Targeting etiologic molecular mechanisms to treat human diabetes

One of the major goals of modern medicine is to develop more efficient personalized therapies for diseases that impose a heavy burden on our society, including debilitating chronic diseases such as diabetes mellitus. The drugs that are currently used to treat diabetes do not aim to correct the molecular causes of the disease but simply aim to lower blood sugar, and therefore do not prevent disease progression. The most common form of this disease is known as Type 2 diabetes. Recent genetic studies have pinpointed to candidate genetic factors that predispose to this form of diabetes. This promises to facilitate the development of treatments that target specific genes that are truly involved in the disease mechanisms. Such treatments can theoretically be more efficient for individuals in whom diabetes is shown to be caused by those particular mechanisms. In this project we have set out to discover novel therapies that target the molecular mechanism in patients who develop diabetes due to mutations in a gene named HNF1A. This defect is the most common form of diabetes in which the genetic derangement is unequivocally established, although it is rare compared to the overall frequency of Type 2 diabetes. Nonetheless, there is evidence indicating that some genetic factors associated to HNF1A might also affect the risk to develop more common classic forms of Type 2 diabetes. Because the genetic defect in HNF1A diabetes is clear, it provides an ideal test bed to develop therapies that target genetic factors in diabetes. We will use a combination of chemical and genomic approaches to identify candidate compounds to treat HNF1A diabetes, and also to unravel the mechanisms that mediate their beneficial effects. We will also create new models of HNF1A-deficient diabetes for testing and developing new drugs. This programme is therefore designed to deliver novel candidate therapies for people with mutations in the HNF1A gene, and theoretically for a subset of individuals with Type 2 diabetes that have genetic risk factors associated with this same gene. The therapies that we propose to develop have the potential to be rapidly translated into the clinic. These drugs can impact the underlying causes and thereby modify the progression of disease.

One of the major goals of modern medicine is to develop more efficient personalized therapies to treat chronic diseases that impose a heavy burden on our society. Recent progress in our understanding of the genetic predisposition of Type 2 diabetes promises to facilitate personalized therapies that target the molecular mechanisms that underlie this disease. We have set out to discover novel therapies that target the molecular mechanism in patients who develop early-onset diabetes to heterozygous mutations in the gene encoding the transcription factor HNF1A. This genetic defect represents the most common known form of Mendelian diabetes. Although it is rare compared to classic late-onset Type 2 diabetes, sequence variants near HNF1A predispose to late-onset disease, suggesting that different variants in the same locus might lead to different forms of diabetes. HNF1A-deficient diabetes is of interest to us because it has a clearly recognizable molecular defect. In the current proposal we plan to develop novel therapies that target this molecular defect. We will use an integrative chemical and genomic approach that is designed to uncover the molecular mechanisms that mediate the beneficial effects of novel therapies. We will also create new genetic models of HNF1A-deficient diabetes for in vivo drug testing and development. In conclusion, this programme is expected to deliver candidate targeted therapeutics for patients with highly penetrant mutations in HNF1A, and possibly for individuals that harbor Type 2 diabetes risk variants in the HNF1A locus. Such therapies have the potential for rapid translation into the clinic, and unlike current drugs that simply modify glycemia, they can impact the underlying pathogenic defects and thereby modify the progression of disease.

The primary beneficiaries of the research proposed here should be the general public, the UK Pharmaceutical industry, and the Scientific community.

1. UK healthcare. Type 2 diabetes affects ~3m UK subjects and ~30m Europeans. These values are predicted to grow further in an "epidemic" driven by increasingly sedentary lifestyles and obesity. The disease is a major cause of stroke, blindness, amputations painful neuropathy, renal failure, cardiovascular disease and is now also associated to increased risk of cancer. The high prevalence of diabetes was recently predicted to contribute to a lowered overall life expectancy in the UK for the first time in 200 years. The direct economic costs account for 7-13 % of health care costs in most developed societies (IDF Diabetes Atlas, 2003) and are further aggravated by increased absenteeism and decreased individual productivity.
One of the major goals of modern medicine is to develop personalized medicines. It is widely accepted that Type 2 diabetes is a heterogeneous disorder, and therefore different patients are expected to respond differently to diverse therapies. A small proportion of patients diagnosed with Type 2 diabetes have severe defects in the HNF1A gene, whereas many others have sequence variants near this gene, potentially regulating HNF1A, which increase the risk for developing Type 2 diabetes. This project seeks to identify therapies that specifically ameliorate diabetes in those individuals in which HNF1A plays a role in the development of the disease. Furthermore, because the treatment does not simply ameliorate blood sugar, but actual targets the molecular cause, it has the potential to block the progression of the disease. This could have significant impact on the requirement of further medications such as insulin, and most importantly may impact chronic complications that are a major burden for western healthcare systems.

2. The UK Pharmaceutical Industry. The global market for anti-diabetes drugs is estimated to be worth ~$30 billion. Following its joint Workshop with the Association of British Pharmaceutical Industries (ABPI) in March 2011, the MRC concluded that pancreatic beta cell biology should become a Strategic Priority, alongside Stratified Medicine. The present application addresses both of these areas. New drug targets and leads are desperately needed for the Pharmaceutical industry to produce novel approaches to diabetes treatment. By addressing a target that is unequivocally important for human beta cells, the proposed study will enhance feeds of new Intellectual Property to this sector.
Numerous pharmaceutical companies have a specific interest in the development of novel types of therapies diabetes. The PIs are members of two trans-European diabetes academic and industrial partnerships named "DIRECT" http://www.direct-diabetes.org/ (JF) and "IMIDIA" (http://www.imidia.org/) (GR). The PIs therefore have excellent continued access to UK and Europe-based companies and plan to approach them to exploit the findings for the development of new diabetes therapies.

3. The scientific community. This programme aims to demonstrate the utility of a therapeutic strategy that has potential ramifications for the treatment of human haploinsufficient conditions beyond diabetes. It will also generate knowledge on central regulatory mechanisms in pancreatic beta cells, and provide a broad range of chemical and genetic research tools that should accelerate research in the islet research field. Collaborative interactions with clinical diabetes investigators will help advance clinical science in UK. Finally, the programme will have a significant training component. Each of the research fellows directly involved in the project will enhance their professional skills with training in basic biomedical research and thus their develop their skill set for application in both the academic and commercial sectors.