Diabetes gene therapy

Gene therapy is emerging as a promising approach to address the limitations of conventional diabetes treatments, such as insulin therapy, islet transplantation, and immunosuppressive regimens. Recent advancements focus on enhancing cell engraftment, immune evasion, and targeted gene delivery to restore glucose homeostasis. This article highlights key trends and innovations presented at the recent American Society of Gene & Cell Therapy (ASGCT) meeting 2025, showcasing breakthroughs across multiple studies. Notable developments include organoid transplantation, AAV-mediated gene silencing, engineered regulatory T cells (EngTregs), and novel therapeutic delivery platforms. Collectively, these approaches offer the potential for durable glycemic control, reduced immune rejection, and improved clinical outcomes for patients with diabetes and related metabolic disorders.

Advantages of Gene and Cell Therapy for Diabetes Compared to Current Treatments Like GLP-1 Agonists

Gene and cell therapies offer several advantages over current diabetes treatments, such as GLP-1 agonists. While GLP-1 agonists require frequent administration and are limited by short half-lives, patient adherence challenges, and high costs, gene and cell therapies have the potential to deliver long-lasting or even curative benefits through a single treatment. By targeting the root causes of disease, such as beta-cell dysfunction or insulin deficiency, these therapies can achieve precise, tissue-specific expression of therapeutic genes (e.g., insulin, GLP-1, or transcription factors like Pdx1 and MafA), potentially restoring endogenous insulin production and glucose regulation. Moreover, gene therapy can minimize systemic side effects, reduce treatment burden, and eliminate the need for daily injections, offering a transformative strategy for both type 1 and type 2 diabetes.

Key Innovations in Gene and Cell Therapy for Diabetes

1.  AAV-Based Gene Delivery

Transcription Factor-Induced Beta Cell Regeneration Using Pdx1 and MafA

Researchers from the University of Pittsburgh developed a dual-gene therapy approach using AAV to deliver Pdx1 and MafA, reprogramming pancreatic alpha cells into insulin-producing beta-like cells. In diabetic non-human primates (NHPs), intraductal delivery of rAAV6 significantly improved glucose tolerance and reduced insulin needs. While anti-AAV immune responses were observed without immunosuppression, a three-month regimen of rituximab, rapamycin, and steroids effectively prevented these responses. Immune tolerance persisted even after immunosuppression ceased, underscoring the importance of immune modulation in sustaining rAAV-based gene therapy benefits.

Intramuscular Delivery of Insulin and Glucokinase Genes to Reverse Hyperglycemia

In collaboration with the Universitat Autònoma de Barcelona, researchers from Kriya Therapeutics developed KRIYA-839, an AAV1-based gene therapy delivering human insulin (hINS) and glucokinase (hGCK) via intramuscular injection. In STZ-induced diabetic mice, KRIYA-839 significantly improved glycemic control, reduced fasting glucose, HbA1c, and triglyceride levels without causing hypoglycemia. These findings support KRIYA-839 as a non-pancreatic, durable gene therapy candidate for type 1 diabetes.

Endoscopic Ultrasound–Guided Delivery of GLP-1 Gene Therapy

Researchers at Fractyl Health, Inc. developed RJVA-001, an AAV-based pancreatic gene therapy designed to enable long-term, beta-cell-driven GLP-1 expression. Using endoscopic ultrasound-guided, transgastric infusion, RJVA-001 was delivered safely to the pancreas in Yucatan pigs, resulting in localized GLP-1 expression with no toxicity or inflammation. These findings support the feasibility and clinical potential of RJVA-001 as a durable alternative to conventional GLP-1 therapies for type 2 diabetes.

2.  Immune Modulation Strategies

Engineered Regulatory T Cells (EngTregs) for the Treatment of Type 1 Diabetes

Researchers at GentiBio developed a modular EngTreg platform using dual AAV vectors and gene editing to stably express FOXP3 and a chemically inducible IL-2–mimicking signal. This enhances Treg survival in IL-2-deficient environments. The platform enables disease-specific targeting via CARs, TCRs, or alarmin receptors, with candidates in development for type 1 diabetes (GNTI-122), B cell–driven autoimmunity (CAR19 EngTregs), and tissue repair in acute conditions (Tissue EngTregs).

In collaboration with Seattle Children’s Research Institute, the University of Washington, and the San Raffaele Institute (Milan), GentiBio advanced CAR19 EngTregs to suppress both B cells and autoreactive T cells. These allogeneic EngTregs demonstrated reduced cytokine release, preserved regulatory markers, and superior tissue protection, positioning them as a safer, more versatile alternative to traditional CAR T therapies.

3.  Non-Viral and Alternative Gene Delivery Systems

3D-Printed PLG Scaffolds for Enhanced Cell Delivery in Diabetes

Researchers at Dimension Inx engineered 3D-printed, highly porous PLG scaffolds (~80% intrafiber porosity) to enhance therapeutic cell engraftment in diseases like type 1 diabetes and liver disease. In preclinical models, scaffolds seeded with primary human islets or hepatocytes restored glycemic control and albumin production while promoting vascularization. Histological analysis confirmed long-term cell viability and integration, demonstrating the platform’s promise for regenerative medicine.

Gene Delivery of GLP-1 and GIP Mimetics via Electroporation

The Wistar Institute developed a single-dose gene therapy using plasmid-encoded incretin mimetics (pGLP1-mFc, pGIP-mFc) delivered via electroporation. In diet-induced obese mice, these constructs led to sustained incretin expression, significant weight loss, improved glucose tolerance, and reduced food intake for four weeks. This non-viral approach offers a durable, cost-effective alternative to traditional GLP-1 and GIP peptide therapies.

4.  Gene Editing and Silencing

 AAV-Mediated Smad2 Knockdown in Beta Cells

The University of Pittsburgh and UPMC researchers developed an AAV-based therapy to silence Smad2, a TGF-β pathway mediator linked to beta-cell dysfunction. AAV vectors expressing Smad2 shRNA under a rat insulin promoter achieved 65% in vitro and 75% in vivo knockdown, with improved glucose regulation in high-fat-fed mice. This beta cell–specific strategy holds promise as a targeted gene therapy for type 2 diabetes.

Gene Silencing of Inhbe with Advanced siRNA

Wave Life Sciences developed GalNAc-conjugated, stereopure siRNAs targeting Inhbe mRNA to treat obesity. In diet-induced obese mice, a single subcutaneous dose of INHBE-00002 achieved over 50% gene knockdown and sustained weight loss for 84 days. Combination with semaglutide further enhanced weight reduction. These results support Inhbe-targeting siRNAs as a durable, liver-directed therapy for obesity and metabolic disease.

5.  Cell Reprogramming and Tissue Engineering

 Patch-Based Organoid Transplantation (Patch Grafting)

Led by Lola Reid at UNC School of Medicine and collaborators from global institutions, researchers developed a dual-layer hydrogel patch system for transplanting organoids into solid organs. The inner soft hydrogel supports tissue integration, while the outer layer provides protection and site specificity. This method enabled successful integration of organoids into the liver, pancreas, intestine, kidneys, and bile ducts in mice and pigs, rescuing disease phenotypes such as tyrosinemia and type 1 diabetes.

Stem Cell–Derived Islet Replacement Therapy

Seraxis Inc. developed SR-02, a stem cell–derived islet therapy delivered in a retrievable omental pouch to avoid graft dispersal and microvascular obstruction. Derived from mature donor islet tissue, SR-02 forms vascularized endocrine clusters mimicking native islets. In preclinical models, SR-02 demonstrated sustained function and is now under evaluation in a Phase 1/2 clinical trial (NCT06651515).

Challenges and Future Directions

Despite exciting progress, several challenges must be addressed before these therapies can reach routine clinical use. Durability remains a concern, as most approaches demonstrate short- to mid-term efficacy in preclinical models without long-term human data. Improving tissue specificity is also critical—many viral vectors exhibit off-target effects, such as liver sequestration. Additionally, regulatory frameworks are not yet equipped to handle complex combination products like gene-edited cells integrated with biomaterials. Looking ahead, the field is moving toward personalized, durable solutions that integrate gene editing, immune engineering, and advanced delivery systems. Continued interdisciplinary collaboration and iterative innovation will be vital to realizing the full clinical potential of these breakthrough therapies.

 Reference

ASGCT 2025 Meeting Abstracts 

About Marin Biologic Laboratories

Our Recent Publication/Meeting Presentation on Gene Therapy

1.  Development of a Pharmacokinetic (PK) Mouse Serum GLP ELISA for an Anti–CD19–AntiCD3 Diabody
bioRxiv 2025.03.19.644217; doi: https://doi.org/10.1101/2025.03.19.644217
2. Cell-Based Potency Assay for Anti-CD3-Anti-CD19 Diabody. bioRxiv 2025.04.15.648836v1 https://www.biorxiv.org/content/10.1101/2025.04.15.648836v1
3.  American Society of Hematology (ASH) Annual Meeting 2024.
Abstract link: Using Gene Therapy to Solve Challenges with CAR-T Cell Immunotherapy: Lead Selection and Preclinical Development of an Adeno-Associated Virus with Reduced Immunogenicity  Exhibiting Efficient and Long-Term Expression of an Anti-CD19 T-Cell Engager.

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