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Identification of small molecule compound that reverses experimental telomere-related diseases

New research has shown that it may one day be possible to treat people with telomere-related diseases using small molecule compounds that restore telomerase levels to normal levels. Telomeres are protective segments of DNA at the ends of chromosomes, and telomerase is the protein responsible for maintaining the telomere-forming DNA sequences. Each time a cell divides, the telomeres become shorter because the telomerase is not very efficient at reading the DNA sequence all the way to the end. Eventually, the telomeres become so short that the cell can no longer divide—leading to telomere-related diseases (e.g., blood diseases such as dyskeratosis congenita). Continued research over the past 30 years has illuminated many important molecules that regulate telomerase activity. Among them, the protein PARN (poly(A)-specific ribonuclease) has been shown to stabilize a component of telomerase, and thus the overall ability of telomerase to do its work. Notably, people with dyskeratosis congenita have been shown to have mutations in the PARN gene. Opposing the action of PARN is the protein PAPD5 (poly(A) polymerase associated domain-containing protein 5), which destabilizes telomerase activity. Strategies that target PAPD5 could potentially maintain the optimal function of telomerase by balancing PARN and PAPD5 activities.

In this study, researchers employed a high-throughput screening approach to test over 100,000 small molecules (chemical compounds), and they identified the small molecule BCH001 as capable of inhibiting PAPD5 at very low concentrations. Using cells from people with dyskeratosis congenita, BCH001 improved telomerase activity and elongated telomeres in cells with PARN mutations. To underscore the strategy of targeting PAPD5 to improve telomerase activity, the scientists tested another PAPD5 inhibitor, called RG7834, for its ability to restore telomerase activity. In this set of experiments, mice were transplanted with human blood stem cells that contained an experimentally mutated PARN gene. The researchers then gave the mice RG7834. Remarkably, oral administration of RG7834 reversed telomere shortening in PARN-deficient human blood cells compared to a control. This first-in-class therapeutic lead is an exciting new direction for potential treatment of telomere-related diseases.

Nagpal N, Wang J, Zeng J,…Agarwal S. Small-molecule PAPD5 inhibitors restore telomerase activity in patient stem cells. Cell Stem Cell 26: 896-909.e8, 2020.