Project: Isosteviol as a new drug for use as treatment of type 2 diabetes and cognitive impairment

All project Ps have an interest in isosteviol drug development. The objectives are to obtain solid knowledge of the efficacy and mode of action of isosteviol related to its pharmacological properties in type 2 diabetes (T2D) and cognitive impairment. Also, a novel and fully cGMP qualified route of API production will be developed, independent of the Stevia Rebaudiana plant that until now has been the only source for raw material for isosteviol API production. The work will include thorough insulin secretion analyses and transcriptomics to reveal pathways activated by isosteviol and leading to insulin release. Peripheral effects of isosteviol will be clarified by euclycemic hyperinsulinemic clamp in rat. Central effects of isosteviol will be addressed using transcriptomics on nuclei tissue and beneficial effects on cognitive function will be addressed in vivo. Obained data will complement data from clinical studies that will run in parallel with the current proposal and be invaluable for receiving regulatory authority approval as a T2D and/or Alzheimer drug._x000D__x000D_Isosteviol (ent-16-ketobeyeran-19-oic acid) can be produced from stevioside by acidic hydrolysis. Stevioside in turn, is extracted from the leaves of the plant Stevia Rebaudiana. Stevia glycosides have a very sweet taste and have been used as sweetener for decades in parts of the world, such as in Japan, and is now gaining approval also in the western world (GRAS obtained in 2008 in US and approval in the EU as food granted 2011). In contrast, isosteviol is not a sweetener._x000D__x000D_Stevioside has shown glucose lowering effects in T2D subjects and blood pressure lowering effects in hypertensive patients, and the metabolism of stevioside in humans and animals is rather well known. Stevioside is subjected to degradation of the glucose residues from the steviol backbone by the microbial flora in the intestine. The deglycosylated form (steviol) is then absorbed and transported to the liver where it is glucuronidated and excreted through the urine. _x000D__x000D_Isosteviol (MW 318) is absorbed more rapidly than stevioside (MW 805) without prior bacterial degradation, and reaches a Tmax after 10-15min in rats compared to stevioside where it can take up to 4h. Isosteviol uptake is less prone to the individual differences in the gut microflora which will give a more consistent drug efficacy. Isosteviol is also glucuronidated in the liver._x000D__x000D_Bridge Bioresearch (BBR) has permission from the Danish ethical committee to enter clinical trials with Isosteviol in T2D subjects – trials will be initiated in Q2 2012 and are not included in this proposal. In in vivo studies in KKay mice, chronic Isosteviol significantly reduced glucose, insulin, triglycerides and insulin resistance and in ZDF rats subjected to an IVGTT, isosteviol significantly decreased glucose values. Importantly, this was not seen in normoglycemic Wistar rats in the same experiment, confirming in vitro experiment with isolated mice pancreatic islets where Isosteviol increased insulin secretion only at elevated glucose levels._x000D__x000D_Mice chronically treated with Stevia compounds have been tested in models for learning and memory. Data showed that Stevia extract promoted explorative behaviour, associative- and spatial- learning and memory in aged mice. In rats treated with scopolamine in order to induce amnesia stevioside abolished the scopolamine-induced memory deficits as investigated in the Morris water maze test. _x000D__x000D_BBR has extensive experience in the pre-clinical development phase of drug targets and is experienced with the risks, regulations and mechanisms pertinent to this field with the CO focus on metabolic disorders such as T2D. BBR has the IPR for developing Isosteviol as a drug for treating T2D and also cognitive impairment._x000D__x000D_Evolva (EVO) will use its platform technology to produce isoteviol and its glucuronide derivative by fementation, therefore delivering a more purified product and at the same time overcome traditional issue with supply from natural organisms. EVO is well familiar with the Stevia compounds experienced in producing highly purified forms of the sweetener Stevia by fermentation in yeast. EVO expect to produce steviol in a single step fermentation process in yeast. Developing a cost-efficient production process for Isosteviol will assure availability of isosteviol for future API production that will be independent of any natural, political or economical factor affecting the crop or yield of the Stevia plant._x000D__x000D_The academic P Copenhagen University (Department of Biology) will supply innovative and potentiating drug discovery methodology and unique experimental setups, for transcriptomic analysis as well as cellular and animal studies._x000D__x000D_Part of the work load will be subcontracted to European university facilities (University of Basel, ETH Zürich and University of Buckingham), all with complementary state of the art methodology and experience relevant to all the needs of the project.

Acronym ISO4U2 (Reference Number: 7547)
Duration 01/05/2012 - 30/04/2014
Project Topic Isosteviol is being developed as a drug to treat type 2 diabetes and might also have beneficial effects on cognitive impairment. This proposal aims to obtain a thorough understanding of the effects and mode of action of this molecule which will enhance the likelyhood of regulatory approval.
Network Eurostars
Call Eurostars Cut-Off 8

Project partner

Number Name Role Country
3 Bridge Bioresearch Danmark Coordinator Denmark
3 Department of Biology, Copenhagen University Partner Denmark
3 Evolva SA Partner Switzerland