Queen's University

<p><strong>Overview</strong></p>
<p>Founded in 1841, Queen’s University in Kingston, Ontario is one of Canada’s leading research-intensive institutions, combining quality and intensity in research with excellence in undergraduate and graduate education.</p>
<p>Research is a core component of the mission of Queen’s University. A member of the U15, a group of Canada’s leading research-intensive universities, Queen’s ranks highly in terms of research funding and research intensity amongst universities nationally.</p>
<p>Their commitment to research excellence is evident in the many exceptional national and international accolades awarded to their researchers, most recently Queen’s Professor Emeritus Dr. Arthur B. McDonald was awarded the 2015 Nobel Prize in Physics – with co-recipient Takaaki Kajita of Japan – in Stockholm, Sweden.</p>
<p>This excellence, found across disciplines – from health care, the environment, materials, energy, law, economics, culture, and many others – attracts the best students, the best faculty, and the best collaborators from local and global communities, other institutions, government, and industry.</p>
<p>Through their diverse programs, Queen’s university promotes social innovation, fosters creative expression, and explores how societies work best. And it’s this culture of excellence that has made Queen’s one of Canada’s leading research universities.</p>
<p><strong>Queen’s Partnerships and Innovation</strong></p>
<p>The Queen’s Partnerships and Innovation (QPI) team supports the advancement of partnerships, research collaborations, and knowledge mobilization as well as innovation, entrepreneurship, and economic development. The QPI team develops and facilitates partnerships with industry, governments, not-for-profit organizations, and other academic institutions to advance the research enterprise at Queen’s and the commercialization of inventions, and to strengthen the regional innovation ecosystem in Kingston and Eastern Ontario. </p>
<p>With support from external funding, the QPI team offers numerous services, resources and programs to support entrepreneurs, including those from Queen’s, and to accelerate the growth of startups and small to medium-sized enterprises (SMEs) within Kingston and Eastern Ontario. The team has transformed more than 1,000 invention disclosures into hundreds of technologies covered by at least one patent; additionally, the team has supported the founding and-or acceleration of hundreds of startups and SMEs in the Kingston region.</p>


<h1 id="background">Background</h1>
<p>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.</p>
<p>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 upto 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.</p>
<h1 id="technology-overview">Technology Overview</h1>
<p>Hyaluronic acid (HA) is a high molecular weight (&gt; 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 &lt; 500 kDa) in a number of diseases including being pro-inflammatory. </p>
<p>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 &lt; 100 kDa.(4) </p>
<p>This researchers have created novel N‑acyl hyaluronic acids to prevent the negative effects of endogenous LMWHA. This has been demonstrated <em>in vitro</em> 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.</p>
<p>These experiments were followed up by demonstration of successful efficacy of NBH <em>in vivo</em>. 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. </p>
<ol>
<li><p>Wu J et al. RHAMM induces progression of rheumatoid arthritis by enhancing the functions of fibroblast-like synoviocytes. BMC Musculoskeletal Disorders, 19:455 (2018).</p>
</li>
<li><p>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.</p>
</li>
<li><p>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. </p>
</li>
<li><p>Kohi S et al. KIAA1199 is induced by inflammation and enhances malignant phenotype in pancreatic cancer. Oncotarget, 8(10): 17156-17163, 2017.</p>
</li>
</ol>
<h1 id="benefits">Benefits</h1>
<ul>
<li>Broad platform technology with many cosmetic and medical uses simply by replacing existing HA</li>
<li>Maintains benefits of native HMW HAs but without pro-inflammatory effects from degraded LMW HA</li>
<li>As TLR4 antagonist can be used to treat any TLR4-related diseases</li>
<li>Broad chemical flexibility to expand chemical space of HA and create many more products</li>
<li>Validated in preclinical models of gout, hyperuricemia, wound healing and rheumatoid arthritis </li>
</ul>
<h3 id="further-details">Further Details</h3>
<ol>
<li>Babasola O et al. Chemically modified N-acylated hyaluronan fragments modulate proinflammatory cytokine production by stimulated human macrophages. J Biol Chem. 2014 Sep 5;289(36):24779-91. <a href="https://www.ncbi.nlm.nih.gov/pubmed/25053413">https://www.ncbi.nlm.nih.gov/pubmed/25053413</a></li>
<li>Lanzhou et al. Pharm. Biol. N‑butyrylated hyaluronic acid ameliorates gout and hyperuricemia in animal models. 57(1):717-728, 2019. <a href="https://pubmed.ncbi.nlm.nih.gov/31622116/">https://pubmed.ncbi.nlm.nih.gov/31622116/</a></li>
<li>Gao, Y et al. A low molecular weight hyaluronic acid derivative accelerates excisional wound healing by modulating pro‑inflammation, promoting epithelialization and neovascularization, and remodeling collagen.   Int J Mol Sci. 20(15):3722, 2019. <a href="https://pubmed.ncbi.nlm.nih.gov/31366051/">https://pubmed.ncbi.nlm.nih.gov/31366051/</a></li>
</ol>
<h1 id="applications">Applications</h1>
<ul>
<li>Treatment of arthritis - gouty arthritis, rheumatoid arthritis and likely osteoarthritis ‑ a large existing injectable market</li>
<li>Cosmeceuticals</li>
<li>Drug delivery vehicle</li>
<li>Eye treatments</li>
<li>Other pharmaceutical treatments - sepsis, COPD, COVID‑19 respiratory distress, wound healing, cancer therapy</li>
</ul>
<h1 id="opportunity">Opportunity</h1>
<ul>
<li>Preclinical Development</li>
<li>Seeking exclusive licensee or research collaborator</li>
</ul>
