Bioactive Injectable Implants for Functional Intervertebral Disc Regeneration

Intervertebral disc degeneration is strongly implicated as a cause of low back pain. Over a 10 year period, more than 130,000 active service members received diagnoses of disc degeneration, with annual incidence rates more than doubling during this time. Current treatment approaches are mostly conservative, and in severe cases, patients may undergo surgical procedures such as spinal fusion, which do not maintain or restore native tissue structure or mechanical function. The earliest manifestations of disc degeneration typically occur in the central nucleus pulposus (NP), where decreasing proteoglycan content and hydration compromise the ability of this tissue to transfer compressive loads, leading to progressive structural breakdown of the entire intervertebral joint. Cells within the NP lose their anabolic phenotype and begin to show a fibrotic phenotype, resulting in the fibrotic transformation of the NP extracellular matrix. Combined, this proteoglycan loss and progressive fibrotic NP remodeling pushes the entire disc tissue towards a degenerative state. The NP is therefore a key target for regenerative therapies, particularly early interventions addressing mild to moderate severity degeneration. Arresting and reversing this fibrotic transition is key to restoring healthy disc structure and mechanical function. Delivery of therapeutic RNA using lipid nanoparticles (LNPs) is a novel strategy with the potential to arrest and reverse fibrotic tissue changes in the NP. An advantage of LNPs is their modular design, whereby their properties can be optimized to improve biodistribution and intracellular delivery for specific tissues, and non-viral nucleic acid delivery is safer than viral vector-based gene therapy. The overall goal of this proposal is to establish a safe and effective, extended-release RNA-based therapy that arrests and reverses the pro-fibrotic changes that drive progressive structural and functional failure of the disc NP during degeneration. In Aim 1 we will optimize an LNP formulation and establish a novel extended release microcarrier for delivery of therapeutic RNA to NP cells over clinically relevant time scales. Next, in Aim 2 we will undertake in vitro cell culture studies to optimize the RNA therapy to synergistically arrest the pro-fibrotic transformation of the NP via ablation of mechano-active signaling and stimulation of healthy tissue formation. Finally, in Aim 3, the safety, efficacy and cellular mechanisms of the optimized therapy will be evaluated in ex vivo organ culture and an in vivo large animal model of moderate severity disc degeneration. Project Number: 2I01RX001321-11A2 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Robert Mauck (+1 co-PI) | Institution: PHILADELPHIA VA MEDICAL CENTER, PHILADELPHIA, PA | Activity Code: I01 | Study Section: Regenerative Rehabilitation[RRD0] View on NIH RePORTER: https://reporter.nih.gov/project-details/11100497