In what a September 26, 2024 Nature News commentary describes as a “world first,” type 1 diabetes (T1D) has reportedly been reversed in a woman by virtue of a transplant of chemically induced pluripotent stem-cell (CiPSC)-derived islet cells originally from her own body. The results of a one-year follow-up were published September 25, 2024 in Cell by a group led by scientists from the Chinese Academy of Medical Sciences. The Cell article is titled “Transplantation of Chemically Induced Pluripotent Stem-Cell-Derived Islets Under Abdominal Anterior Rectus Sheath in a Type 1 Diabetes Patient.” In the Nature News commentary, James Shapiro, a transplant surgeon and researcher at the University of Alberta in Edmonton, Canada, is quoted as saying that “the results of the surgery are stunning. They’ve completely reversed diabetes in the patient, who was requiring substantial amounts of insulin beforehand.”
The commentary continued to say that in June 2023, in an operation that lasted less than half an hour, the physicians injected the equivalent of roughly 1.5 million islets into the woman’s abdominal muscles — a new site for islet transplants. Most islet transplants are injected into the liver, where the cells cannot be observed. But by placing them in the abdomen, the researchers could monitor the cells using magnetic resonance imaging, and potentially remove them if needed. Two-and-a-half months later, the woman was producing enough insulin to live without needing top-ups, and she has sustained that level of production for more than a year. By that time, the woman had stopped experiencing the dangerous spikes and drops in blood glucose levels, which remained within a target range for more than 98% of the day. “That’s remarkable,” says Daisuke Yabe, a diabetes researcher at Kyoto University. “If this is applicable to other patients, it’s going to be wonderful.” Yabe was quoted in the commentary and was not involved in the study.
Study Participant Pre-Transplant
In their Cell article, the researchers described the study patient “as a 25-year-old woman who was diagnosed with T1D for 11 years (as of time of transplantation in 2023). Her weight was 75 kg, and her body mass index was 27.3 kg/m2. Her medical history included two liver transplantations due to cryptogenic cirrhosis in 2014 and 2016, respectively, and a whole pancreas transplantation in 2017 due to unstable glycemic control. The pancreas graft was removed after a year due to severe thrombotic complications. The patient was under regular immunosuppression for liver transplant maintenance.”
“Prior to enrollment, the patient’s plasma C-peptide levels were below the limit of detection (6.6 pmol/L) under both fasting and glucose-challenged conditions. Despite receiving intensive insulin treatment at a daily dose of 54 ± 0.9 units (mean ± SD) under the supervision of an endocrinologist, the patient was still not able to achieve target glycemic control. Her HbA1c level during the 2 years before enrollment was 7.40%–8.00%, higher than the American Diabetes Association (ADA)’s recommended target for T1D management (<7.0%).”
“Continuous glucose monitoring (CGM) measurements during the three months before transplantation showed severe glucose variability and endangerment by hypoglycemia, and the patient experienced 3 incidences of severe hypoglycemic events in the prior year.”
“Her fasting glucose fluctuated greatly, with an average value of 210 ± 59 mg/dL (mean ± SD). Her time in the target glucose range (TIR) was 43.18% (the ADA target is >70%) during the 3 months prior to the transplantation, and her time in the very low range of blood glucose (<54 mg/dL) was 2.01% (the ADA target is <1%).”
The researchers said that “these data indicated that intensive insulin therapy was insufficient for achieving adequate glycemic control. The patient’s clinical presentation, including glycemic lability, b cell depletion, and hypoglycemia, aligned with the indications for clinical islet transplantation.”
Transplantation & Follow-Up
The authors reported autologous transplantation of CiPSC-islets in this patient with type 1 diabetes (T1D). As noted, “before transplantation, the patient suffered from long-term, hard-to-control diabetes complicated by episodes of severe hypoglycemia. After CiPSC-islet transplantation, the patient achieved insulin independence within 3 months post-trans-plantation, ultimately achieving over 98% blood glucose time in target range (TIR) without exogenous insulin use. These findings supported the viability of CiPSC-islet transplantation underneath the abdominal anterior rectus sheath, which led to relatively rapid restoration of insulin-independent glycemic control in the patient.”
“This report demonstrates attainment of insulin-independent glycemic control in the patient, as seen by a blood glucose TIR of over 98% after month 4 post-transplantation and decrease in HbA1c to a non-diabetic level. Previous studies have shown that increased TIR reduces the hazard ratio for complications, while each 1% reduction of HbA1c toward the physiological level has been associated with a 21% reduction in risk of diabetes-related complications and death. Importantly, a crucial clinical benefit of islet transplantation is the protection from severe hypoglycemic events, which is a predominantly life-threatening condition and a source of fear and distress in T1D patients. No occurrence of severe hypo-glycemic events was observed throughout 1-year follow-up after CiPSC-islet transplantation. Taken together, the findings suggest a positive impact on the metabolic outcomes of the patient using this treatment approach.”
Site of Transplant
“This report describes for the first time the use of stem-cell-derived islet transplantation underneath the abdominal anterior rectus sheath in human. Alternative islet transplantation sites have been reported over the years, including the omentum and intramuscular site in the forearm; however, clear improvements over the conventional intraportal site have not been well demonstrated. The positive metabolic data seen in this clinical study are consistent with that seen in our preclinical study in nonhuman primates, in which we sought to identify an optimal transplant site for CiPSC-islets. We compared the transplantation of hPSC-islets underneath the abdominal anterior rectus sheath and an intramuscular and subcutaneous site in nonhuman primates and found the anterior rectus sheath to be beneficial in supporting the engraftment, vascularization, and functional maturation of the PSC-islets, resulting in markedly increased C-peptide secretion when compared with intrahepatic transplantation. Other important advantages of this transplant site include the circumvention of graft loss from IBMIR. These findings suggest that the favorable engraftment microenvironment at this site may be an underlying factor to the robust C-peptide secretion and relatively rapid reversal of diabetes observed in the patient.”
“In comparison to intraportal transplantation, the abdominal rectus sheath site also encompasses other safety considerations, such as ease of access for transplantation and imaging and site retention of graft. After CiPSC-islet transplantation into the patient, we demonstrate that the graft could be routinely imaged by ultrasound and MRI as necessary for regular detection of morphological changes at the site. The possibility for routine safety monitoring at this transplant site is an important step forward that is critical to exploratory stem-cell-based cellular therapies. Importantly, transplantation to this site supports graft retrieval if necessary. Taken together with our preclinical studies, the clinical data in this report support the clinical value of this transplantation strategy, warranting continued exploration.”
Autologous Chemically Induced Stem-Cell-Derived Islets
“The patient in this study suffered from hard-to-control diabetes despite intensive insulin treatment. To improve glycemic control, the patient had previously received a pancreas transplantation in 2017, which had to be removed a year later due to thrombotic complications. However, on account of her PRA-positive status, an allogeneic pancreas or islet transplant would be at high risk for rejection, making the opportunity for an autologous transplant for this patient a valuable treatment option.”
“CiPSCs possess characteristics that are potentially advantageous to the clinical manufacture of autologous stem cells. The small molecules used in the chemical reprogramming approach offer ease of manufacture and standardization and are highly controllable, scalable, and cost-effective, which are important for standardized manufacturing of therapeutic cells. In addition, potential benefits of CiPSCs in comparison to transcription factor-reprogrammed iPSCs have been demonstrated in studies analyzing mouse CiPSCs, which demonstrated potential improvements in genomic stability and closer epigenetic features to embryonic stem cells. While further evaluation is required, these findings suggest potential advantages of CiPSCs for clinical applications.”
“In this study, good-manufacturing-practice-compliant manufacture of personalized CiPSC-islets for autologous transplantation was conducted, allowing for the first report of clinical transplantation of CiPSC-derived cells. Taken together, these findings indicate the feasibility of chemically induced autologous PSCs for cell therapy, constituting a viable personalized medicine strategy.”
“Taken together, this study reports positive clinical data in this patient after CiPSC-islet transplantation, as well as the realization of routine, non-invasive graft monitoring underneath the abdominal anterior rectus sheath. Overall, the findings support further clinical studies in this direction and mark a step forward in achieving the potential of personalized cell therapy using CiPSCs to treat disease.”
Summary
In their Cell article summary, the authors write: “We report the 1-year results from one patient as the preliminary analysis of a first-in-human phase I clinical trial (ChiCTR2300072200) assessing the feasibility of autologous transplantation of chemically induced pluripotent stem-cell-derived islets (CiPSC islets) beneath the abdominal anterior rectus sheath for type 1 diabetes treatment. The patient achieved sustained insulin independence starting 75 days post-transplantation. The patient’s time-in-target glycemic range increased from a baseline value of 43.18% to 96.21% by month 4 post-transplantation, accompanied by a decrease in glycated hemoglobin, an indicator of long-term systemic glucose levels at a non-diabetic level. Thereafter, the patient presented a state of stable glycemic control, with time-in-target glycemic range at >98% and glycated hemoglobin at around 5%. At 1 year, the clinical data met all study endpoints with no indication of transplant-related abnormalities. Promising results from this patient suggest that further clinical studies assessing CiPSC-islet transplantation in type 1 diabetes are warranted.”
Highlights of the Cell article were noted as follow:
–Patient-derived islets were generated with chemically induced pluripotent stem cells.
–Transplantation of these islets to an abdominal site led to engraftment in one patient.
–Exogenous insulin-independent glycemic control was restored in the patient.
–All safety and efficacy clinical endpoints were met at 1-year follow-up of the patient.