Novel Drug Target for Regulating Telomeres in Disease

Background

Human chromosomes, which carry genetic information and play an essential role in inheritance and normal tissue regeneration, are capped in structures called telomeres, which protect the chromosomes from fraying during the cell replication process. With each cell replication, telomeres become shorter until the cell can no longer divide. This gradual reduction in telomere length is part of the natural aging process. However, some genetic diseases can accelerate telomere shortening due to the misregulation or alteration of the telomerase enzyme. Increased telomerase dysfunction speeds up telomere shortening, leading to accelerated aging and degenerative diseases such as dyskeratosis congenita, aplastic anemia, liver cirrhosis, pulmonary fibrosis, and certain cancers. Currently, there are no effective therapies for regulating telomere length in these genetic diseases except for preventing exposure of affected individuals to other factors that accelerate such processes as UV light and other forms of chemical or radiation exposure. Therefore, restoring telomere length may be a therapeutic tool for all these degenerative pathologies.

Technology Overview

Boston Children’s Hospital researchers have identified the cellular metabolism of thymidine nucleotide as a critical pathway to control human telomere length. An increasing amount of thymidine nucleotide is associated with an increased length of telomeres, while degradation of thymidine nucleotide reduces telomeres length. Moreover, the team identified SAMHD1 protein (thymidine nucleotide degrading protein) as a possible target for small molecule drugs, shRNAs, and CRISPR/Cas9. Inhibition of SAMHD1 results in an increased lifespan of thymidine nucleotide and a consequential increase of telomeres length. These results have the potential to be used for developing therapeutic interventions for all neuro-degenerative diseases, associated with premature telomere shortening, and further decrease the natural aging process.

Applications

• Treatment of neurodegenerative disease and cancer associated with telomere instability
• Reducing the effects of the physiological aging process

Advantages

• Highly effective in increasing telomerase length
• Targeting by small molecules significantly decreases the cost of treatment of these pathologies

Patents

• PCT Pending WO 2023/250015

Publications

William Mannherz, Suneet Agarwal. Manipulation of Thymidine Nucleotide Metabolism Controls Human Telomere Length and Promotes Telomere Elongation in Dyskeratosis Congenita Patient Derived Cells. Blood. 2022; 140 (Supplement 1): 988–989. doi: https://doi.org/10.1182/blood-2022-167273.

William Mannherz , Suneet Agarwal. Thymidine nucleotide metabolism controls human telomere length. Nature Genetics. 55, 568–580 (2023). doi: https://doi.org/10.1038/s41588-023-01339-5