Selective control of DNA damage response at telomeres as an innovative therapeutic approach for Dyskeratosis Congenita

Dyskeratosis Congenita (DC) is a rare genetic disease characterized by severe clinical features, including bone marrow failure (BMF, decreased production of blood cells), pulmonary fibrosis and cancer. To date the only treatment is hematopoietic stem cell transplantation, with all the risks associated including infections and rejection, and without significant impact on the pulmonary fibrosis. Therefore, a treatment that targets most symptoms of the disease is necessary.

DC patients have mutations in genes involved in the maintenance of telomeres, portions of DNA made of the same repeated sequence, protecting the ends of chromosomes. When telomeres are shortened or dysfunctional, as is the case in DC patients, they trigger a process known as DNA Damage Response (DDR) to signal their presence and attempt repair. However, this damage is hard to repair and the resulting persistent DDR ends up being a chronic signal of danger for the cells that is deleterious and contributes to the manifestations of the disease. In our laboratory, we designed specific compounds known as telomeric antisense oligonucleotides (tASOs), that selectively inhibit telomeric DDR activation.

We have demonstrated that tASOs can revert pulmonary fibrosis in a mouse model of DC known as Terc^-/- and increase the lifespan of another mouse model characterized by telomere dysfunction and severe BMF. We therefore propose to study tASOs effects in the DC model Terc^-/-, which also show abnormalities in the hematopoietic system similar to those found in DC patients.

The goal is to treat the broad clinical features of DC with a single therapy.