Therapeutic inhibition of telomeric DNA damage response rescues hematopoietic dysfunction driven by telomere shortening and aging

Alessia Oppezzo, Sara Sepe, Fabrizio d'Adda di Fagagna

1. 01

   tASO suppression of telomeric DDR reduced senescence and inflammation in hematopoietic organs

2. 02

   Hematopoietic stem cell fitness improved in telomerase-deficient and physiologically aged wild-type mice

3. 03

   Ex vivo tASO treatment improved function of human HSCs from aged donors

4. 04

   Identifies tDDR as a pathogenic driver of hematopoietic decline, independent of telomere length restoration

Study Design

Preclinical Study

Sample Size

Not reported

Study Duration

Not reported

Methodology

Antisense oligonucleotide targeting of telomeric noncoding RNAs in telomerase-deficient and naturally aged mouse models, plus ex vivo treatment of human hematopoietic stem cells from aged donors.

Limitations

Mouse in vivo plus human ex vivo only. No in vivo human exposure, no safety or pharmacokinetic data in people, and no lifespan endpoint. Antisense oligonucleotide delivery to human marrow in vivo remains unsolved.