Genome

Small Molecules Restore Telomere Length in Human Cells

Posted on 28 April 2020

Harvard researchers have discovered a set of molecules capable of restoring shortened telomeres, a key feature of ageing. Their findings could lead to a treatment for genetic diseases affecting telomeres, or even a way to slow down the ageing process itself.

Telomeres are DNA sequences that cap the end of chromosomes and protect them from damage. Telomeres become shorter each time a cell replicates, eventually preventing the cell from dividing further. This mechanism is protective against cancer, as any cells dividing uncontrollably will eventually have their replication arrested by telomere shortening. However, genetic diseases that accelerate telomere shortening can be devastating. One such disease is dyskeratosis congenita, a condition that somewhat resembles premature ageing and mainly affects the skin, although 80% suffer progressive bone marrow failure leading to early mortality.

In this study, researchers screened over 100 000 known chemicals in search of compounds that could preserve the function of the PARN gene. PARN is a protein that stabilises part of telomerase, an enzyme that elongates telomeres. When the PARN gene is mutated, telomerase activity is compromised, leading to rapid telomere shortening. The research found a handful of molecules that could preserve PARN by inhibiting another enzyme, PAPD5, which unravels PARN.

Structure of the PARN enzyme
Source: Protein Data Bank

The team then tested these molecules on stem cells from dyskeratosis congenita patients, and found that telomeres were restored to their normal length. They also took human blood stem cells and induced a PARN gene mutation that is associated with dyskeratosis congenita. They then implanted these cells into mice and treated them with one of the new compounds. They report that treatment restored telomere length in the implanted cells, while the animals did not appear to suffer any negative effects.

We envision these to be a new class of oral medicines that target stem cells throughout the body. We expect restoring telomeres in stem cells will increase tissue regenerative capacity in the blood, lungs, and other organs affected in DC and other diseases.

Suneet Agarwal, MD, PhD, study senior investigator

Much work will still need to be done before these molecules can be considered for clinical use. While the compounds appear to be capable of restoring telomeres, there is no guarantee that they will provide an effective treatment for dyskeratosis congenita or other such conditions. This is something that the team aims to investigate next, alongside the safety of the chemicals.


References

Small-Molecule PAPD5 Inhibitors Restore Telomerase Activity in Patient Stem Cells: https://doi.org/10.1016/j.stem.2020.03.016

Researchers identify lead compounds for treatment of telomere diseases: https://www.drugtargetreview.com/news/60552/researchers-identify-lead-compounds-for-treatment-of-telomere-diseases/

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