PRG4

Scientists identify a new molecular model and potential therapeutic target for gout, the most common form of inflammatory arthritis. Many Americans think of gout as a disease from a bygone era, akin to rickets or scurvy. The condition commonly afflicted the rich and royal, including American historical figures such as Benjamin Franklin and Thomas Jefferson. Gout is indeed one of the earliest known diseases, first identified by the ancient Egyptians around 2640 BC. But the disease is more prevalent now than ever, affecting more than 10 million people in the United States or approximately 5 percent of the adult population. Gout is the most common form of inflammatory arthritis, in which urate (a byproduct of purine-rich foods like meat and alcohol) builds up in the body and forms needle-shaped crystals in and around the joints, usually starting in the foot. The crystal deposits lead to flares of severe pain, joint swelling and tenderness, and can progress to chronic joint damage that limits patients' movement and quality of life. Excess urate circulating in the blood (known as hyperuricemia) has long been considered the major cause of gout, but counterintuitively, most people with high urate levels do not actually develop the disease. In fact, asymptomatic hyperuricemia is approximately four times more prevalent than gout. Gout patients also show mysteriously higher levels of urate in their joint fluid compared to their blood. Thus hyperuricemia must not be the only thing stimulating urate crystal deposition in the joints. So what else could be causing the disease? In a new study published online on December 1, 2022 in Arthritis & Rheumatology, an international research team led by University of California San Diego School of Medicine identified a novel molecular pathway that causes gout and its progression to joint tissue erosion. The findings position lubricin, a protein found in joint fluid, as a novel therapeutic target for both the prevention and treatment of the disease. The scientists were interested in exploring the genetic factors that lead not to high levels of circulating urate, but specifically to urate production and crystal deposition within joints. To do this, they studied a rare case of gout in which the patient had developed urate crystal deposits and erosion in her joints but did not show high levels of urate in her blood. "This naturally occurring and extremely unusual disorder provided a unique opportunity to look at gouty arthritis through a different lens, and understand what molecular processes contribute to the disease independent of hyperuricemia," said senior author Robert Terkeltaub, MD, professor at UC San Diego School of Medicine and section chief of Rheumatology at the Veterans Affairs San Diego Healthcare System. Using whole genome sequencing, RNA-sequencing and quantitative proteomic methods, the researchers were able to identify a major molecular pathway that was disrupted in the patient, centering on a significant reduction in lubricin. The mucinous protein provides essential lubrication and protection to joint tissues, and regulates the function of a specific type of white blood cell that promotes inflammation in the joint. Additional experiments confirmed that under healthy conditions, lubricin suppresses the secretion of urate and xanthine oxidase (an enzyme that produces urate) by activated white blood cells, and also blocks urate from crystallizing in the joint. The researchers then assessed several patients with the common form of gout and confirmed that they too had markedly decreased levels of lubricin. The authors suggest that whether or not a hyperacemia patient goes on to develop gout may thus be influenced by which gene variants they have for lubricin and other molecules that control its production or degradation in the joint. "Our findings show that lubricin may be a new biomarker for tracing patients' risk of developing gout, and that new drugs to maintain and increase lubricin could limit the incidence and progression of gouty arthritis," said Terkeltaub. Co-authors include: Leigh-Ana Rossitto, Ru LiuBryan, Majid Ghassemian, Anaamika Campeau and David J. Gonzalez at UC San Diego; Marin Miner at Veterans Affairs San Diego Healthcare System; Khaled Elsaid and Sandy Elsayed at Chapman University; Amanda Phipps-Green, Tony R. Merriman and Murray Cadzow at University of Otago; Jacob Karsh at University of Ottawa; Gregory D. Jay at Rhode Island Hospital; Marwa Qadri at Jazan University; Talia J. Dambruoso at Brown University; Tannin Schmidt at University of Connecticut Health Center; Nicola Dalbet and Ashika Chhana at University of Auckland; Jennifer Höglund at University of Gothenburg; Nancy Maltez at Ottawa Riverside Hospital; and Niclas G. Karlsson at Oslo Metropolitan University.

April 7, 2017 By Mark Terry , BioSpace.com Breaking News Staff Swiss-based Novartis exercised an option to in-license ECF843 for dry eye and other ophthalmic indications from a four-person biotech company, Lubris BioPharma , based in the Boston area. Although financial details were not disclosed, a source told The Boston Business Journal that after upfront payments and potential milestones, it could be worth $1 billion. ECF843 is described as “recombinant human lubricin (rh-Lubricin) protein.” Lubricin is a naturally-occurring protein in the human body, which, as John Carroll describes in Endpoints News , “is found just about wherever two tissues in the bodies meet.” Lubris isolated and industrialized it. In a Phase II clinical trial in 40 patients with moderate to severe dry eye, ECF843 was tested against standard therapy, sodium hyaluronate (HA). Carroll writes, “Symptoms of the disease dropped 70 percent from baseline and CEO Ed Truitt tells me that when the study transitioned to self-application Lubricin patients used much less of it to get better results.” The results were published in the journal The Ocular Surface. The results stated, “The primary endpoint was met. Lubricin supplementation achieved greater than a 72 percent reduction from baseline in foreign body sensation (<.013), burning/stinging, pain, sticky feeling (P<.0432), blurred vision (P<.0013), and photophobia (P<.011) in at least one eye.” With little or no fanfare, Novartis signed an option deal with Lubris last year. Novartis gets the technology for eye-related indications globally except in Europe. Lubris has a licensing deal for Europe with Italian drug company Dompe Group . Lubris will also retain the commercial rights for non-ophthalmological indications, for example, osteoarthritis. “ECF843 has the potential to be the first therapeutic to provide rapid relief of dry eye symptoms and significantly improve signs,” said Vasant Narasimhan , Novartis’ Global Head, Drug Development and Chief Medical Officer, in a statement. “Exercising our option to in-license ECF843, along with our recent acquisition of Encore Medical for the treatment of presbyopia, underscores our commitment to treating diseases of the front of the eye which impact millions of people worldwide.” Novartis’ ophthalmology and dry eye treatments include Systane, Tears Naturale and Genteal. Lubris is a virtual company. The company’s chief executive, Truitt, is based in Seattle. There’s also an office in Framingham, Mass. One of its scientific founders, Tannin Schmidt , is at the University of Calgary , and the other, David Sullivan , is at Mass Eye and Ear. To date, funding has been generated by angel investors and high net worth individuals. Carroll writes, “Now that Novartis has put money into the company, following a European deal with Milan-based Dompe Group , Truitt has a ‘substantial runway’ to go after the next set of non-eye targets, says the CEO. That will start with dry mouth, maybe a side effect of head and neck cancer therapy that destroys the salivaryglands. Interstitial cystitis, recoating the damaged bladder lining, is on the short list.” Schmidt and others have published on the rule of lubricin in osteoarthritis and as an inflammatory.