Ruipu Chenchuang's RGB-5088 Islet Cell Injection: Pioneering China's First Stem Cell-Based Therapy for Diabetes Enters Clinical Trial Phase

Diabetes is a chronic disease caused by abnormal insulin secretion and impaired insulin utilization. Symptoms in the early stages of diabetes are often subtle, while in the middle to late stages, the disease may lead to chronic, progressive damage to organs and tissues such as the eyes, kidneys, nerves, heart, and blood vessels, and can trigger acute, severe metabolic disturbances. Notably, diabetes is closely associated with lifestyle habits and genetic factors, often exhibiting familial aggregation.

According to the 2023 publication “Current Status of Diabetes Care Target Achievement in China: A National Cross-Sectional Study,”China Has the Largest Number of Diabetic Patients Worldwide.Diabetes imposes a heavy socioeconomic burden. In 2019 alone, direct medical expenditures for diabetes in China reached $109 billion, ranking second globally, just behind the United States at $295 billion.

For various reasons, diabetes treatment has become a hot topic of global concern. In July 2024, Chinese enterprises took another critical step forward in this field.

According to the Center for Drug Evaluation (CDE) of the National Medical Products Administration,Hangzhou Reprogenix Bioscience, Inc. (hereinafter referred to as “Reprogenix”) has had its Investigational New Drug (IND) application for “RGB-5088 Islet Cell Injection” accepted, potentially making it the first approved human pluripotent stem cell-derived islet cell therapy for diabetes in China.

Currently, diabetes treatment faces three major challenges: difficulty in blood glucose control, scarcity of donors for islet transplantation, and the management difficulties associated with brittle diabetes.

Glycemic control is the cornerstone of diabetes management. Achieving optimal glycemic control relies not solely on pharmacological interventions but also requires patients to modify their dietary and exercise habits, as well as manage their psychological well-being, all of which demand high levels of patient adherence.

Furthermore, patients with diabetes often present with multimorbidity, including comorbidities such as hypertension and hyperlipidemia. These conditions themselves can impair glycemic control and increase the complexity of treatment. Meanwhile, patients with multimorbidity are required to take a large number of medications daily, and drug-drug interactions may compromise the efficacy of glucose-lowering agents, thereby making blood glucose control difficult.

Among all types of diabetes, brittle diabetes is the most distinctive. This condition is characterized not only by extreme instability and wide fluctuations in blood glucose levels, but also by abnormal sensitivity to insulin, whereby even minor changes in insulin dosage can cause significant fluctuations in the patient's blood glucose.

Islet transplantation is currently one of the more effective treatments for diabetes, but its widespread adoption remains challenging, primarily due to a shortage of donors.To ensure the success rate and safety of transplantation, donors must undergo rigorous screening and evaluation. Only those whose blood type, histocompatibility, and a series of biological characteristics match those of the recipient can serve as donors. This process is already highly selective, akin to finding one in a hundred; however, islet cells may still suffer loss and damage during the transplantation procedure. A single patient with diabetes often requires islet transplants from multiple healthy, qualified donors to increase the likelihood of successful engraftment, thereby exacerbating the scarcity of islet donors.

Amid this predicament, stem cell therapy is held in high hope. Its primary mechanism involves the differentiation of stem cells into various required cell types, including pancreatic beta cells, which are crucial for insulin secretion and play a vital role in blood glucose regulation. Current research has demonstrated that patients with diabetes who undergo stem cell therapy may potentially discontinue medication entirely and restore their bodies to a healthy state.

Professor Deng Hongkui, Chief Scientist at Hangzhou Reprogenix Bioscience, Inc., has dedicated decades to the field of stem cell research. He successfully reprogrammed human somatic cells into pluripotent stem cells using small chemical molecules, thereby pioneering a novel technological approach for generating pluripotent stem cells.In 2014, Dr. Ding Lieming, Ms. Lou Shengqiong, and Professor Deng Hongkui jointly established a robust R&D technical team with comprehensive expertise and abundant clinical resources to explore therapeutic approaches for diabetes using pluripotent stem cells.

The concept of induced pluripotent stem cells (iPSCs) was first proposed by Japanese researcher Shinya Yamanaka in 2006. A year later, his team successfully reprogrammed human somatic cells into stem cells that exhibited gene expression profiles and pluripotency similar to those of human embryonic stem cells. For this breakthrough, Yamanaka was awarded the 2012 Nobel Prize in Physiology or Medicine, sparking a global surge in research on pluripotent stem cells.

Due to their robust capabilities for in vitro expansion, replication, and differentiation, low immunogenicity, and high gene-editing efficiency, pluripotent stem cells have been widely applied in disease modeling as well as drug discovery and development.

However, the reprogramming of human somatic cells into pluripotent stem cells still presents certain drawbacks. First, human somatic cells may exhibit instability during processes such as gene editing, in vitro culture, or passaging, thereby introducing genetic mutations. These mutations may even affect the properties of the resulting induced pluripotent stem cells, compromising therapeutic efficacy for diseases and potentially causing adverse reactions.

Furthermore, significant genetic heterogeneity may exist among human somatic cells from different sources, making it difficult to ensure the consistency and safety of therapeutic efficacy for stem cell products.

Furthermore, regarding differentiation, the reprogramming efficiency of human somatic cells remains low, and the process is complex and time-consuming. This will also impact the mass production of stem cell products.

To circumvent potential issues that may arise during human somatic cell differentiation,Reprogenix Bioscience’s proprietary seed cell technology enables the induction of human somatic cells into pluripotent stem cells using small-molecule compounds, breaking through international technical patent blockades and monopolies.This technology avoids the risk of genetic mutations by eliminating the need for exogenous gene introduction. Meanwhile, small-molecule compounds are abundantly available, ensuring scalability for mass production while enhancing cellular stability and controllability.

In 2022, Hangzhou Reprogenix Bioscience, Inc., together with several renowned research institutions and universities, published a scientific paper titled “Human Pluripotent Stem Cell-derived Islets Ameliorate Diabetes in Nonhuman Primates,” detailing experimental advances and research findings on stem cell therapy for diabetes, in Nature Medicine.The first experimental study globally to evaluate the safety and efficacy of stem cell-derived islets in non-human primate models of diabetes.

The Route of Administration Is Critical to the Efficacy of Stem Cell Therapy. Traditional islet transplantation typically employs intrahepatic portal vein infusion. The slow blood flow in the portal vein allows transplanted islet cells to lodge and engraft within the hepatic sinusoids, thereby effectively increasing their local concentration and survival rate in vivo. Furthermore, compared with peripheral venous transplantation, this approach reduces the incidence of systemic adverse reactions.

However, this transplantation route is not the optimal choice for patients with diabetes. Patients with diabetes have impaired tissue repair capabilities, and transplantation via the hepatic portal vein may pose a high risk of hemorrhage and coagulation complications. Furthermore, an immediate inflammatory response occurs in the early stage of islet transplantation, leading to massive islet cell death; for diabetic patients, such adverse reactions can be life-threatening. Additionally, the transplanted islets are diffusely distributed throughout the liver, making them difficult to monitor and impossible to remove. If diabetic patients experience discomfort, the transplanted islet cells act like a "ticking time bomb," posing a potential threat to their health at any moment.

To this end, the team at Hangzhou Reprogenix Bioscience, Inc. decided to explore a new transplantation route to enable diabetic patients to safely receive stem cell therapy.After multiple attempts, the team concluded that islet cell transplantation beneath the anterior rectus sheath is safe and feasible.

The anterior rectus sheath is located in the anterior abdominal wall and forms a specific space with the aponeurotic edge of the rectus sheath and the internal oblique aponeurosis. Implanting islet cells into this defined space confines the graft to this location, enabling future monitoring and management via imaging modalities to ensure patient safety.

Furthermore, most critically, the vascular density in the anterior rectus sheath is relatively low; procedures in this region require only ultrasound guidance, thereby avoiding hemorrhage and coagulation risks during transplantation and ensuring greater safety.

Professor Gordon Weir, a renowned international expert in the field of diabetes research, spoke highly of this study, stating that the survival rate and function of the transplanted tissue at this site were impressive.

Currently, the IND application for “RGB-5088 Islet Cell Injection” has been accepted.We look forward to this technology smoothly entering clinical trials in the future, bringing hope for a cure to patients with type 1 diabetes in China.

In addition to its type 1 diabetes program, Hangzhou Reprogenix Bioscience, Inc. is simultaneously advancing a type 2 diabetes project. A senior executive at Hangzhou Reprogenix Bioscience stated, “Moving forward, the team will leverage its existing cell technology to gradually expand into the development of additional functional cell types, thereby providing therapeutic solutions for a broader range of complex and refractory diseases.”