The distinctive biochemistry of senescent cells has enabled researchers to produce proof of concept demonstrations for a range of ways to destroy senescent cells while having relatively little effect on non-senescent cells. The most established approach to date is to target well explored mechanisms that function to hold back senescent cells from programmed cell death. Senescent cells are primed to undertake programmed cell death, unlike normal cells. Thus sabotaging those mechanisms in normal cells has little effect, and delivering a sabotaging small molecule to a mix of normal and senescent cells will only kill large numbers of the senescent cells.
A more recent approach that is now progressing towards the clinic involves the use of prodrugs. A cytotoxic molecule, such as a chemotherapeutic drug, is modified to become a prodrug molecule with some added structure that interferes in its normal cell-killing function, making it safe. The trick lies in ensuring that this modification can be reversed only in the target cells that the prodrug is intended to affect. For example, senescent cells express high levels of β-galactosidase, which removes galactose where that decoration is added to another molecule. When the β-galactosidase inside a senescent cells interacts with a prodrug created by conjugating a chemotherapeutic with galactose, the toxic chemotherapeutic is unmasked. In normal cells, the prodrug remains intact and produces no harm.
Selective clearance of senescent cells has shown promise for the treatment of the degenerative joint disease of osteoarthritis, in which inflammation drives loss of cartilage and joint dysfunction. Senescent cells are responsible for generating much of that inflammation, in addition to disrupting tissue structure and maintenance in other ways. Unfortunately, early trials by UNITY Biotechnologies employed a local administration strategy and class of senolytic drug that were likely suboptimal. The results in human patients were poor in comparison to the results in animal models, and will probably discourage further clinical work on osteoarthritis until such time as senolytic drugs are approved by regulators for other uses.
Cellular senescence plays an important role in the pathogenesis of osteoarthritis (OA). Elimination of senescent chondrocytes by senolytic small molecule compounds show therapeutic effects in OA mice. However, results from a recent phase II clinical trial in the treatment of patients with painful knee OA were not optimistic. Hence, the development of new senolytics with different mechanisms for OA anti-ageing therapy is appealing. SSK1, a prodrug that consists of gemcitabine modified with an acetyl galactose moiety, could target senescence-associated β-galactosidase and eliminate senescent fibroblasts. SSK1 improves physical function and lifespan in aged mice and demonstrates good anti-inflammatory effect in non-human primates. The therapeutic action of SSK1 in OA disease deserves comprehensive investigation.
An oxidative stress-induced cellular senescence model was established to evaluate cell viability, replication, and genotoxicity after SSK1 treatment. Human OA chondrocytes and explants were collected to evaluate the therapeutic effect of prodrug SSK1 in vitro. In vivo evaluation was performed in young and aged male murine models. SSK1 (intra-articular injection every 3 days) was administrated 2 weeks after anterior cruciate ligament transection (ACLT) surgery. Animals were sacrificed 8 weeks after surgery. OA phenotype was analysed by micro-computerised tomography (μCT), histology, and pain-related behaviour tests.
SSK1 showed precise, efficient, and broad-spectrum elimination of senescent chondrocytes. When co-cultured with human osteoarthritic chondrocytes and cartilage explants, the senolytic SSK1 prevented the generation of senescence-associated secretory phenotype factors, enhanced production of extracellular matrix (ECM) molecules, and promoted a regenerative chondral environment. Intra-articular administration of SSK1 showed improved pain response, enhanced retention of ECM, and remodelled subchondral bone homeostasis in both young and aged ACLT-induced OA murine model. Thus SSK1 is an effective candidate for senolytics in alleviating OA. The anti-ageing therapeutic effect of SSK1 lies in restoring a regenerative phenotype by improving the proliferation microenvironment, and reducing the accumulation of apoptotic signals in the joint microenvironment.
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