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The biotechnology company Captozyme is spearheading an innovative approach to nutrition to prevent the formation of painful kidney stones and other complications arising from the absorption of calcium oxalate from food. The company’s research efforts are led by Dr Qing-Shan Li, co-founder and CSO of the company.

Solutions set in stone: an innovative, nutrition-based approach to managing kidney stones

Oxalate, a plant-based dietary substance with no known positive effects on the human body, is responsible for several debilitating

health problems. These include the painful condition known as kidney stones. Dr Qing-Shan Li and associates at the biotechnology company Captozyme (www.captozyme.com) are dedicated to the prevention and treatment of these problems.

OXALATE: THE ANTI-HEROOxalate can be present in high concentrations in many plant foods, including rhubarb, beets, okra, spinach, sweet potatoes, nuts, beans, tea, chocolate, and soy products. It is, therefore, a common component of the average Western diet. Up to approximately 25 percent of the oxalate consumed in the diet is absorbed into the human bloodstream through the intestines. The unabsorbed oxalate can chelate (bind to) the dietary nutrients magnesium, iron and calcium, both in food and in the gastrointestinal tract, forming salts with these elements and limiting their bioavailability in the body. Thus, oxalate can, effectively, be described as an anti-nutrient: a substance that works against the nutritional value of food by rendering certain nutrients unattainable.

THE FORMATION OF CALCIUM OXALATE KIDNEY STONESDietary oxalate can become actively harmful when too much of it is absorbed; oxalate is a component of the most common type of kidney stone. As an illustration, approximately 75% of all kidney stones in patients in the United States consist of calcium oxalate. It is estimated that 1 in 11 adults in industrialised countries will develop a kidney stone, and preventative measures employed to date are of limited efficacy.

Kidney stones arise from an excessive urinary excretion of oxalate, or hyperoxaluria. Hyperoxaluria has two sub-types, primary hyperoxaluria and secondary hyperoxaluria, which differ in their pathogenesis, severity of clinical presentation, and treatment plan. However, both disorders can cause recurrent kidney stones, nephrocalcinosis, and end-stage renal disease, and for primary hyperoxaluria there is no existing treatment. Oxalate can also cause complications in patients who have inflammatory bowel disease (IBD) and short-bowel syndrome.

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Captozyme has taken the innovative approach of reducing the oxalate

concentration in food through adding an oxalate-degrading enzyme

People consuming typical Western diets tend to have a serum oxalate concentration that is much lower than the saturation concentration (the point at which it will start to solidify out of the solution). However, water re-absorption in the kidney concentrates oxalate in urine by more than 100 times, with the result that urinary calcium oxalate is often supersaturated. Calcium oxalate supersaturation is thought to be the primary cause of the formation of calcium oxalate stones, but the process is complex, not well understood, and may involve a number of critical factors. Reducing the ingestion of oxalate can keep the concentration in urine below the point at which it starts to solidify and therefore prevent the formation of an abnormal level of calcium oxalate precipitate.

EXISTING TREATMENTS AND THERAPIESHumans do not naturally produce enzymes to break down oxalate and so a combination of lifestyle changes and medication is the usual approach to preventing kidney stones. Doctors may recommend that patients drink water throughout the day to produce more urine and flush calcium oxalate out of their systems. Reducing both salt intake and consumption of animal protein, promoting oxalate excretion through increased calcium intake, increasing urine alkalinity, and avoiding dietary oxalate ingestion are also typical methods for reducing the chances of developing calcium oxalate kidney stones and other oxalate-related conditions.

High Oxalate Foods

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However, as oxalate is contained in many different foods, often at different levels in a single food, avoiding oxalate consumption while maintaining a balanced diet is difficult. Moreover, available therapies do not address the formation of calcium oxalate within the body. Captozyme has addressed these problems, taking the innovative approach of using oxalate-degrading enzymes to remove oxalate in the digestive tract and to reduce the oxalate concentration in food. Their approach tackles oxalate absorption at the first possible moment.

LIMITING THE FLOWCaptozyme has developed enzyme products that degrade oxalate, thereby promoting its removal from both the diet and the body. These enzymes can act throughout the gastro-intestinal tract, from the stomach to the large intestine. Cz2294, is an oxalate-degrading enzyme that is highly stable in acid environments and can remove oxalate in the stomach. In contrast, the enzyme Cz1408 removes oxalate throughout the intestine. This combination means that oxalate is removed throughout the digestive system, thereby limiting the amount of

RESEARCH OBJECTIVESAs Chief Scientific Officer at Captozyme, Dr Qing-Shan Li focuses his research on developing products to help remove oxalate either from the digestive system or from the diet.

FUNDINGCaptozyme’s research and development efforts have been aided by the company’s participation in the US National Institutes of Health’s CAP programme (Commercialisation Acceleration Programme), specifically by a grant from the National Center for Complementary & Alternative Medicine (for further details see: http://grantome.com/grant/NIH/R44-AT006065-03).

COLLABORATORSVictoria Bird, MD at University of Florida University of Illinois at Chicago University of Wisconsin BASi, Mt. Vernon, IN Product Safety Labs, Dayton NJ

BIO Dr Qing-Shan Li has over 20

years of experience in protein engineering, expression and fermentation and his work has resulted in 33 papers published

in peer-reviewed journals and several patent applications. Dr Li

has held research positions at Kyoto University, Stuttgart University, and at the University of Kansas under the direction of Professors Robert Hanzlick and Robert Borchardt. In 2009 he co-founded Captozyme Inc., where he currently acts as Chief Scientific Officer.

CONTACT Helena Cowley, MS, MBA, COOCaptozyme Inc5745 SW 75th Street #298Gainesville, FL 32608, USA

E: helena.cowley@captozyme.com T: 352 672 5320W: www.captozyme.com

Detail

Given that oxalate has always been a naturally-occurring component in our diets, are there specific lifestyle factors that predispose modern-day humans to hyperoxaluria? Or have people always been at the same level of risk?The level of risk is increasing despite oxalate content in food items staying at the same level. This increase in risk is due in large part to a change in diet and a change in the environment: the majority of people now eat less calcium per day than the recommended daily intake and they do not hydrate well using the best fluid, water. The environment has also changed with warmer temperatures making hydration even more important. Poor hydration and an imbalance in calcium oxalate intake will cause our urine to become saturated in calcium and oxalate, which causes precipitation of calcium oxalate crystals. Increased presence of crystals in urine, known as crystalluria, has been linked to kidney stones.

How did you become interested in oxalate-degrading enzymes?I have worked with enzymes and proteins throughout my career ranging from the engineering of enzymes for specific properties to expression of enzymes in E. coli, yeast and mammalian cells. Enzymes are fascinating for their capacity to catalyse reactions and the vast applications that are possible. Oxalate-degrading enzymes became interesting to me as I was working with an oxalate-degrading organism. This organism, Oxalobacter, has oxalate-degrading enzymes functioning within the cell and I became interested in exploring the characteristics of stand-alone enzymes

with the same capacity of degrading oxalate but outside of a microbe.

What kind of foods can we expect to find in the forthcoming range?Any food that can be processed to remove oxalate. In the near future, these are beverages such as vegetable juices, teas and beer. Oxalate can also be removed from canned goods and soup. More foods are being evaluated for removal of oxalate but it will require some more development.

Do you foresee your enzyme-based approach transferring into the prevention and treatment of other diet-related disorders?This approach of using enzymes to allow management of diets and promotion of health is one that I definitely foresee as a promising tool in diet-related disorders. Awareness around nutrition and how it links to disease is increasing and the scientific community is also learning more about how the gut and diet intake affect our wellbeing. Our diet is a big part of who we are and how we feel and if an enzyme can help us remove anti-nutrients from our diet then that is a good thing that should be shared with all of those who need it.

Where are the enzymes that you use found in nature and are they something that we have lost from our diets over time?The enzymes we use can be found in nature but in low quantities. In certain diets, they are ingested as part of fungi or fermented foods but this is not generally a common dietary intake.

oxalate that is absorbed in the intestines and reducing the risk of kidney stones without compromising nutritional requirements.

STRAIGHT TO THE SOURCEIn addition, Captozyme’s enzymes can be used in a range of food products to remove oxalate from food and beverages before packaging. This processing would degrade the oxalate present in the food, unlocking the potential of the iron, calcium, and magnesium within the regular diet and avoiding the need for dietary restrictions. Captozyme is also poised to introduce a supplement to address oxalate sensitivity and is developing its proprietary enzymes as stand-alone therapeutics for the treatment of more severe diseases caused by oxalate. These enzymes are the culmination of almost a decade’s worth of funded research, testing and refinement.

PHILOSOPHY FOR SUCCESSIn addition to developing its enzymatic oxalate-degrading products, Captozyme seeks to build on growing positive consumer behaviour towards food and nutrition by providing education about anti-nutrients and simple personal nutrition solutions. Unlike those requiring a gluten-free or lactose-free diet, Captozyme regards the oxalate-sensitive population as having been ‘completely underrepresented’ by specialty foods and is determined to address this.

The success of Captozyme’s approach in applying research to commercial opportunities exemplifies how the support currently given to small businesses leads to innovative solutions and commercial success.

Novel Compound Development

Our diet is a big part of who we are and how we feel – if an enzyme can help us remove anti-nutrients from

our diet then that is a good thing

Oxalate can be described as an anti-nutrient: a substance that works against the nutritional value of food

A graphical rendering of one type of oxalate-degrading enzyme; oxalate decarboxylase

or OxDC. Captozyme specialises in oxalate-degrading enzymes but their research

programmes also include other enzymes for a different set of sensitivities and ailments.