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Targeting the Endocannabinoid System within Islets of Langerhans to Protect against Immune Destruction.

Periodic Reporting for period 1 - DIRECtA (Targeting the Endocannabinoid System within Islets of Langerhans to Protect against Immune Destruction.)

Reporting period: 2018-01-03 to 2020-01-02

Diabetes affects 60 million people in Europe leading to premature death and a number of complications that highly decrease patient´s quality of life. Estimated total direct and indirect costs for health systems are around €142 billion. Insulin-dependent diabetes, or type 1 diabetes (T1D), is an autoimmune disease affecting both females and males that results in progressive destruction, and finally an almost absolute loss, of the cells that produce insulin (beta cells), leading to the lack of insulin in blood and, consequently, to sustained high glucose levels in the blood (hyperglycemia). Beta cells are in the pancreas, forming dispersed round structures called islets of Langerhans; destruction of beta cells is preceded by an autoimmune attack, a process known as insulitis. Europe has the highest incidence per capita of children with T1D, with 21,600 new cases diagnosed each year. Hyperglycemia because of diabetes is associated to macro- and microvascular complications: atherosclerosis, strokes, heart attacks and heart failure and peripheral vascular disease. Diabetes also increases the risk of renal failure, blindness, peripheral neuropathy, limb amputation and premature death. To date neither prevention nor cure exists for T1D, hence patients require exogenous insulin injections for life. Existing treatments are scarce and aim to reduce/prevent immune cell reactivity at early stages of T1D, when islets are still not completely destroyed. However, these treatments fail to show durable effects and have life-threatening effects on the patient’s immune system.

In this scenario, it is clear that new therapeutic approaches for T1D are needed, especially those focused in finding a cure for this disease. The American/European Association for the Study of Diabetes agree that new drugs or a combination of drugs capable of stopping insulitis and/or promoting regeneration of lost beta cells need to be explored.

Based on our preliminary result, we proposed to investigate in mice a novel approach to prevent the immune attack, such that beta cells death is avoided. This new approach lies on a signalling system within our body named the endocannabinoid system. This system was originally described to be involved in the psychotropic effects of cannabis; however, it is now well established that it plays an important role in regulating metabolism and immune action. Three key components of this signalling system are the receptors CB1R, CB2R and GPR55, which mediate metabolic and immune effects. Interestingly, drugs targeting these receptors have previously been found to improve autoimmune diseases such as multiple sclerosis, Crohn's disease, fibromyalgia and rheumatoid arthritis. Of note, CB1R and GPR55 are present on beta cells, where they regulate beta cell function and proliferation, while CB2R is mainly in immune cells, regulating their activation. We hypothesized that the use of drugs targeting the CB1R, CB2R and GPR55 could be a powerful treatment to prevent insulitis, thus preserving living beta cells and stopping progression toward loss of endogenous insulin production. The overall objective of DIRECtA was to study the impact of targeting these receptors on insulitis and the onset of T1D.

We obtained interesting results confirming our hypothesis in mice, and we concluded that drugs targeting these receptors may be useful in counteracting the immune attack during early stages of T1D. These achievements are an important step forward into validating this kind of drugs for T1D. Full assessment of these findings in human as well as further development of clinical trials investigating the efficacy and security of drugs targeting these receptors in people with T1D should be the next steps in the way to transfer these findings into clinical practice
This project has been performed at the Regional Hospital of Malaga (Spain) – Biomedical Research Institute of Malaga (IBIMA) within a multidisciplinary team. Researchers from different expertise participated in the project, including immunologists, endocrinologists and molecular biologists. The fellow performed experimentation using genetically modified animal models of T1D and islets of Langerhans. Some experimentation was also performed at other research institutions in Andalusia (CABD and CABIMER, Seville). Moreover, we obtained regional funds from the Ministry of Health and Families of Andalusia to support the full experimentation required to achieve the aims of DIRECtA.

Overall, we have found that pharmacological and/or genetic modulation of CB1R, CB2R and GPR55 provided benefits in beta cells during the immune attack that precedes T1D onset in mice, thus protecting from T1D development.

Accomplishment of this project has led to one peer-reviewed Open Access article recently published in Frontiers in Endocrinology (doi: 10.3389/fendo.2020.00103) and three other manuscripts that are under preparation.

Regarding to the exploitation of the results, we have also collaborated with a pharmaceutical company experienced in developing cannabinoid-based drugs that is highly interested in the results of DIRECtA.

Dissemination to citizenship of project’s progress has also been addressed through public talks, videos on local TVs, meetings with neighborhood associations and through social media such as Twitter and our institutional web page. Once the results are published we will also issue press releases, tweets and plain information in our web page in order to let the citizens know about the results of DIRECtA.

At the same time a continuous dissemination of DIRECtA has been performed, in the form of lectures, conferences, scientific manuscripts and videos.
The research performed at DIRECtA advanced on the research for novel therapies for T1D by validating at the preclinical level the use of synthetic cannabinoids. Thus, it has potential to impact future patient's quality of life and, since T1D is a chronic disease, also on the costs generated from the comorbidities associated to diabetes.

By means of DIRECtA we brought a unique mouse strain -genetically modified-, developed at governmental facilities within the United States of America (USA), to the European research context, thus increasing European competitiveness and excellence in research. The use of the mentioned strain can be applied not only for DIRECtA, but also for future projects developed in the European Union.

Moreover, our impacting results are already being awarded with further funding, that will allow to expand our knowledge on the regulation of insulitis by cannabinoid receptors onto humans. Also, DIRECtA has been disseminated at various socio-economical levels, impacting society in different ways.

Importantly, through this MSCA, the program H2020 directly impacted on the Spanish research scene by reinstating a European researcher from a state-of-the-art research institute (the National Institute of Health) within a country outside the European Union, the USA. The fellow was proficiency trained in the state-of-the-art techniques for the study of diabetes at the National Institute of Health, techniques that she has implemented in the hosting laboratory in Spain, transferring advanced knowledge onto the European community.
Schematic of DIRECtA