New avenues in metabolic disease treatment: duodenal mucosal resurfacing and gene therapy

Abstract

Metabolic diseases including obesity, type 2 diabetes mellitus (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD) are increasing rapidly worldwide and contribute substantially to morbidity, mortality, and healthcare costs. Current therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), have transformed metabolic disease management but remain limited by high costs, adverse effects, treatment discontinuation, and the need for chronic administration. Duodenal mucosal resurfacing (DMR) and gene therapy represent potential long-term strategies for metabolic disease modulation. DMR is a minimally invasive endoscopic procedure that ablates and regenerates the duodenal mucosa, with clinical studies demonstrating improvements in glycemic control, insulin sensitivity, and liver fibrosis markers in patients with T2DM and MASLD. Although the precise mechanisms remain incompletely understood, recent evidence suggests that DMR may induce significant genetic, enteroendocrine, and gut microbiota changes involving pathways associated with glucose uptake, intestinal differentiation, and metabolic signaling. In parallel, advances in gene therapy using adeno-associated viral (AAV) vectors and lipid nanoparticles (LNPs) have shown potential in sustained modulation of insulin secretion, GLP-1 signaling, and β-cell regeneration. These approaches may overcome several limitations of conventional pharmacotherapy by providing longer-lasting therapeutic effects with fewer pharmacokinetic fluctuations. This review highlights the biological rationale underlying DMR and gene therapy, evaluates current preclinical and clinical evidence, and discusses limitations related to safety, efficacy, delivery specificity, manufacturing scalability, and ethical accessibility. Additionally, it explores the potential intersection between DMR and gene therapy, proposing that genes identified through DMR-mediated metabolic remodeling may serve as future therapeutic targets. This review also hypothesizes how DMR and gene therapy could be used together to have long-lasting complementary effects. Together, these technologies represent promising and potentially complementary strategies that could reshape the therapeutic landscape for obesity, diabetes, and MASLD.

Keywords

metabolic diseases / duodenal mucosal resurfacing / obesity / diabetes / metabolic dysfunction-associated steatotic liver disease (MASLD) / glucagon-like peptide 1 / adeno-associated virus gene therapy / lipid nanoparticle gene therapy

References

[1] Lourie J, Goraltchouk A, Hollander JM, Berger NJ, Rosen HG, Fujishiro AA, et al. A novel gene therapy platform for the treatment of type 2 diabetes and obesity. Mol Ther Nucleic Acids. 2025; 36: 102739.

[2] Tantu MT, Farhana FZ, Haque F, Koo KM, Qiao L, Ross AG, et al. Pathophysiology, noninvasive diagnostics and emerging personalized treatments for metabolic associated liver diseases. npj Gut Liver. 2025; 2: e2.

[3] Horwitz A, Birk R. Adipose Tissue Hyperplasia and Hypertrophy in Common and Syndromic Obesity-The Case of BBS Obesity. Nutrients. 2023; 15: 3445.

[4] Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB, et al. Pathophysiology of Type 2 Diabetes Mellitus. Int J Mol Sci. 2020; 21: 6275.

[5] Younossi ZM, Kalligeros M, Henry L. Epidemiology of metabolic dysfunction-associated steatotic liver disease. Clin Mol Hepatol. 2025; 31: S32-50.

[6] McEwan P, Faurby M, Lübker C, Padgett T, Toliver JC. The evolving burden of obesity in the US: a novel population-level system dynamics approach. J Med Econ. 2025; 28: 1512-25.

[7] Azzam AY, Mora LM, Morsy MM, Essibayi MA, Altschul DJ, Nassar M. Epidemiological Patterns of Diabetes Mellitus in The United States of America: An Observational Multicenter Analysis From 1990 to 2024. ASIDE Intern Med. 2025; 1: 1-7.

[8] Meiring S, Aydin Ö, van Baar ACG, van der Vossen EWJ, Rampanelli E, van Grieken NCT, et al. From Endoscopic Inspection to Gene-Expression: A Thorough Assessment of the Duodenal Mucosa After Resurfacing-A Prospective Study. Dig Dis Sci. 2025; 70: 1052-63.

[9] Oussaada SM, van Galen KA, Cooiman MI, Kleinendorst L, Hazebroek EJ, van Haelst MM, et al. The pathogenesis of obesity. Metabolism. 2019; 92: 26-36.

[10] Cardoso P, Dennis JM, Pearson ER. GLP-1RA precision medicine in people with type 2 diabetes: current insights and future prospects. J Clin Investig. 2026; 136: e136.

[11] Yao H, Zhang A, Li D, Wu Y, Wang CZ, Wan JY, et al. Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis. BMJ. 2024; 384: e076410.

[12] Collins L, Costello RA. Glucagon-Like Peptide-1 Receptor Agonists. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.

[13] Ying Z, van Eenige R, Ge X, van Marwijk C, Lambooij JM, Guigas B, et al. Combined GIP receptor and GLP1 receptor agonism attenuates NAFLD in male APOE∗3-Leiden.CETP mice. eBioMedicine. 2023; 93: 104684.

[14] Li P, Varghese JS, Shah MK, Galindo RJ, Pasquel FJ, Ali MK, et al. Prescribing Trends of Glucagon-Like Peptide 1 Receptor Agonists for Type 2 Diabetes or Obesity. JAMA Netw Open. 2025; 8:e2540890.

[15] Salerno ENM, Fumarulo I, Garramone B, Vaccarella M, Ierardi C, Burzotta F, et al. GLP1-RAs: long-term use versus discontinuation events of an emerging therapy for obesity and cardiovascular diseases. Curr Probl Cardiol. 2026; 51: 103213.

[16] Tzang CC, Wu PH, Luo CA, Chen ZT, Lee YT, Huang ES, et al. Metabolic rebound after GLP-1 receptor agonist discontinuation: a systematic review and meta-analysis. eClinicalMedicine. 2025; 90: 103680.

[17] Quarenghi M, Capelli S, Galligani G, Giana A, Preatoni G, Turri Quarenghi R. Weight Regain After Liraglutide, Semaglutide or Tirzepatide Interruption: A Narrative Review of Randomized Studies. J Clin Med. 2025; 14: 3791.

[18] van Baar ACG, Beuers U, Wong K, Haidry R, Costamagna G, Hafedi A, et al. Endoscopic duodenal mucosal resurfacing improves glycaemic and hepatic indices in type 2 diabetes: 6-month multicentre results. JHEP Rep. 2019; 1: 429-37.

[19] Brzozowska MM, Isaacs M, Bliuc D, Baldock PA, Eisman JA, White CP, et al. Effects of bariatric surgery and dietary intervention on insulin resistance and appetite hormones over a 3 year period. Sci Rep. 2023; 13: 6032.

[20] Verdam FJ, Greve JW, Roosta S, van Eijk H, Bouvy N, Buurman WA, et al. Small Intestinal Alterations in Severely Obese Hyperglycemic Subjects. J Clin Endocrinol Metab. 2011; 96: E379-83.

[21] Theodorakis MJ, Carlson O, Michopoulos S, Doyle ME, Juhaszova M, Petraki K, et al. Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP. Am J Physiol-Endocrinol Metab. 2006; 290: E550-9.

[22] Rajagopalan H, Cherrington AD, Thompson CC, Kaplan LM, Rubino F, Mingrone G, et al. Endoscopic Duodenal Mucosal Resurfacing for the Treatment of Type 2 Diabetes: 6-Month Interim Analysis From the First-in-Human Proof-of-Concept Study. Diabetes Care. 2016; 39: 2254-61.

[23] Mingrone G, van Baar AC, Devière J, Hopkins D, Moura E, Cercato C, et al. Safety and efficacy of hydrothermal duodenal mucosal resurfacing in patients with type 2 diabetes: the randomised, double-blind, sham-controlled, multicentre REVITA-2 feasibility trial. Gut. 2021; 71: 254-64.

[24] Nie LJ, Cheng Z, He YX, Yan QH, Sun YH, Yang XY, et al. Role of duodenal mucosal resurfacing in controlling diabetes in rats. World J Diabetes. 2025; 16: 102277.

[25] Chiu HHC, Wang JS. Potential of duodenal mucosal resurfacing in achieving glycemic control in Asians with type 2 diabetes. Ther Adv Endocrinol Metab. 2024; 15: 20420188241252308.

[26] Chen M, Lu X, Lu C, Shen N, Jiang Y, Chen M, et al. Soluble uric acid increases PDZK1 and ABCG2 expression in human intestinal cell lines via the TLR4-NLRP3 inflammasome and PI3K/Akt signaling pathway. Arthritis Res Ther. 2018; 20: 20.

[27] Meiring S, van Baar ACG, Sørensen N, Holleman F, Soeters MR, Nieuwdorp M, et al. A Changed Gut Microbiota Diversity Is Associated With Metabolic Improvements After Duodenal Mucosal Resurfacing With Glucagon-Like-Peptide-1 Receptor Agonist in Type 2 Diabetes in a Pilot Study. Front Clin Diabetes Healthc. 2022; 3: 856661.

[28] Meiring S, Meessen ECE, van Baar ACG, Holleman F, Nieuwdorp M, Olde Damink SW, et al. Duodenal mucosal resurfacing with a GLP-1 receptor agonist increases postprandial unconjugated bile acids in patients with insulin-dependent type 2 diabetes. Am J Physiol-Endocrinol Metab. 2022; 322: E132-40.

[29] Angelidi AM, Belanger MJ, Kokkinos A, Koliaki CC, Mantzoros CS. Novel Noninvasive Approaches to the Treatment of Obesity: From Pharmacotherapy to Gene Therapy. Endocr Rev. 2021; 43: 507-57.

[30] Lisowski L, Tay SS, Alexander IE. Adeno-associated virus serotypes for gene therapeutics. Curr Opin Pharmacol. 2015; 24: 59-67.

[31] Alharbi AG. Translational Barriers to AAV and CRISPR Gene Therapy in Diabetes. Saudi Med J. 2026; 47: 626-52.

[32] Pancreatic Delivery of AAV-Pdx1/MafA Reverses Hyperglycemia in a Preclinical Model of Type 2 Diabetes [Internet]. [cited 2026 May 15]. Available from: https://www.genprex.com/wp-content/uploads/2026/05/2026-ASGCT-Poster_FINAL.pdf

[33] Matsuoka TA, Kawashima S, Miyatsuka T, Sasaki S, Shimo N, Katakami N, et al. Mafa Enables Pdx1 to Effectively Convert Pancreatic Islet Progenitors and Committed Islet α-Cells Into β-Cells In Vivo. Diabetes. 2017; 66: 1293-300.

[34] Jaguar Gene Therapy. Pipeline [Internet]. Lake Forest (IL): Jaguar Gene Therapy, LLC; c2026 [cited 2026 Jul 18]. Available from: https://jaguargenetherapy.com/pipeline/

[35] Zajec A, Trebušak Podkrajšek K, Tesovnik T, Šket R, Čugalj Kern B, Jenko Bizjan B, et al. Pathogenesis of Type 1 Diabetes: Established Facts and New Insights. Genes. 2022; 13: 706.

[36] Lau HH, Krentz NAJ, Abaitua F, Perez-Alcantara M, Chan JW, Ajeian J, et al. PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development. Nat Commun. 2023; 14: 6119.

[37] Fonseca VA. Defining and Characterizing the Progression of Type 2 Diabetes. Diabetes Care. 2009; 32 Suppl 2: S151-6.

[38] Fractyl Health Advances Rejuva® Gene Therapy Platform with Submission of First Clinical Trial Application Module in Europe for RJVA-001 in Type 2 Diabetes [Internet]. Burlington (MA): Fractyl Health, Inc.; [cited 2026 Jul 18]. Available from: https://ir.fractyl.com/news-releases/news-release-details/fractyl-health-advances-rejuvar-gene-therapy-platform-submission

[39] Fractyl Health Authorized to Initiate First-in-Human Trial of RJVA-001 in the Netherlands: First Gene Therapy Candidate to Enter Clinical Development for Type 2 Diabetes [Internet]. Washington (DC): U.S. Securities and Exchange Commission, EDGAR Index; c2026 [cited 2026 Jul 18]. Available from: https://www.sec.gov/Archives/edgar/data/1572616/000119312526215662/guts-ex99_1.htm

[40] A Nutrient-Regulated GIP/GLP-1 AAV Gene Therapy to Durably Treat Obesity [Internet]. [cited 2026 May 15]. Available from: https://www.fractyl.com/wp-content/uploads/2026/05/Fractyl-ASGCT-2026-RJVA-002-Poster-FINAL.pdf

[41] Tasyurek MH, Altunbas HA, Canatan H, Griffith TS, Sanlioglu S. GLP-1-mediated gene therapy approaches for diabetes treatment. Expert Rev Mol Med. 2014; 16: e7.

[42] Tonne JM, Sakuma T, Deeds MC, Munoz-Gomez M, Barry MA, Kudva YC, et al. Global gene expression profiling of pancreatic islets in mice during streptozotocin-induced β-cell damage and pancreatic Glp-1 gene therapy. Dis Models Mech. 2013; 6: 1236-45.

[43] Hirose J, Aizawa E, Yamamoto S, Iwai S, Suzuki K. Targeted in vivo gene integration of a secretion-enabled GLP-1 receptor agonist reverses diet-induced non-genetic obesity and pre-diabetes. Commun Med. 2025; 5: 269.

[44] Hou X, Zaks T, Langer R, Dong Y. Lipid nanoparticles for mRNA delivery. Nat Rev Mater. 2021; 6: 1078-94.

[45] Digiacomo L, Renzi S, Quagliarini E, Pozzi D, Amenitsch H, Ferri G, et al. Investigating the mechanism of action of DNA-loaded PEGylated lipid nanoparticles. Nanomedicine. 2023; 53: 102697.

[46] Wang J, Ding Y, Chong K, Cui M, Cao Z, Tang C, et al. Recent Advances in Lipid Nanoparticles and Their Safety Concerns for mRNA Delivery. Vaccines. 2024; 12: 1148.

[47] Mashima R, Takada S. Lipid Nanoparticles: A Novel Gene Delivery Technique for Clinical Application. Curr Issues Mol Biol. 2022; 44: 5013-27.

[48] Khan ES, Däinghaus T. HSP47 in human diseases: Navigating pathophysiology, diagnosis and therapy. Clin Transl Med. 2024; 14:e1755.

[49] Hostinar CE, Ross KM, Chen E, Miller GE. Early-Life Socioeconomic Disadvantage and Metabolic Health Disparities. Psychosom Med. 2017; 79: 514-23.