ESR11: “Development of senolytic strategies against age-related diseases”

IRB (M. Serrano group): Development of senolytic strategies against age-related diseases

i. Objective of research: To understand how senolytic strategies operate.

ii. Current state of the art: Senescent cells accumulate in many ageing-associated diseases and targeting these cells has recently emerged as a promising therapeutic approach. Clearance of senescent cells with drugs such as navitoclax has been suggested to benefit several areas of pathology such as decline in renal function, atherosclerosis, or different types of fibrosis. We have observed that gal-encapsulation of drugs also results in a preferential delivery within senescent cells and lesions, in particular lung fibrosis. In addition, we are also developing gal-linked probes and different types of therapeutic prodrugs to target senescent cells in the context of disease.

iii. Research methodology and approach: Our ESR will develop senolytic strategies by taking advantage of the high β-galactosidase (β-gal) activity of senescent cells. We have already designed a targeted drug delivery system based on the encapsulation of drugs with galacto-oligosaccharides, and have observed a therapeutic effect. Our ESR will further develop two-photon fluorescent probes for the visualization of β-gal activity, and senolytic gal-linked probes. In addition, our ESR will perform a Crispr-Cas9 screening in differentiated ES cells to identify senolytic targets. We will use in vivo models of senescence such as tumor xenografts undergoing chemotherapy-induced senescence, irradiation, kidney fibrosis, lung fibrosis, and patient derived-xenografts.

iv. Originality and innovative aspects of the project: Using our recently developed senolytic strategies, such as gal-encapsulation, we have already observed a high senolytic activity coupled with a reduction in the toxic side effects of the cytotoxic drugs; these findings are promising and of immense interest to both the academia and the industry.

v. Integration of the ESR project to the overall research programme: Our ESR will assess the effect of senolytic drugs on animal models with telomere dysfunction (with the Gilson group) and NER progeria (with the Garinis group).