The Peter de Keizer lab at Erasmus University Rotterdam has unveiled a D-retro-inverso (DRI) peptide mimetic of the p53-FoxO4 interface that selectively kills senescent cells (TASC, targeted ablation of senescent cells, “senolytic”).
This strategy rejuvenated aging hallmarks in naturally aged and accelerated aging (DNA damage mutant) mice. In addition, the peptide cleared senescent cells resulting from chemotherapy treatment. The Judith Campisi lab at the Buck Institute, where senior author Peter de Keizer was a postdoc, has long studied the role of senescence in the tragic accelerated aging post-chemotherapy. Many chemo drugs are DNA-damage inducing agents, or are otherwise cytotoxic, and result in accumulated senescent cells that secrete the pro-aging, pro-inflammatory Senescence Associated Secretory Phenotype (SASP, see this Annual Reviews article). De Keizer worked on the FoxO4 peptide in the Campisi lab, but it did not work properly. Later, the D-retro inverso modification was found to be critical for molecular stability and efficacy.
Last year, Unity Biotechnology raised a $116M series B financing to pursue senolytics for osteoarthritis and other age-related conditions. Spun out of the Buck Institute and Mayo Clinic, their focus has been on small molecules developed by Abbot/AbbVie, such as ABT-263, a selective inhibitor of BCL-2 family proteins (primarily BCL-xL and BCL-2). This drug has undergone clinical trials in oncology, but dose-limiting thrombocytopenia occurred (thrombocytes are highly dependent upon BCL-xL for survival). This year it became clear that Unity will repurpose ABT-263 or its analogs for local administration into the intra-articular space of the joints afflicted by arthritis, thereby avoiding off-target effects.
Rumor has it that the FoxO4-DRI peptide will be translated into a biotech development effort in the near future. This company is unlikely to pursue osteoarthritis as an indication. Pending further confirmation, as long as the FoxO4-DRI peptide lacks the side effects of ABT-263, it could be much more promising than Unity’s lead candidate. The possibility of systemic administration opens the door to cardiovascular and oncology indications in particular, where senescence and the SASP have been shown to play a critical role in pathogenesis.
de Keizer et al. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell 2017.
Elisseeff, Campisi, Unity, et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nature Medicine 2017.