The Problem
The immune system, including natural killer cells (NK cells), has an ability to patrol for and destroy senescent, or aged cells. However, this protective function deteriorates over time, permitting senescent cells to accumulate in our tissues and drive age-related disease. Drugs used to destroy senescent cells – senolytics – use a brute-force method that can disrupt natural function. The immune system clears out the aged cells at the best time, in the best way, allowing for natural function.
The Goal
Using CAR technology designed for cancer treatment, our team is engineering NK cells to seek out and destroy senescent cells by targeting an identifying marker. They would act as improved or super-powered immune cells to improve overall function in aging tissues.
The Status
The new cells – dubbed “CAR-NK” cells – are currently being optimized with the new target marker. They will be tested in mice that are aged and in those designed to mimic their primary disease target, IPF.
Novel senolytic strategies: secondary senescence, new metabolic targets, and enhanced immune surveillance
Ways to optimize senolytic strategies to maximize ablation of senescent cells (SEN) while minimizing effects on nonsenescent cells or SEN engaged in physiological processes are being developed. In this project, they seek to rejuvenate and reinforce the intrinsic SEN immunosurveillance by natural killer cells (NK cells) using the established chimeric antigen receptor (CAR) biotechnology, creating CAR-NK. While the ongoing accumulation of SEN are known to drive age-related disease, senescence is also critical to many physiological processes, including wound healing, injury resolution and regeneration, and endometrial maturation and therefore has been optimized to clear senescent cells at the appropriate time during these processes: neither too early (interfering with the acute stages of wound closure) nor too late (leading to unresolved fibrosis).
To enhance this SEN immunosurveillance, the lab employed a proteomic screen of senescent fibroblasts. Through the use of several assays, they have further characterized the five most promising candidates in primary human endothelial cells, and confirmed them using irradiated and oncogene-induced senescence models. Once optimized, the senolytic CAR-NK will be tested in aging mice and a mouse model of idiopathic pulmonary fibrosis (IPF). The two principal existing therapies for IPF do not improve quality of life or increase life expectancy, leaving patients to a progressive loss of physical capacity and death from respiratory failure and complications.
Team Members
Dr. Amit Sharma
Principal Investigator
Dr. Amit Sharma was awarded a Master’s degree in Biomedical Sciences from Delhi University, India. He received his PhD in 2009 in Biotechnology from University of Pune for his work demonstrating microRNA regulation of cytokines involved in allergic inflammation in mice model. Dr. Sharma’s postdoctoral research at the Buck Institute, Novato California involved investigating novel molecular regulatory pathways involved in genotoxic stress and cellular senescence in invertebrate and mammalian models.
Dr. Sharma has recently joined SENS Research Foundation as Group Lead in the Senescence Immunology Research Group. His research focus involves studying how aging and senescence affects the immune system and his research group will also investigate strategies to harness the immune system in mitigating deleterious effects of senescent cells with translational focus.
Funding
Annual Budget
125,000 USD
