Overview of Project DR. BONE
(A Novel Gout Therapeutic Approach)
Our project focuses on developing a new kind of medicine which can reduce the elevated uric acid level effectively. Unlike the current treatments for diseases such as gout and cardiovascular diseases (caused by hyperuricemia), our project aims to find an effective therapeutic approach to reduce and regulate the level of uric acid effectively in human body.
Hyperuricemia is one of the cause of gout and other cardiovascular and kidney diseases. Purine which is intaken from our diet will be broken down to uric acid under several biological processes. Uric acid in blood plasma is one of the risk factor for hyperuricemia (Hosoya and Ohno, 2011). The level of uric acid in blood and other tissues would be crucial for the treatment of the gout. However, the enzyme, urate oxidase, for digesting the uric acid into a more soluble form of allantoin is absent in our human body due to a non-sense mutation in our gene. Several researches have revealed that approximately one third of uric acid is excreted in the intestinal tract. Reduction of the amount of uric acid in the intestinal tract will lead to a decrease in the reabsorption of the uric acid.
This phenomenon causes a worldwide issue, more and more people have to suffer from acute attacks by gout or other cardiovascular diseases. For example, in Taiwan, one of 16 people suffered from gout. Apart from that, medicines for gout are too expensive and not easy to afford. For instance, annual healthcare costs for a gout patient were around USD 25000. These urge us to discover new therapeutic approach by transporting gene of uricase (enzyme to break down uric acid) into Nissle 1917.
Most of the developed countries have a high prevalence of gout. In men, the risk of gout increases steadily with age but in women, who have a lower prevalence of gout than men at all ages, the risk increases sharply after menopause. The reason behind the large difference in gout risk in men and women might relate largely to the loss of uricosuric action of oestrogen. It has long been recognised that diet, especially in excessive seafood consumption and alcohol consumption have an important role in the development of gout. Evidence linking gout to metabolic syndrome, cardiovascular disease and renal diseases is ample. For instance, obesity as a part of the metabolic syndrome is consistently reported to increase risk of gout. The cumulative incidence of gout at age 70. Ethnic background clearly affects gout prevalence and incidence and supports a substantial genetic predisposition to gout. The search for candidate genes that influence SUA levels has provided preliminary evidence of specific genetic polymorphisms that confer risk of gout. in the 2000s have identified single nucleotide polymorphisms (SNPs) in genes encoding transporters involved in renal and gut clearance of uric acid (such as SLC22A12 [also known as URAT1], SLC2A9 [also known as GLUT9] and ABCG2) that contribute to the heritability of common gout.137
During a discussion, one of our teammates shared his experience that his grandmother has been suffering from gout for a long period of time. Gout sometimes caused acute attacks which brought an extreme pain for her. Besides that, gout hindered her movements and disrupted her normal daily life activities. It was heartbreaking to see an old woman had to suffer so much at her age. Therefore, we were motivated to search and find a suitable therapeutic approach for gout. Surprisingly, we discovered that gout is a big worldwide medical issue, but with no current effective medical treatments at all!
Among the current treatments, there were medicines such as allopurinol and pegloticase available in the market. Disappointedly, they had major limitations and may bring side effects to patients. For example, allopurinol inhibits xanthine oxidase, which can reduce uric acid level greatly, but excess amount of allopurinol will cause other health problems such as kidney stones. These medicines couldn’t solve the problem successfully, so that there were still large number of patients in Hong Kong, Taiwan, Australia and United States etc.
Furthermore, despite of these limitations, these medicines cost very expensively. These early investigations innovated us to help those patients suffering from gout, especially the old people as they are more easily to get this disease. In order to develop a better therapeutic approach, we tried our best to do scientific researches to lower uric acid level by bringing uricase into the human body to break down uric acid. We discovered some previous IGEM teams had also contributed on this issue. However, they didn’t prove whether the uricase works or conduct more further investigations on developing a new kind of treatment. As a result, we want to produce a new kind of medicine with higher efficiency, lower cost and less side effects than the current treatments. Therefore, it became our inspiration and motivation to investigate and carry out researches and experiments on this issue till now and so on.
- Song, P., Wang H., Xia Wei., Chang X., Wang M. and An. L (2018) Prevalence and correlates of hyperuricemia in the middle-aged and older adults in China. Scientific Reports. 8:1-9
- Kuo C., Grainge M.J., Zhang W. and Doherty M. (2015) Global epidemiology of gout: prevalence, incidence and risk factors . Nat. Revi. Rheumatol. 11: 649-662
- Lee, Y. Y., Tang, C.H., Chen, J.H. Kuo, L.N. and Ko, Y. (2018) Evaluation of healthcare costs and utilization for patients with gout: a population-based matched cohort study. Current Medical Research and Opinion. 34(4): 735-740
- Wertheimer, A., Morlock, R. and Becker, M.A. (2013) A revised estimate of the burden of illness of gout. Current Therapeutic Research. 75: 1-4.
- Ndrepepa, G. (2018) Uric acid and cardiovascular disease. Clinica Chimica Acta. 484: 150 - 163
- P. Richette and T. Bardin (2010) Gout. Lancet. 375: 318 -328
- Chao, H.H., Liu, J.C., Chen, C.H., Wu, C.H., Chen, T.H. (2008) Uric acid stimulates endothelin-1 gene expression associated with NADPH oxidase in human aortic smooth muscle cells. Acta Pharmacol. Sin. 29: 1301 – 1312
- Ndrepepa, G. (2018) Elevated serum uric acid – a marker and mediator of increased stress on myocardium. Coron, Artery Dis. 29: 183-185
- Ravichandran. R., Hemassri, S., Cameotra, S.S. and Jayaprakash, N.S. (2015). Purification and characterization of an extracellular uricase from a new isolate of Sphingobacterium thalpophilum (VITPCB5). Protein Expression and Purification. 114: 136 - 142
- Hernando, H., Von Bunau, R., Nadarajah, M., Singer, M.V. and Harder, H. (2008). Influence of E. coli strain Nissle 1917 (EcN) on intestinal gas dynamics and abdominal sensation. Dig Dis Sci. 53(2): 443 – 450
- Kouturek, P.C., Silwowski, Z., Koziel, J., Ptak-Belowska, A., Burnat, G., Brzozowski, T. amd Konturek, S.J. (2009) Probiotic bacteria Escherichia coli strai Nissle 1917 attenuates acute gstric lesions induced by stress. Journal of Physiology Pharmacol. 6: 41 -48
- Nuki George (2012) Uricase Therapy of Gout. Gout and Other Crystal Arthropathies. pp 174-186