Intervertebral disc degeneration—Current therapeutic options and challenges

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TL;DR

This review comprehensively examines the causes and current therapeutic strategies for intervertebral disc degeneration (IVDD), a primary contributor to low back pain. It highlights that while classic therapies only alleviate symptoms, advanced approaches including cell therapies, extracellular vesicles, scaffolds, small molecules, growth factors, and gene therapy show promise in preclinical studies but face significant challenges in clinical translation. The paper emphasizes the multifactorial nature of IVDD and the need for combined, targeted therapies to achieve true regeneration.

Full summary

4,450 CHARS

**Background:** Low back pain (LBP) is a major global health concern, affecting 70–85% of the population at some point and costing the US economy 560–630 billion dollars annually. Intervertebral disc degeneration (IVDD) is the most common cause of LBP. The intervertebral disc (IVD) is a fibrocartilaginous cushion composed of a central nucleus pulposus (NP), an annulus fibrosus (AF), and cartilaginous endplates (CEP). The NP is avascular, with a low cell density (~3,000 cells/mm³) and relies on diffusion for nutrient supply. IVDD is characterized by loss of proteoglycans, reduced hydration, and progressive mechanical instability. Causes include genetic polymorphisms (e.g., in ACAN, COL11A1, VDR, GDF5), environmental factors (metabolic stress, mechanical overload, smoking, obesity), and aging. The review summarizes current and emerging therapeutic options and their challenges.

**Methods:** This is a narrative review that synthesizes findings from preclinical studies (in vitro and in vivo animal models) and clinical trials. It covers multiple therapeutic categories: classic therapies (surgery, NSAIDs, opioids), cell therapies (mesenchymal stem cells [MSCs], notochordal cells, NP cells), extracellular vesicle (EV) therapies, scaffold-based therapies (natural and synthetic), small molecule and growth factor therapies, and gene therapy (viral vectors, RNAi, CRISPR/Cas9). The review references numerous preclinical studies (Table 1) and clinical trials (Tables 3 and 4) from sources including clinicaltrials.gov.

**Key Results:** - **Cell therapies:** MSCs (especially from bone marrow, adipose tissue, and umbilical cord) are promising due to their multipotency and immunosuppressive properties. However, challenges include poor survival in the harsh IVD environment, risk of tumorigenesis, and high costs. Clinical trials (e.g., MPC-06-ID, NOVOCART® Disc) have shown limited efficacy, with placebo effects influencing outcomes. - **EV therapies:** EVs (exosomes, 50–150 nm) derived from MSCs, NP cells, and notochordal cells can carry miRNAs (e.g., miR-142-3p, miR-532-5p, miR-410) that reduce apoptosis, pyroptosis, and inflammation. Preclinical studies in rodents show slowed IVDD progression. A clinical trial (NCT04849429) using platelet-derived exosomes is ongoing. - **Scaffold-based therapies:** Natural scaffolds (collagen, silk, chitosan, alginate, gellan gum, decellularized ECM) and synthetic scaffolds (PLA, PGA, PLGA, PCL) provide structural support. Conductive/smart biomaterials (e.g., piezoelectric collagen) may enhance tissue remodeling. NuCore® injectable hydrogel and Discseel® are FDA-approved but lack long-term clinical evidence. - **Small molecules and growth factors:** Small molecules (e.g., curcumin, icariin, resveratrol, berberine) show anti-inflammatory, anti-apoptotic, and anti-oxidative effects in vitro by downregulating IL-1 and TNF-α. Growth factors (e.g., BMPs, GDF-5, PDGF) promote ECM synthesis but have short half-lives. Clinical trials of intradiscal rhGDF-5 (NCT01158924, NCT00813813, NCT01182337, NCT01124006) showed unclear improvements and placebo effects. - **Gene therapy:** Viral vectors (adenovirus, lentivirus, AAV) and RNAi have been used in animal models to deliver therapeutic genes (e.g., Sox9, TGF-β) or silence catabolic genes (e.g., ADAMTS5, MMP3). CRISPR/Cas9 has been applied to target β-catenin in mice and epigenome-edit TNFR1 in human IVD cells. No clinical trials for gene therapy in IVDD have been reported.

**Clinical Implications:** Despite extensive preclinical research, no curative therapy for IVDD exists. Classic therapies only provide symptomatic relief. Advanced therapies face major hurdles: (1) the avascular nature of the IVD limits systemic delivery and requires intradiscal injection, which risks leakage; (2) cell therapies suffer from poor cell survival and senescence; (3) EV therapies face production and standardization challenges; (4) small molecules lack specificity and clinical relevance; (5) gene therapy carries risks of immune responses, off-target effects, and insertional mutagenesis. The review emphasizes the need for combined approaches (e.g., scaffolds loaded with EVs, growth factors, or MSCs) and better animal models (large animals) to improve translatability. Future research should focus on identifying master regulators of IVDD through single-cell RNA sequencing and genome-wide association studies across diverse populations.