Poster Presentation 4th Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity Meeting 2024

Targeting neurofibrosis to potentiate incretin therapies (#187)

Feiyue Shi 1 , Cait Beddows 1 , Sagar Dalal 2 , Nicolle Packer 2 , Edward Moh 2 , Garron Dodd 1
  1. University of Melbourne, Carlton, VIC, Australia
  2. ARC Centre of Excellence in Synthetic Biology, Sydney, NSW, Australia

Metabolic diseases such as obesity and Type-2 diabetes are set to be leading causes of death by 20301. However, recent real-world data suggest current treatments like glucagon-like peptide-1 (GLP-1) analogues deliver insufficient efficacy in managing metabolic disease remission. Liraglutide has been proven to be less effective in reducing weight2 and HbA1c levels3 in diabetic patients with BMI of ≥40. Metabolic improvements are largely reverted towards pre-treatment baseline in one year after withdrawing treatment4. Mechanism of why impaired efficacy of GLP-1 agonists occurs in progressive disease states remains unknown, offering therapeutic opportunities to potentiate capacity of current therapeutics. 

Our lab has previously demonstrated perineuronal net (PNN) surrounds GLP-1 receptor-positive neurons within the ARC. PNN becomes augmented and pathologically remodelled during disease progression, a process termed neurofibrosis5. Despite neurofibrosis impairing GLP-1 analogues entry into the ARC, there are no existing therapeutics targeting neurofibrosis.

To address this, we have identified "first-in-class" small-molecule inhibitors, UOM6005 and its analogues. Centrally administered UOM6005 ameliorated ARC neurofibrosis with reductions in PNN proteoglycan and glycosaminoglycan composition. This resulted in weight loss, improved insulin resistance and glycaemic control in diet-induced obese and late-stage diabetic mice. Therapeutic utility of this novel mechanism was substantiated using structural and functional analogues of UOM6005.

We also explored if combination therapy of neurofibrosis inhibitors potentiates actions of incretin agonists including liraglutide, tirzepatide and retatrutide. Co-administration of these drugs with or without UOM6005 attenuated ARC neurofibrosis and facilitates drug access to the ARC parenchyma. Reduced neurofibrosis enhanced metabolic improvements driven by GLP-1 analogues and sustained improvements in whole-body metabolism in diet-induced obese mice. Dual administration of UOM6005 and GLP-1 analogues prolonged weight-loss effect by heightened energy expenditure and altered fuel utilization and maintained glycaemic improvements following a long-term OFF-treatment period.

Collectively, our findings unveil a novel class of therapeutics targeting neurofibrosis to treat metabolic disease.

 

  1. Chew, N. W. S. et al. The global burden of metabolic disease: Data from 2000 to 2019. Cell Metab 35, 414-428.e413 (2023). https://doi.org/10.1016/j.cmet.2023.02.003
  2. Wharton, S. et al. Weight loss and persistence with liraglutide 3.0 mg by obesity class in the real-world effectiveness study in Canada. Obes Sci Pract 6, 439-444 (2020). https://doi.org/10.1002/osp4.420
  3. Mosikian, A. A., Golikova, T. I., Martjanova, M. V. & Babenko, A. Y. Prediction scale of response to liraglutide therapy as the method for increase of treatment efficacy in type 2 diabetes. Future Sci OA 8, Fso779 (2022). https://doi.org/10.2144/fsoa-2021-0070
  4. Wilding, J. P. H. et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab 24, 1553-1564 (2022). https://doi.org/10.1111/dom.14725
  5. Beddows, C. A. et al. Pathogenic hypothalamic extracellular matrix promotes metabolic disease Nature In Press (Accepted 01/05/2024) (2024).