Phaedon Institute is honored to co-host the 2nd Senotherapeutics Summit alongside the 10th Annual ICSA Conference.
This landmark gathering will take place September 16th–19th at the prestigious National Research Council (CNR) in Rome, Italy. Bringing together the brightest minds in senescence biology, these premier events will unite world-renowned scientists, industry pioneers, and visionaries, fostering collaboration and innovation to push the boundaries of therapeutic advancements in cellular senescence.
Title: p16Ink4a– ATTAC Mouse Model: From Proof of Concept to Senolytic Gene Therapy to Increase Healthy Lifespan
Authors: Keshav Karki, Ph.D., Daniel Jasinski, Ph.D., Meena Balakrishnan, Kyra Courtney, Kevin Slawin, MD. and David Spencer, Ph.D.
In a series of landmark studies, Baker et al. in 2011 initially, and then again in 2016, demonstrated proof-of-concept that in a genetic mouse model built using technology related to Bellicum’s CaspaCIDe™ iCasp9 “suicide” switch, periodic and regular removal of senescent cells (“SnCs”) by apoptosis leads to a reversal of the aging phenotype**. The genetic mouse model, named p16Ink4a– ATTAC, was designed to induce apoptosis in p16Ink4a-expressing SnCs of these genetically modified mice by injection of a dimerizer drug “trigger”, AP20187, which induced crosslinking and subsequent activation of a caspase genetically fused to the drug-binding domain, FKBP12-V36.
They showed that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16Ink4a-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs, including kidney, heart and fat, without apparent side effects. They demonstrated that p16Ink4a-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs and suggested that their therapeutic removal may be an attractive approach to extend healthy lifespan. Other investigators soon followed with similar studies using the p16Ink4a– ATTAC Mouse Model to show reduction in age-related bone loss (Farr et al.), reduction in obesity-related metabolic dysfunction (Palmer et al.), and reduction in age-related brain inflammation and cognitive impairment (Ogrodnik et al.) with dimerizer-induced elimination of SnCs.
We have developed a novel, proprietary gene therapy vector, ApoptiCIDe-CE-GERO-002™, carrying the iCasp9 ”suicide” switch, that targets SnCs via a proprietary p16Ink4a -specific promoter, leading to their elimination following administration of the ApoptiCIDe enhanced proprietary dimerizer “trigger” molecule, PTC-1202. Over ~60% to 70% of splenic SnCs are eliminated compared to negative controls in naturally aged 75-week-old mice. Accordingly, Lamin B1 expression increases significantly in a dimer-dependent fashion.
Phoenix SENOLYTIX is developing gene therapy technologies to more specifically and efficiently target senescent cells for elimination utilizing an improved, proprietary version of CaspaCIDe™, named ApoptiCIDe™, an improved version of the technology originally used in the p16Ink4a– ATTAC Mouse Model. Pre-clinical PoC validation of this approach provides a solid rationale for future clinical trials in patients.
Join us as we shape the future of longevity science and transformative medicine.
