Poster Presentation 50th International Society for the Study of the Lumbar Spine Annual Meeting 2024

Introduction: Age is the leading risk factor for intervertebral disc degeneration (IDD) that underlies many debilitating spine-related disorders, including chronic low back pain (LBP).  Previously we demonstrated through genetic strategy that systemic clearance of p16^INK4a-positive senescent cells reduced age-dependent IDD in mice, effectively demonstrating the causal role of cellular senescence in disc aging.  Senolytics are pharmacologic drugs that selectively eliminate senescent cells by interfering with the anti-apoptotic pathway commonly upregulated in these cells.  The senolytic Bcl-xl/Bcl-2 PROTAC degrader 753b induces apoptosis of senescent cells by targeting the Bcl-xl/Bcl-2 anti-apoptotic pathway.  The objective of this study is to determine whether treating aging mice with the 753b senolytics reduces age-associate IDD.

Methods: 16 months old female and male mice were treated with vehicle or our new senolytic Bcl-xl/Bcl-2 PROTAC degrader 753b (Intraperitoneal injection. 5 mg/kg x2/week for 2 weeks per cycle with an interval of two weeks of rest between the cycles, n = 5 mice/group) to clear senescent cells.  Disc histology (H&E), aggrecan content by immunohistochemistry (IHC), aggrecan proteolytic degradation (Western) were performed to examine the effects of 753b on intervertebral disc health.

Results: 753b treatment suppressed age-related IDD as assessed by reduced H&E histological disc scores (Fig1, 2), decreased aggrecan proteolytic fragmentation and enhanced aggrecan matrix content (IHC) in disc nucleus pulposus in old male mice but not female mice. These results are also consistent with the improved overall appearance, activity, and grip strength in male mice compared to female mice post treatment with 753b.

Discussion: 753b yielded beneficial effects on intervertebral discs of aging male mice but not female mice, requiring further investigation to understand the sex-dependent responses to this senolytic drug.  These findings provide proof of the concept of the powerful therapeutic potential of using senolytics to treat IDD and discogenic LBP.