Over the past decade a growing body of scientific evidence demonstrated the critical role of senescent cells in driving aging and age-related diseases. In particular, we and others reported that targeted apoptosis of senescent cells restores tissue function in response to chemotoxicity and aging in animal models (Baar et al., 2017).

At Rubedo Life Sciences we are developing a novel small molecule approach to selectively target and clear senescent cells from aged or pathological tissues, supporting tissue regeneration and restoring organ function.

Our approach will result in novel pharmacological treatments that are selective for senescent cells and designed to improve tolerability in older, frail, and sick individuals.

The small molecules developed from our our discovery platform ALEMBIC are engineered to be selectively activated in target cells that emerge with age-related diseases driving the chronic degenerative pathology. We recently released in pre-print, currently under peer-review, a proof of concept paper where we present initial results on a tool compound that is based on a prodrug strategy. This approach takes advantage of a known enzymatic activity enriched in senescent cells, the hydrolase beta-Galactosidase, well known to be a marker of senescent cells. Our data demonstrates this strategy of converting a pan-cytotoxic drug into a selective and well tolerated senolytic prodrug capable of ameliorating age-related diseases such as Frailty and the loss of cognitive and muscle function, in geriatric preclinical models (Doan et al., 2020). 

At Rubedo we are advancing novel generations of small molecule leads that are more sophisticated and potent. These compounds are based on different metabolic functions, beyond Beta-galactosidase, that we discovered and applied in the design of our engineered small molecules aimed toward clinical development to treat specific unmet clinical needs. 


Targeted senolytic prodrug is well tolerated and results in amelioration of frailty, muscle regeneration and cognitive functions in geriatric mice

Mammalian aging coincides with an accumulation of senescent cells. Depletion of senescent cells shows promise to treat age-related diseases. However, many of the senolytic drugs used to deplete senescent cells cause profound toxic side effects. Here we tested a prodrug form of a pan-cytotoxic drug and demonstrated dramatically reduced side effects in geriatric mice while gaining senolytic selectivity.

Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging

The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53.

Silicon Valley, CA, USA

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