Related Experiment Video

Updated: Dec 23, 2025

Utilizing Murine Inducible Telomerase Alleles in the Studies of Tissue Degeneration/Regeneration and Cancer
08:34

Utilizing Murine Inducible Telomerase Alleles in the Studies of Tissue Degeneration/Regeneration and Cancer

Published on: April 13, 2015

10.6K

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

Neha Nagpal1, Jianing Wang2, Jing Zeng3

  • 1Division 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.

Cell Stem Cell
|April 23, 2020
PubMed

Insights

Small molecules inhibiting PAPD5 restore telomere length and telomerase activity. This approach offers a potential therapy for stem cell diseases like dyskeratosis congenita and pulmonary fibrosis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Stem Cell Biology

Background:

  • Genetic defects reducing telomerase activity impair stem cell replication, leading to diseases like dyskeratosis congenita (DC) and pulmonary fibrosis (PF).
  • Current therapeutic strategies to restore telomerase function in stem cells systemically are limited.

Purpose of the Study:

  • To identify and evaluate small-molecule inhibitors of PAPD5 as a therapeutic approach for restoring telomere length and telomerase activity.
  • To investigate the efficacy of PAPD5 inhibition in cellular and animal models of telomere biology disorders.

Main Methods:

  • In vitro screening and characterization of PAPD5 inhibitors.
  • Assessment of telomere length and telomerase activity in patient-derived induced pluripotent stem cells (iPSCs).
  • Xenotransplantation of human blood stem cells with DC-associated mutations into immunodeficient mice, followed by oral administration of a PAPD5 inhibitor (RG7834).

Main Results:

  • Identified BCH001, a specific PAPD5 inhibitor, which restored telomerase activity and telomere length in DC patient iPSCs.
  • Oral treatment with RG7834 in a mouse model rescued telomere length and TERC 3' end maturation in human blood stem cells carrying PARN mutations.
  • PAPD5 inhibition demonstrated efficacy in both in vitro and in vivo models, targeting the destabilization of the telomerase RNA component (TERC).

Conclusions:

  • Small-molecule PAPD5 inhibitors can effectively restore telomere length and telomerase activity.
  • Systemic administration of PAPD5 inhibitors shows promise for treating stem cell exhaustion in diseases like DC and PF.
  • These findings establish a foundation for developing novel systemic telomere therapeutics for aging-related diseases.
Keywords:
PAPD5PARNRG7834TENT4BTERCdihydroquinolizinonehigh throughput screentelomerasetelomeresxenotransplantation

More Related Videos

Semi-quantitative Detection of RNA-dependent RNA Polymerase Activity of Human Telomerase Reverse Transcriptase Protein08:26

Semi-quantitative Detection of RNA-dependent RNA Polymerase Activity of Human Telomerase Reverse Transcriptase Protein

Published on: June 12, 2018

10.3K
Fluorescence-based Monitoring of PAD4 Activity via a Pro-fluorescence Substrate Analog08:37

Fluorescence-based Monitoring of PAD4 Activity via a Pro-fluorescence Substrate Analog

Published on: November 5, 2014

10.2K

Related Concept Videos

Telomeres and Telomerase02:41

Telomeres and Telomerase

In eukaryotic DNA replication, a single-stranded DNA fragment remains at the end of a chromosome after the removal of the final primer. This section of DNA cannot be replicated in the same manner as the rest of the strand because there is no 3’ end to which the newly synthesized DNA can attach. This non-replicated fragment results in gradual loss of the chromosomal DNA during each cell duplication. Additionally, it can induce a DNA damage response by enzymes that recognize single-stranded...
26.5K
Telomeres and Telomerase02:41

Telomeres and Telomerase

6.7K
Replicative Cell Senescence02:15

Replicative Cell Senescence

Replicative cell senescence is a property of cells that allows them to divide a finite number of times throughout the organism's lifespan while preventing excessive proliferation. Replicative senescence is associated with the gradual loss of the telomere — short, repetitive DNA sequences found at the end of the chromosomes. Telomeres are bound by a group of proteins to form a protective cap on the ends of chromosomes. Embryonic stem cells express telomerase — an enzyme that adds...
4.2K
iPS Cell Differentiation01:22

iPS Cell Differentiation

The ability of induced pluripotent stem cells or iPSCs to differentiate into most body cell types has stimulated repair and regenerative medicine research over the past few decades. iPSC-derived blood cells, hepatocytes, beta islet cells, cardiomyocytes, neurons, and other cell types can repair injuries or regenerate damaged tissue in diseases such as diabetes and neurodegenerative disorders.
3.0K