Cellular senescence is the irreversible arrest of proliferation associated with a proinflammatory phenotype that can lead to tissue dysfunction and is implicated in numerous diseases. Natural Killer cells have an innate ability to remove senescent cells, however immune evasion can occur, which contributes to an accumulation of senescent cells with age. Several genetic and pharmacological studies have shown that elimination of senescent cells can ameliorate hallmarks of aging in both mice and humans, however more specific therapeutic interventions are required.
Aims, Hypothesis & Results
Dr. Amit Sharma is developing Chimeric Antigen Receptor Natural Killer (CAR-NK) cells to precisely and safely eliminate senescent cells in vivo. The team have identified a number of senescence-specific surface markers which could be targeted for senescence removal. They will focus on their most promising candidate senescent cell markers which will be more extensively validated using additional cell model paradigms (stressors), as well as in mouse models (cross-species validation). Validated surface markers will be used to generate monoclonal antibodies, which will then be confirmed for specificity against the target antigen. Appropriate CAR-NK cells will be created to further establish proof-of-concept for their approach of selective removal of senescent cells in their various model systems.
The Sharma Lab will target the senescent cells they have identified by generating monoclonal antibodies against their senescence-specific surface markers. These monoclonal antibodies will then be used to create CAR-NK cells that can selectively eliminate senescent cells.
Required Funding: $430,000
Duration: 24 Months
VitaDAO Board Evaluation Writeup
Dr. Amit Sharma has a strong scientific background in senescence and is based at the SENS Research Foundation, which provides strong support with a track record of successful spin-outs (e.g. Underdog Pharma 1). The removal of senescence cells is an attractive therapeutic approach to combat aging and promote longevity. Data from Dr. Sharma’s team and others showing NK cell cytotoxicity towards senescent cells provides proof-of-concept that using CAR-NK cells is a feasible strategy to eliminate senescent cells. The team’s identification of senescence-specific cell surface markers in vitro is extremely promising and if these markers are also expressed in senescent cells in vivo, this has the potential to be an effective senolytic therapy.