Development and optimization of ASO targeting telomere dysfunction-induced ncRNA for the treatment of human telomere-driven diseases


Fabrizio D’Adda di Fagagna






Telomere dysfunction (either following shortening or damage) and the ensuing DNA damage response (DDR) activation are associated with several pathologies and aging in several cells and organs, in various animals, including humans. What is its actual contribution to pathologies and to the aging process is presently unknown. This is in part also due to the lack of adequate tools to selectively inhibit telomeric DDR signaling and gauge its impact. 

We recently discovered that damage-induced non-coding RNA, generated at the site of damage, are necessary for the full DDR activation. Importantly, and differently from all the other protein components of the DDR, they are unique to individual damaged sites. Thus their inhibition allows unprecedented selective, site-specific, DDR inhibition. 

Telomeres, when critically short or damaged, trigger a DDR that is dependent on damage-induced telomeric non coding RNA. 

Antisense oligonucleotides are one of the tools that can allow the selective targeting of nuclear non coding RNAs. We will study the dependency on telomeric ncRNA of telomeric DDR and its contribution to healthspan and different pathologies caused by telomere dysfunction.


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