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Molecularly Engineered Islet Cell Clusters for Diabetes Mellitus Treatment
Yook, Simmyung,Jeong, Jee-Heon,Jung, Yoon Suk,Hong, Sung Woo,Im, Bok Hyeon,Seo, Jin Won,Park, Jun Beom,Lee, Minhyung,Ahn, Cheol-Hee,Lee, Haeshin,Lee, Dong Yun,Byun, Youngro SAGE Publications 2012 CELL TRANSPLANTATION Vol.21 No.8
<P>Pancreatic islet transplantation is a promising method for curing diabetes mellitus. We proposed in this study a molecularly engineered islet cell clusters (ICCs) that could overcome problems posed by islet transplantation circumstances and host's immune reactions. A gene containing highly releasable exendin-4, an insulinotropic protein, was delivered into single islet cells to enhance glucose sensitivity; thereafter, the cells were reaggregated into small size ICCs. Then the surface of ICCs was modified with biocompatible poly(ethylene glycol)-lipid (PEG) (C18) for preventing immune reactions. The regimen of ICCs with low doses of anti-CD154 mAb and tacrolimus could effectively maintain the normal glucose level in diabetic mice. This molecularly engineered PEG-Sp-Ex-4 ICC regimen prevented cell death in transplantation site, partly through improving the regulation of glucose metabolism and by preventing hypoxia- and immune response-induced apoptosis. Application of this remedy is also potentially far-reaching; one would be to help overcome islet supply shortage due to the limited availability of pancreas donors and reduce the immunosuppressant regimens to eliminate their adverse effects.</P>
( Simmyung Yook ),( Jee Heon Jeong ),( Youngro Byun ) 영남대학교 약품개발연구소 2014 영남대학교 약품개발연구소 연구업적집 Vol.24 No.0
One of the major obstacles to successful intraportal islet transplantation is the early portal vein embolizationelicited by the infused islets. Thus, reducing the size and the number of islets is an important process to alleviatethe damage of liver after intraportal islet transplantation. In our previous studies, we developed a strategy to constructgenetically modified islet cell clusters (ICCs) and demonstrated their superiority in maintaining better viabilityand functionality in vivo. In this study, signal-peptide linked exendin-4 transduced islet cell clusters (Sp-Ex-4 ICCs)were used to reverse diabetes after intraportal islet transplantation in hyperglycemic mouse model. Group of micereceiving 500 islet equivalent (IEQ) of unmodified ICCs failed to restore normoglycemia following transplantation. Although 500 IEQ of ICCs was insufficient to reverse hyperglycemia in diabetic mice, no significant acute liverdamage or life-threatening liver embolization was observed. When 1000 IEQ ICCs were infused into the portal vein,all animals died within 24 h post-surgery. In order to clarify the effect of Sp-Ex-4 gene transduction in improvingICCs functionality, 500 IEQ of Sp-Ex-4 ICCs were infused into the portal vein of diabetic mice. Following transplantation,75% of diabetic mice returned to normoglycemia and the survival fraction was 100%. In conclusion, intraportaltransplantation of Sp-Ex-4 ICCs successfully reversed diabetes in hyperglycemic mice by reducing the mass requiredfor the treatment. Therefore, intraportal transplantation of small islets (genetically engineered ICCs) can be proposedas a new strategy to overcome early graft embolization after intraportal transplantation.
Jeong, Jee-Heon,Yook, Simmyung,Byun, Youngro The Polymer Society of Korea 2016 Macromolecular Research Vol.24 No.12
Improvements in preventing pancreatic islet rejection are needed for successful treatment of type 1 diabetes. Our objective was to develop an optimized protocol combining modification of islets with polyethyleneglycol (PEG) chains and administration of tacrolimus (FK506, Prograf), an immunosuppressive drug for preventing rejection following transplantation. Freshly isolated islets were incubated with different concentrations (0.25, 1.00, 10.00, and 25.00%) of FITC-labeled mPEG-SCM (MW. 20 KDa) for various incubation times. 1% mPEG-SCM incubated with islets for 1 h is optimized surface coverage condition without cell toxicity. In addition, in order to optimize the concentration of tacrolimus (FK506, Prograf), different concentrations (0.1, 0.5 or 2.0 mg/kg) were injected into the diabetic mice following transplantation of PEGylated islets. The PEGylated islet survival time in mice injected daily with 0.1 mg/kg and 0.5 mg/kg of tacrolimus was significantly better than in the group without tacrolimus injection. The graft survival time in mice injected daily with 2.00 mg/kg of exhibited no prolonged survival time. Finally, immunohistochemical staining of left kidney containing PEGylated islets (injected with 0.1 mg/kg of tacrolimus) demonstrated strong staining for insulin, glucagon, and somatostatin but very weak CD20 staining was observed in the islet transplanted area. In conclusion, 1% mPEG-SCM incubated with islets for 1 h was the optimal condition for PEGylation without affecting the cell viability. A dose of tacrolimus between 0.1-0.5 mg/kg was highly effective for inhibiting immune cell activation. These results are promising for their application in developing a novel immunosuppressive protocol for successful pancreatic islet transplantation in the treatment of type 1 diabetes.
Duwa Ramesh,정지헌,Yook, Simmyung 한국약제학회 2021 Journal of Pharmaceutical Investigation Vol.51 No.4
Background Parkinson’s disease (PD) is the most common progressive neurodegenerative disorder and is characterized by the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNC). To date, none of the strategies, such as pharmacological, non-pharmacological, and neurosurgical therapies, have been capable of fundamental treatment of PD. These types of treatments provide only symptomatic relief, and effective targeting for PD has lagged behind other disease areas, due to drug delivery challenges caused by the blood–brain barrier (BBB). Area covered This review focus on the immunologic and nanoformulation strategies used for the treatment of PD. In this review, we discuss the current strategies that offer the development of immunotherapies, antibody-based therapies, and nanoparticles (NPs)-based therapy to reduce the burden of degeneration of DA neurons due to synucleinopathies and elevation of proinflammatory cytokines in the central nervous system (CNS). Furthermore, this review presents current ongoing clinical trials. Expert opinion The accumulation and transmission of α-synuclein and activation of glial cells cause the death of dopaminergic neurons and lead to the progression of PD. Many studies have investigated the immunotherapies and NPs-based therapy that target α-synuclein, and microglia, which have been shown to effectively prevent the progression of α-synuclein deposition and microglia deactivation. Furthermore, at present, the formulations of different drugs, such as DA, levodopa (L-DOPA), monoamine oxidase inhibitors (MAO-I), and antioxidants, is administered with a multifunctional carrier that can penetrate the BBB. Therefore, rapid clinical progression on these strategies gives new hope in the therapy of PD.
Advances in alginate encapsulation of pancreatic islets for immunoprotection in type 1 diabetes
쩌우더리디네스,Nguyen Tiep Tien,Yook, Simmyung,정지헌 한국약제학회 2023 Journal of Pharmaceutical Investigation Vol.53 No.5
Background Islet transplantation is a promising minimally invasive approach that dispenses with many challenges, especially immunological complications such as instant blood-mediated inflammatory reaction, autoimmunity, and allogeneic or xenogeneic rejection. Besides, scare of islet donor, side effects of immunosuppressant, and poor angiogenesis are also crucial factors for long-term islet survival and function. Approaches to the encapsulation of islets have been introduced to address aforementioned challenges. Area covered In this review, we summarize the concept of islet encapsulation using alginate to minimize the immunological complications, maintain islet morphology, and exchange of nutrients, hormones, and metabolic waste via isolating pancreatic islets from host immune cells. Alginate encapsulation technologies like dripping, microfluidics, and 3D printing are also briefly introduced. Similarly, this review outlines islet encapsulation strategies (co-encapsulation with other cells, peptides, drugs, etc.,) and approaches (nano-, micro-, and macroencapsulation) using alginate. Alongside this, this review introduces the use of alginate in an oxygenation system to overcome the hypoxic environment faced by encapsulated islets. Finally, challenges and opportunities for islet encapsulation using alginate are also discussed in terms of clinical applications. Expert opinion With the aim of immunoisolation, islet encapsulation using alginate reduces immunological attacks and enhances the survivability of islets after transplantation. Alginate shows promise based on its biocompatibility, non-toxicity, and easy and fast gelation under physiological conditions. Intriguingly, it can also co-encapsulate islets with other biomolecules and shows compatibility with other polymers. With ongoing strides in research on islet encapsulation, alginateencapsulated islets could be available for the treatment of type 1 diabetes in the near future.