Telomere shortening and the hereditary bone marrow (BM) failure syndrome dyskeratosis congenita (DC) are two conditions brought on by mutations in the TINF2 gene, which produces the shelterin protein TIN2. Unfortunately, the lack of appropriate model systems restricted the mechanistic knowledge of telomere shortening in stem cells and impeded the creation of BM failure therapeutic alternatives.

For a study, researchers used human embryonic stem cells (hESCs) and human hematopoietic stem and progenitor cells (HSPCs) to introduce endogenous TIN2-DC mutations to analyze the illness mechanism and find a gene-editing technique that reversed the disease phenotypes. The short telomere phenotype seen in DC patients was also seen in the hESCs carrying the T284R disease mutation. However, when developed into telomerase-negative cells, mutant hESC telomeres did not exhibit increased telomere shortening or DNA damage responses at telomeres.

The telomere length in stem cells and the ability of differentiated cells to proliferate were restored after the mutant TINF2 allele was disrupted by the introduction of a frameshift mutation in exon 2. Similarly, to evaluate changes in telomere length and proliferative capability, they introduced TIN2-DC disease variants in human HSPCs. Lastly, they demonstrated that TINF2 exon 2 editing, which restored telomere length in hESCs, could be produced in HSPCs from TINF2-DC patients.

The study provided a flexible platform to evaluate the effectiveness of prospective therapy strategies in vivo and shows how a straightforward genetic intervention may be used to recover the TIN2-DC illness phenotype in stem cells.

Reference: ashpublications.org/blood/article/140/6/608/484949/Editing-TINF2-as-a-potential-therapeutic-approach