Pancreatic Cell Implants for Type 1 Diabetes (SUGR Trial)
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Seraxis
No Placebo Group
Trial Summary
What is the purpose of this trial?This study will evaluate the safety, efficacy and durability of SR-02 administered to the omentum of patients of Type 1 diabetes with severe recurrent hypoglycemia. The study will also help establish the optimal treatment dose. Although this study is open to patients with all HLA or blood types, immunosuppression to prevent rejection will be required in this first in human study.
How does the treatment of Allogeneic Pancreatic Endocrine Cell Clusters for Type 1 Diabetes differ from other treatments?
This treatment is unique because it uses 'Neo-Islets', which are 3-D organoids made from mesenchymal stromal and islet cells, to restore insulin production without the need for anti-rejection drugs. Unlike traditional pancreas or islet transplants, this approach is designed to be immune-protected and can potentially provide a long-term solution for Type 1 Diabetes by normalizing blood sugar levels.
1791213What data supports the effectiveness of the treatment Allogeneic Pancreatic Endocrine Cell Clusters for Type 1 Diabetes?
Research shows that similar treatments, like islet transplantation, have improved metabolic control and reduced severe low blood sugar episodes in patients with Type 1 Diabetes. Additionally, studies on 'Neo-Islets' in animals have shown promising results in maintaining normal blood sugar levels without the need for anti-rejection drugs.
2561013Will I have to stop taking my current medications?
The trial requires that you have not used any anti-diabetic medications other than insulin in the last 3 months, so you may need to stop those if you are taking them. The protocol does not specify about other medications, so it's best to discuss with the trial team.
Is the pancreatic cell implant treatment safe for humans?
Pancreatic cell implants, also known as allogeneic pancreatic islet transplants, have been reviewed by the FDA and are considered a standard treatment for type 1 diabetes in several countries. While there are challenges in manufacturing and licensing, the treatment has shown promising results in clinical trials, and procedure-related risks are being refined.
346811Eligibility Criteria
This trial is for individuals with Type 1 diabetes who frequently experience severe low blood sugar episodes. Participants must be willing to undergo immunosuppression therapy to prevent their body from rejecting the treatment.Inclusion Criteria
I am willing to use a device to monitor my blood sugar levels continuously.
I am between 18 and 65 years old and have been diagnosed with Type 1 Diabetes.
I was diagnosed with Type 1 Diabetes before turning 40.
I have been dependent on insulin for 5 or more years.
I frequently experience severe low blood sugar.
Exclusion Criteria
I haven't taken diabetes medication other than insulin in the last 3 months.
I have not taken weight loss medications in the last 3 months.
Participant Groups
The study tests the safety and effectiveness of implanting pancreatic endocrine cell clusters into the omentum (a part of the abdomen) in patients with Type 1 diabetes, aiming to find the best dose.
1Treatment groups
Experimental Treatment
Group I: SR-02 Allogeneic pancreatic endocrine cell clustersExperimental Treatment1 Intervention
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
University of PennsylvaniaPhiladelphia, PA
UPMC Presbyterian ShadysidePittsburgh, PA
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Who is running the clinical trial?
SeraxisLead Sponsor
References
Histologic differentiation of human fetal pancreatic explants transplanted into nude mice. [2019]The transplantation of human fetal pancreas has been suggested as a means of treatment of insulin-dependent diabetes in man. We have obtained human fetal pancreata during the second trimester of pregnancy and transplanted 1-mm3 explants subcutaneously (s.c.) into both diabetic and nondiabetic nude mice, some of the tissue being cultured in vitro before implantation. These implants coalesced and grew. They were removed at intervals up to 37 wk later and showed selective differentiation of endocrine tissue that normally occurs in the fetus and neonate, with formation of bipolar, mantle, and mature islets. There was growth of this endocrine tissue with significantly more islets than in the freshly stained fetal pancreas assuming an average dimension larger than 150 micron, which is the reported mean diameter of a neonatal islet. Duct and fibrous tissue remained viable, but there was no definitive acinar tissue seen. The pancreata uncultured before implantation reached a larger size than that attained by those implants cultured before being transplanted, the difference probably being the amount of ductular and mesenchymal tissue still present. Of those glands cultured before transplantation, the longer the period of culture, the smaller the size the implants reached. Culture beyond 3 wk in vitro made it difficult to macroscopically locate the implant. These data show that, in human fetal pancreas removed from its usual environment, both selective differentiation of the endocrine component and growth of the islets can occur.
Transplantation of dispersed pancreatic islet tissue in humans: autografts and allografts. [2019]Islet transplantation is successful in animals and holds considerable promise as endocrine replacement therapy for patients with diabetes mellitus, but clinical application to diabetic patients has been difficult. We have shown the technical feasibility of human islet transplantation by autotransplantation of dispersed pancreatic islet tissue into the portal vein in three patients with chronic pancreatitis and incapacitating, intractable pain who underwent near-total (greater than 97%) pancreatectomy. In all three patients, the excised pancreas was dispersed by collagenase digestion, but no effort was made to purify the islets. Islet yield, as judged by tissue insulin content, ranged from 24 to 55%. The first patient, who never received insulin after the pancreatectomy and islet autotransplantation, had a normal oral glucose tolerance test by 3 wk and has remained normoglycemic for over 2 yr. In the second patient, viable islets were histologically identified in the liver parenchyma. The third patient was treated with hyperalimentation for 3 wk after the pancreatectomy and islet autotransplantation and, during this period, required insulin. After cessation of hyperalimentation and initiation of oral geedings, the patient was withdrawn from insulin. Although abnormalities of carbohydrate metabolism were present, the patient did not require insulin for more than 1 yr. Seven diabetic renal allograft recipients have received allografts of dispersed pancreatic islet tissue prepared in the same way. No patients were cured of diabetes, although transient evidence of islet function--increase in serum or urinary C-peptide levels or decrease in exogenous insulin requirements--occurred in some. Although rejection was probably responsible for most of the failures, transplantation of allogeneic human islet tissue as a free graft is metabolically inefficient. With the current state of immunosuppressive therapy, the primary role of islet transplantation may be in a situation where rejection cannot occur: as an autograft to obviate the occurrence of diabetes after extensive pancreatectomy for benign disease.
Islet transplantation: current status and future directions. [2021]Pancreatic islet transplantation has gone a long way to finally enter the armamentarium of today's clinicians for the battle against diabetes. The proof of principle has been made and current clinical islet transplant trials need to further refine this attractive treatment modality. We review the post-Edmonton era, the selection of islet transplant recipients, the production of islet grafts, and the need for immunosuppression and procedure-related risks. The success of islet transplantation and expansion of clinical trials with islet networks are also discussed.
Update on regulatory issues in pancreatic islet transplantation. [2019]Over the past 12 years, the US Food and Drug Administration (FDA) has reviewed more than 40 investigational new drug applications for the use of allogeneic pancreatic islets to treat type 1 diabetes mellitus. Recent advances in islet cell isolation, transplantation, and immunosuppressive maintenance have led to multiple centers reporting promising results in the treatment of type 1 diabetes with allogeneic islet cells. The FDA held an advisory committee meeting on October 9-10, 2003, to explore the potential for licensing allogeneic islets as a therapy for severe type 1 diabetes. This article highlights the manufacturing challenges, discussed by the FDA advisory committee, that remain to be resolved before allogeneic islets can be approved for treatment of type 1 diabetes. This article also briefly addresses the challenges facing the clinical trial design of studies that could be used to support licensure.
Transplantation: current developments and future directions; the future of clinical islet transplantation as a cure for diabetes. [2019]Islet transplantation is now a therapeutic option for patients with unstable type 1 diabetes mellitus (T1DM) with hypoglycemic unawareness. The benefits of this treatment include improvement in metabolic control with normalization of A1c and prevention of severe hypoglycemia. Insulin independence and improved quality of life can be reproducibly obtained by transplanting adequate islet numbers. Current obstacles to the widespread application of beta-cell replacement therapies include limited islet availability and the need for chronic immunosuppression. The emergence of promising interventions may be of assistance in improving islet recovery and favoring engraftment of smaller islet masses with comparable or better efficacy. In the future, regenerative efforts will contribute to overcoming this limitation as well. Combining these approaches with the development of safe immune interventions to induce self tolerance or to induce the permanent acceptance of transplanted tissues will be necessary to achieve long-term success. The steady progress and promising results of recent clinical trials justifies a great optimism toward the widespread application of beta-cell replacement as a treatment of choice for patients with diabetes.
Long-term metabolic and immunological follow-up of nonimmunosuppressed patients with type 1 diabetes treated with microencapsulated islet allografts: four cases. [2022]To assess long-term metabolic and immunological follow-up of microencapsulated human islet allografts in nonimmunosuppressed patients with type 1 diabetes (T1DM).
Engraftment of insulin-producing cells from porcine islets in non-immune-suppressed rats or nonhuman primates transplanted previously with embryonic pig pancreas. [2021]Transplantation therapy for diabetes is limited by unavailability of donor organs and outcomes complicated by immunosuppressive drug toxicity. Xenotransplantation is a strategy to overcome supply problems. Implantation of tissue obtained early during embryogenesis is a way to reduce transplant immunogenicity. Insulin-producing cells originating from embryonic pig pancreas obtained very early following pancreatic primordium formation (embryonic day 28 (E28)) engraft long-term in non-immune, suppressed diabetic rats or rhesus macaques. Morphologically, similar cells originating from adult porcine islets of Langerhans (islets) engraft in non-immune-suppressed rats or rhesus macaques previously transplanted with E28 pig pancreatic primordia. Our data are consistent with induction of tolerance to an endocrine cell component of porcine islets induced by previous transplantation of embryonic pig pancreas, a novel finding we designate organogenetic tolerance. The potential exists for its use to enable the use of pigs as islet cell donors for humans with no immune suppression requirement.
Islet cell transplant not justified. [2016]Transplantation of pancreatic islet cells is feasible but widespread clinical trials cannot be justified at present.
Transplantation of Human Pancreatic Endoderm Cells Reverses Diabetes Post Transplantation in a Prevascularized Subcutaneous Site. [2018]Beta-cell replacement therapy is an effective means to restore glucose homeostasis in select humans with autoimmune diabetes. The scarcity of "healthy" human donor pancreata restricts the broader application of this effective curative therapy. "β-Like" cells derived from human embryonic stem cells (hESC), with the capacity to secrete insulin in a glucose-regulated manner, have been developed in vitro, with limitless capacity for expansion. Here we report long-term diabetes correction in mice transplanted with hESC-derived pancreatic endoderm cells (PECs) in a prevascularized subcutaneous site. This advancement mitigates chronic foreign-body response, utilizes a device- and growth factor-free approach, facilitates in vivo differentiation of PECs into glucose-responsive insulin-producing cells, and reliably restores glycemic control. Basal and stimulated human C-peptide secretion was detected throughout the study, which was abolished upon graft removal. Recipient mice demonstrated physiological clearance of glucose in response to metabolic challenge and safely retrieved grafts contained viable glucose regulatory cells.
Islet transplantation 30 years after the first transplants. [2019]First clinical islet allotransplantation in patients affected by type 1 diabetes mellitus was performed about 30 years ago. Despite the progressive improvement of the success rate, the clinical indication to the islet allotransplantation remains limited to selected patients affected by brittle type 1 diabetes mellitus. The burden of the immunosuppression therapy still represents the main critical issue but other areas might be subject to further improvements, such as the islet production, islet engraftment and long-term function. Several strategies have been proposed to increase the success rate of pancreas digestion and islet purification or to facilitate islet engraftment by reducing islet hypoxia and the inflammatory reaction occurring in the site of transplantation. The co-transplantation of progenitors of beta cell together with the islets has expected to contribute to prolong graft function. Clinical trials are expected soon. Scientific advances, as well as economical efforts, are required to make this procedure a real therapeutical option for patients with type 1 diabetes mellitus.
US food and drug administration (FDA) panel endorses islet cell treatment for type 1 diabetes: A pyrrhic victory? [2021]Allogeneic islet transplantation is a standard of care treatment for patients with labile type 1 diabetes in many countries around the world, including Japan, the United Kingdom, Australia, much of continental Europe, and parts of Canada. The United States is now endorsing islet cell treatment for type 1 diabetes, but the FDA has chosen to consider islets as a biologic that requires licensure, making the universal implementation of the procedure in the clinic very challenging and opening the manufacture of islet grafts to private companies. The commercialization of human tissues raises significant legal and ethical issues and ironically leads to a situation where treatments developed as a result of the scientific and economic efforts of academia over several decades become exploited exclusively by for-profit entities.
Intraperitoneal administration of human "Neo-Islets", 3-D organoids of mesenchymal stromal and pancreatic islet cells, normalizes blood glucose levels in streptozotocin-diabetic NOD/SCID mice: Significance for clinical trials. [2021]Globally, individuals with autoimmune Type 1 diabetes mellitus (T1DM) continue to depend for survival on insulin injections. While pancreas and intrahepatic pancreatic islet transplants can produce insulin-independence and ameliorate serious complications, both therapies depend on potentially toxic anti-rejection drugs. Furthermore, the scarcity of pancreas donors and islet transplant failures limit the general availability of such interventions. Recently, fetal and induced Pluripotent Stem Cells have been successfully differentiated to generate insulin producing β-like cells that generate euglycemia in diabetic mice. However, their clinical use still depends on anti-rejection drugs or immune-isolating encapsulation systems. We reported recently that allogeneic "Neo-Islets" (NI), 3-D organoids of Mesenchymal Stromal and Islet Cells are immune protected and permanently correct autoimmune diabetes in NOD mice by omental engraftment and endocrine cell redifferentiation. This new "endocrine pancreas" delivers islet hormones physiologically into the hepatic portal vein. Furthermore, treatment of insulin-dependent dogs with allogeneic canine NIs (ongoing FDA-approved Pilot Study) consistently improved glycemic control without the need for antirejection drugs. As there remains a critical need for curative therapies of T1DM, we engineered human NIs and tested their ability, after i.p. administration, to reestablish euglycemia in streptozotocin (STZ)-diabetic NOD/SCID mice. This diabetes model reproduces, in part, the clinical situation in which recipients of allogeneic biotherapies must take potent anti-rejection drugs that similarly create a life-long immune-compromised status. The present study demonstrates that human NI therapy (2x10e5/kg bw NIs/mouse) of STZ-diabetic NOD/SCID mice (n = 6), compared to controls (n = 6) significantly improved glycemic control, and most importantly, that a second dose given to the initial group normalized blood glucose levels long-term. Conclusion: Despite the limitations of the utilized diabetic NOD/SCID mouse model, the obtained data show that human NIs are curative, an observation that has high translational relevance and significantly supports the planned conduct of clinical trials with human NIs.
Significant expansion of the donor pool achieved by utilizing islets of variable quality in the production of allogeneic "Neo-Islets", 3-D organoids of Mesenchymal Stromal and islet cells, a novel immune-isolating biotherapy for Type I Diabetes. [2023]Novel biotherapies for Type 1 Diabetes that provide a significantly expanded donor pool and that deliver all islet hormones without requiring anti-rejection drugs are urgently needed. Scoring systems have improved islet allotransplantation outcomes, but their use may potentially result in the waste of valuable cells for novel therapies. To address these issues, we created "Neo-Islets" (NIs), islet-sized organoids, by co-culturing in ultralow adhesion flasks culture-expanded islet (ICs) and Mesenchymal Stromal Cells (MSCs) (x 24 hrs, 1:1 ratio). The MSCs exert powerful immune- and cyto-protective, anti-inflammatory, proangiogenic, and other beneficial actions in NIs. The robust in vitro expansion of all islet hormone-producing cells is coupled to their expected progressive de-differentiation mediated by serum-induced cell cycle entry and Epithelial-Mesenchymal Transition (EMT). Re-differentiation in vivo of the ICs and resumption of their physiological functions occurs by reversal of EMT and serum withdrawal-induced exit from the cell cycle. Accordingly, we reported that allogeneic, i.p.-administered NIs engraft in the omentum, increase Treg numbers and reestablish permanent normoglycemia in autoimmune diabetic NOD mice without immunosuppression. Our FDA-guided pilot study (INAD 012-0776) in insulin-dependent pet dogs showed similar responses, and both human- and canine-NIs established normoglycemia in STZ-diabetic NOD/SCID mice even though the utilized islets would be scored as unsuitable for transplantation. The present study further demonstrates that islet gene expression profiles (α, β, γ, δ) in human "non-clinical grade" islets obtained from diverse, non-diabetic human and canine donors (n = 6 each) closely correlate with population doublings, and the in vivo re-differentiation of endocrine islet cells clearly corresponds with the reestablishment of euglycemia in diabetic mice. Conclusion: human-NIs created from diverse, "non-clinical grade" donors have the potential to greatly expand patient access to this curative therapy of T1DM, facilitated by the efficient in vitro expansion of ICs that can produce ~ 270 therapeutic NI doses per donor for 70 kg recipients.