high throughput screen; telomerase; telomeres; xenotransplantation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Dyskeratosis Congenita* / drug therapy
Humans
Induced Pluripotent Stem Cells* / metabolism
Mice
Mutation / genetics
RNA
Telomerase* / genetics
Telomerase* / metabolism
Telomere / metabolism

Substances

RNA
Telomerase

Abstract

Publication types

MeSH terms

Substances

Grants and funding