Hyaluronic Acid Analogs

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Hyaluronic acid (HA) is a large an unsulfated glycosaminoglycan composed of repeating units of N-acetylglucosamine (GlcNAc) and glucuronic acid (GlcA). HA is a high molecular weight (HMW) polymer typically millions of Daltons in size. HA is detected in all tissues with the bulk found deposited in the skin representing almost 50% of the total body HA. The unique properties of HA make it a platform technology, useful in a number of existing commercial products. For example, HA has unique hydrophilic properties with the ability to hold up to a hundred-fold its own weight of water. This hydrating property makes it useful in cosmeceuticals such as skin lotions/creams and dermal fillers. HA also has high viscoelastic properties which are proposed to be of benefit in the synovial fluid of joints where it acts as a lubricant. Through these biophysical properties, and from interactions with receptors such as CD44 and RHAMM, HAs are also believed to play a role in wound healing, cancer and other diseases. Currently the largest HA markets are injectable HA for treating osteoarthritis and dermal fillers for cosmeceutical use with revenues in excess of $1 billion each per year. Hyaluronic acid (HA) is a high molecular weight (> 1 million daltons) glycosaminoglycan (GAG). HA has unique biophysical properties making it valuable in a number of existing products. Significant research now indicates that HA is more than an inert extracelullar GAG. A number of studies have found elevated levels of HA in serum and synovial fluid from patients with RA. However, further consideration of the molecular size of HA has now revealed the negative effects of endogenous low molecular weight HA (LMWHA; MW < 500 kDa) in a number of diseases including being pro-inflammatory. LMWHA is produced by synthases (HAS1 and 3), by enzymatic cleavage (hyaluronidases, TMEM, PHA20), and by oxidative degradation. The negative effects of LMWHA are mediated by LMWHA‑binding proteins including toll-like receptor 4 (TLR4), CD44, RHAMM and others. For example, RHAMM is overexpressed in RA patient fibroblast-like synoviocytes and is implicated in RA progression, likely via specific binding of LMWHA.(1,2) Studies have also found increases in the HA-degrading enzyme KIAA1199 (aka CEMIP or HYBID) and LMWHA in both serum and synovial fluids of RA patients.(3) This increase in LMWHA is likely due to KIAA1199 as it has been shown to produce HA fragments of < 100 kDa.(4) This researchers have created novel N‑acyl hyaluronic acids to prevent the negative effects of endogenous LMWHA. This has been demonstrated in vitro cell‑based experiments using N‑butyryl HA (NBH). Low (0.05 mg/mL) concentrations of BHA significantly reduced the expression of pro-inflammatory cytokines (TNFα, IL-1β and IL-6) in LPS-activated RAW 264.7 and THP‑1 macrophage cell lines. Competition studies using TLR4 agonists and antibodies demonstrated these effects are mediated in part by selective inhibition of TLR4. These experiments were followed up by demonstration of successful efficacy of NBH in vivo. Preclinical validation has been demonstrated in four disease models: gouty arthritis, hyperuricemia, wound healing, and rheumatoid arthritis. In all four N‑butyryl HA (BHA) demonstrated benefits over existing products used clinically and support high likelihood of translation success into humans . Furthermore, in all models BHA showed to significantly reduce harmful pro‑inflammatory cytokines both within joints, wounds, and systemically. 1. Wu J et al. RHAMM induces progression of rheumatoid arthritis by enhancing the functions of fibroblast-like synoviocytes. BMC Musculoskeletal Disorders, 19:455 (2018). 2. Kouvidi K et al. Role of receptor for hyaluronic acid-mediated motility (RHAMM) in low molecular weight hyaluronan (LMWHA)-mediated fibrosarcoma cell adhesion. J. Biol.Chem. 286(44):38509-38520, 2011. 3. Zhang W et al. Secreted KIAA199 promotes the progression of rheumatoid arthritis by mediating hyaluronic acid degradation in an ANXA1‑dependent manner. Cell Death Dis. 20;12(1):102, 2021. 4. Kohi S et al. KIAA1199 is induced by inflammation and enhances malignant phenotype in pancreatic cancer. Oncotarget, 8(10): 17156-17163, 2017.