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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - GCG-T3 Dyslipidemia (Validation and Molecular Characterization of Novel Glucagon-Thyroid Hormone Conjugates for the Efficient Management of Dyslipidemia and Fatty Liver Disease)

Teaser

Summary

Cardiovascular disease (CDV) is one of the main causes of death worldwide. Elevated levels of blood lipids (dyslipidemia) is a well-documented risk factor for CVD. Particularly, elevated low-density lipoprotein cholesterol (LDL-C) levels are known to play a critical role in the development of this pathology. For this reason, lowering LDL-C levels is one of the main strategies to either prevent or treat CVD.
Among the currently available lipid-lowering agents, the role of statins in reducing CVD has been clearly established. This intervention provides relevant reductions in circulating cholesterol and lowers coronary heart disease risk. However, a considerable number of patients treated with statins fail to meet target reductions in cholesterol and a series of side effects have been described after treatment with this drug.
Fatty liver disease (FLD), the most frequent liver metabolic disease caused by excess lipid accumulation in the liver, is also considered a risk factor for CVD since it alters serum lipids and lipoprotein profile. Importantly, there are no approved pharmacological therapies for FLD, only lifestyle changes are recommended as a therapeutic intervention.
All these factors emphasize the need to develop novel, efficacious and safe therapeutic tools for the treatment of dyslipidemia and FLD that may offer an advancement for treatment of the metabolic syndrome and contribute to decrease mortality risk from cardiovascular events.
In this context, the host group pioneered the development of a new poly-pharmaceutical procedure that allows for peptide-mediated selective tissue targeting of a nuclear hormone, which was proved to be effective for the treatment of obesity. This peptide-based targeting strategy improved the metabolic profile through synergistic co-agonism between both molecules (peptide-nuclear hormone), but also circumvented the potential adverse effects in tissues not expressing the peptide hormone receptor. Based on this innovative concept, we proposed in the current project to develop a novel poly-pharmaceutical therapy for the treatment of dyslipidemia, FLD and the metabolic syndrome by combining two key molecules in the control of metabolic homeostasis: glucagon (a peptide that targets mainly the liver) and thyroid hormone (nuclear hormone implicated in energy metabolism).
Glucagon plays an important role in glucose homeostasis, lipid metabolism and energy balance. The weight-lowering and hypolipidemic effects of glucagon make it an attractive pharmaceutical agent for the treatment of dyslipidemia and the metabolic syndrome. However, the chronic use of this peptide is potentially hampered by its inherent diabetogenic activity.
Thyroid hormones (TH) influence energy expenditure, fat oxidation, and cholesterol metabolism. Although increased TH levels can improve serum lipid profile and reduce fat accumulation in the liver, these positive effects are counterbalanced by their potential harmful effects on the heart and bone.
On the basis of these considerations, the global aim of this project was to characterize and perform an extensive in vivo pharmacological assessment of novel glucagon-T3 conjugates for efficient glucagon-mediated delivery of T3 selectively to the liver in order to reduce serum lipid levels and improve hepatic steatosis without causing adverse cardiovascular and glycemic effects.
The researcher and collaborators demonstrated that chronic intervention with the novel conjugate corrected dyslipidemia, fatty liver, glucose intolerance and reduced body weight in several animal models metabolically compromised. In addition, they showed that treatment with the conjugate improved atherosclerosis in preclinical disease models and that intervention was safe, since no detrimental effects on the heart and bone were found after treatment with the conjugate, and the glycemic control was even improved. These findings suggest that the therapeutic utility of integrating these hormones into a single

Work performed

The researcher and collaborators demonstrated that intervention with the glucagon-T3 conjugate improved dyslipidemia, fatty liver and atherosclerosis in different rodent models of hypercholesterolemia, obesity and atherosclerosis. It was also shown that chronic treatment with the conjugate lowered body weight by increasing energy expenditure.
In order to assess the contribution of each component of the conjugate to the lipid lowering efficacy, the compound was administered to glucagon receptor knockout mice as well as mice lacking the thyroid hormone receptor Î² in the liver. The results showed that the conjugate was unable to improve dyslipidemia in these two knockout lines, which demonstrates the target specificity and liver preference of glucagon-T3 to govern the effects on cholesterol and triglycerides metabolism.
Of important note, it was demonstrated that intervention with the conjugate was not only effective, but also safe. In this sense, chronic treatment with the conjugate improved glycemic control and no detrimental effects on the cardiovascular system and bone health were observed.
All together, these data support the potential therapeutic utility of pairing glucagon and thyroid hormones to a single molecule that might constitute a suitable pharmacological therapy for the chronic treatment of the constellation of disorders associated to the metabolic syndrome, including obesity, FLD, type 2 diabetes, and atherosclerosis.
Considering these promising results, commercial exploitation may be one of the mid/long-terms priorities for this project. After this preclinical testing, contacts may be established with pharmaceutical companies in order to initiate clinical trials in humans. If the results of clinical trials indicate that the new drug is safe and effective, and the European Medicines Agency approves it, the medicine will be commercialized, making it accessible to the public.

Final results

Along the implementation of the project, most of the specific objectives included in the original proposal have been accomplished. The researcher assessed the in vivo efficacy of the conjugate in hypercholesterolemic, atherogenic and obese mice, showing the ability of the compound to improve dyslipidemia and revert hepatic steatosis and atherosclerosis without causing any undesirable effect on the heart, bones or the glycemic control. The researcher and collaborators proved the efficacy and safety of this novel pharmacological approach for treatment of the metabolic syndrome and CVD.
Mortality associated with CVD has a major socio-economic impact in Europe and contribute to significant health inequalities. Therefore, the development of novel, effective and safe therapies to improve the cardiovascular health is needed. According to the results obtained from the project, this glucagon-T3 conjugate may represent a novel pharmacological strategy to combat CVD. However, during the implementation of the action the researcher and collaborators focused on preclinical testing. If this new drug may also be effective and safe in humans, and therefore successful in clinical trials, it may contribute to mitigate the incidence of CVD worldwide, reduce mortality rates related to cardiovascular events and substantially improve the quality of life of society.