Project Description - LEGO

The diabetes and obesity epidemics are worsening globally, with over one billion people were living with obesity in 2022, and the World Health Organization reports that 830 million people had diabetes in 2022. The global increase in type 2 diabetes (T2D) and obesity demands transformative therapeutic strategies that move beyond the limitations of current treatments. Existing approaches are often constrained by their single-target focus, which fails to address the interconnected nature of these diseases, as well as their reliance on invasive injections that compromise patient compliance. While modern dual-agonist drugs (e.g. IDegLira, IGlarLixi and Soliqua) demonstrate the potential of combination therapy, they still require periodic administration..

To overcome these challenges, we present LEGO (Light-induced Expression of GLP-1 and Insulin for Obesity and diabetes treatment), an innovative optogenetic gene therapy system. LEGO is designed for the precise, light-controlled co-expression of insulin and GLP-1 within the body. Activated non-invasively by an orally administered small molecule or wearable programmable light-source, these systems trigger a bioluminescent reaction or use blue-light to control therapeutic protein production with high precision. With future implantability in mind, LEGO offers a reversible, spatiotemporally controlled, and patient-friendly platform for the long-term management of metabolic diseases.

Type 2 diabetes (T2D) and obesity are two of the most pressing public health challenges of the 21st century, contributing to a global metabolic crisis. According to the International Diabetes Federation (IDF), the global prevalence of diabetes reached 537 million adults in 2021, with projections indicating an increase to 643 million by 2030. This surge is particularly prominent in countries such as the USA, India, and China, driven by a complex interplay of genetic, environmental, and societal factors, including urbanization, sedentary lifestyles, and diets rich in processed foods. T2D is characterized by hyperglycemia resulting from insulin resistance in peripheral tissues and a progressive decline in pancreatic β-cell function, often occurring alongside obesity. This creates a vicious cycle: obesity exacerbates insulin resistance, leading to increased demand on β-cells to secrete more insulin, eventually causing their exhaustion and failure.
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Current management strategies for T2D and obesity often fall short of achieving long-term, optimal outcomes. Traditional pharmacotherapies, such as metformin or sulfonylureas, typically focus on single-target approach, prioritizing glycemic control while neglecting the associated issue of weight gain or the complex underlying pathophysiology. Moreover, the subcutaneous injection of insulin or GLP-1 receptor agonists remains a cornerstone of treatment for many patients. These invasive methods are painful, carry the risk of infection, and impose significant patient burdens, leading to poor adherence and suboptimal disease management.

The recent introduction of dual-action drugs, such as IDegLira, IGlarLixi and Soliqua, represents a paradigm shift, highlighting the immense therapeutic potential of targeting multiple pathways simultaneously. By harnessing the combined actions of GLP-1 and insulin, these agents achieve the ideal trifecta in diabetic treatment - robust glycemic control without increased risk of hypoglycemia or weight gain - demonstrating the superior efficacy of this integrated approach. Inspired by this multi-faceted strategy, our project, LEGO (Light-induced Expression of GLP-1 and Insulin for Obesity and Diabetes Treatment), aims to push the boundaries further by integrating dual-hormone therapy with the unparalleled precision of optogenetics, paving the way for personalized, smart medicine.

Biosynthesis and Function of Insulin

The INS gene encodes insulin, a peptide hormone that plays a vital role in regulation of carbohydrate and lipid metabolism. Insulin is the primary hormone responsible for lowering blood sugar (glucose) levels.

After the precursor signal peptide is removed, proinsulin undergoes post-translationally cleavage into three peptides: the B chain and A chain peptides, which are covalently linked by two disulfide bonds to form insulin, and the C-peptide.

Biosynthesis and Function of GLP-1

The GLP-1 preprotein is encoded by the GCG gene. It is secreted by enteroendocrine cells in the intestine and functions to stimulate insulin secretion, slow gastric emptying, and improve lipid metabolism, etc.

GLP-1 requires cleavage of a 6-amino acid N-terminal peptide to form its active form. Direct expression of GLP-1(7-37) produces the mature, active peptide.

We propose an innovative gene therapy system, LEGO (Light-induced Expression of GLP-1 and Insulin), designed to tackle the growing global prevalence of type 2 diabetes and obesity and to overcome the limitations of current treatments.

The LEGO system integrates dual-hormone therapy with optogenetic regulation. By utilizing endogenous light generated through a reconstituted bioluminescence system or a wirelessly controlled wearable light source, we can precisely control light-responsive protein interactions. This core mechanism enables reversible and spatiotemporally precise transcriptional regulation, allowing for the co-expression of both insulin and the mature, active form of GLP-1(7-37). By delivering these two key hormones simultaneously, we target the dual pathologies of hyperglycemia and obesity, mimicking and enhancing the success of modern dual-agonist drugs, all within a single, programmable, and smart genetic circuit.

A pivotal advantage of the LEGO system is its non-invasive, patient-friendly activation. The system is triggered remotely through the oral administration of a safe, small-molecule substrate for the luciferase or via a wearable, programmable light-illuminating device, eliminating the need for frequent injections. This approach significantly improves patient comfort, compliance, and long-term adherence to therapy.

Designed with future clinical translation and implantability in mind, LEGO represents a novel, efficient, and precise approach to the long-term management of metabolic diseases. It surpasses the limitations of single-target drugs and the invasiveness of current delivery methods, offering a comprehensive, sustainable, and personalized solution to a pressing global health challenge.

Dual-action therapy: LEGO simultaneously addresses both diabetes and obesity through coordinated expression of insulin and GLP-1, overcoming limitations of single-target approaches.

Precise optogenetic control: Our system uses light-induced protein-protein interactions to enable spatiotemporal precision in hormone expression, allowing for reversible and tunable therapeutic effects.

Non-invasive activation: Unlike traditional therapies requiring injections, LEGO is activated through oral administration of a small molecule, significantly improving patient compliance and comfort.

Future implantability: Designed with long-term management in mind, LEGO represents a novel approach to metabolic disease treatment that could be implemented as an implantable device.

Wu, C., Wang, T., Ghosh, A., Long, F., Sharma, A. K., Dahlby, T., Noé, F., Severi, I., Colleluori, G., Cinti, S., Giordano, A., Ding, L., Khandelwal, R., Kostidis, S., Giera, M., Balazova, L., Gardeux, V., Abu-Nawwas, L., Deplancke, B., Chourasia, S., … Wolfrum, C. (2025). MTCH2 modulates CPT1 activity to regulate lipid metabolism of adipocytes. Nature communications, 16(1), 8831. https://doi.org/10.1038/s41467-025-63880-7

Drucker, D. J. (2018). Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metabolism, 27(4), 740–756. https://doi.org/10.1016/j.cmet.2018.03.001

Drucker, D. J. (2024). Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity. Diabetes Care, 47(11), 1873–1888. https://doi.org/10.2337/dci24-0003

Gong, B., Li, C., Shi, Z., Wang, F., Dai, R., Chen, G., & Su, H. (2025). GLP-1 receptor agonists: exploration of transformation from metabolic regulation to multi-organ therapy. Frontiers in pharmacology, 16, 1675552. https://doi.org/10.3389/fphar.2025.1675552

Levate, G., & Stimson, R. H. (2025). Molecular signatures of skeletal muscle insulin resistance: bringing personalised diabetes treatment a step closer. Signal transduction and targeted therapy, 10(1), 320. https://doi.org/10.1038/s41392-025-02412-7

Liu, X., Gong, B., Wang, T., Hu, G., Han, J., & Sun, L. (2025). Development of a potent Xenopus GLP-1-derived GLP-1/GIP/Y2 receptor tri-agonist for obesity and type 2 diabetes. International journal of biological macromolecules, 328(Pt 1), 147553. Advance online publication. https://doi.org/10.1016/j.ijbiomac.2025.147553

Magliano, D. J., Boyko, E. J., & IDF Diabetes Atlas 10th edition scientific committee . (2021). IDF DIABETES ATLAS. (10th ed.). International Diabetes Federation.

Norton, L., Shannon, C., Gastaldelli, A., & DeFronzo, R. A. (2022). Insulin: The master regulator of glucose metabolism. Metabolism: Clinical and Experimental, 129, 155142. https://doi.org/10.1016/j.metabol.2022.155142

Tokarz, V. L., MacDonald, P. E., & Klip, A. (2018). The cell biology of systemic insulin function. The Journal of Cell Biology, 217(7), 2273–2289. https://doi.org/10.1083/jcb.201802095