Objective
ARMI will leverage a new SC-islet request system, an automated SC-islet production system and SC-islet distribution that has already undergone proof of concept evaluation, to supply BT1D researchers with sufficient numbers of consistent SC-islets to address the challenges remaining with the use of SC-islets for a T1D treatment or for screening drugs that will be beneficial for this procedure.
Background Rationale
A critical barrier to the development of a cell replacement therapy for Type 1 Diabetes is the lack of a consistent source of cells with which to answer important research questions. At the moment, individual laboratories are largely responsible for generating their own cells, which is time consuming, costly and results in highly variable cells lab-to-lab. A consistent source of cells would allow researchers to focus on the challenges associated with the application of the cells as a therapy or for drug screening without having to fabricate the cells themselves and would improve inter-lab data comparisons.
To overcome this important and fundamental barrier, ARMI collaborated with Jeffrey Millman’s research group at Washington University in Saint Louis under 2-PAR-2020-979-S-B to scale up and automate the production of pancreatic islet-like clusters derived from pluripotent stem cells (SC-islets). Dr Millman’s group had been producing SC-islets routinely in small scale culture and showed that these cells exhibit the hallmarks of bone fide human donor islets, including the composition of their cells, a first and second phase insulin secretion profile that occurs in response to high glucose stimulation, and blood glucose control after implantation into diabetic mice.
To prototype a manufacturing system to automate the production of large numbers of SC-islets, ARMI first scaled up the Millman protocol from roughly 150 cm2 to >3000 cm2 culture surface area using multilayer culture vessels and scaled up the aggregation of SC-islet clusters from cell suspensions by transitioning the process from multi-well plates to a vertical wheel bioreactor. The system was operated in a contained and controlled environment to mitigate the risk of SC-islet contamination.
ARMI recently completed grant 2-PAR-2020-979-S-B by distributing approximately 300 million SC-islet cells to three independent and remote sites across the U.S., including San Francisco, CA, West Lafayette, IN and Miami, FL who confirmed their functionality after transplantation into diabetic models of diabetes in rodents.
Description of Project
Pancreatic islets from deceased donors can restore blood glucose control after transplantation into patients suffering from Type 1 Diabetes (T1D). However, there aren’t enough donor islets from cadaveric pancreata to treat the number of patients with T1D that would benefit from this procedure. Functional islet-like clusters derived from stem cells (SC-islets) can be generated in cell culture in abundance and have been shown in recent early phase clinical studies to restore blood glucose control. Therefore SC-islets present a promising new therapy for the treatment of T1D.
Although ongoing clinical studies have demonstrated their efficacy, several challenges related to the formulation, method and route of administration, evading immune system attack and preserving SC-islets for shelf stability and transport remain to be addressed. Addressing these challenges will require a consistent supply of SC-islets for researchers.
Generating SC-islets by laboratories specializing in stem cell differentiation has been routine for several years. However, insufficient scale of production of SC-islets has limited their widespread distribution and consistency within and between labs has limited the ability of researchers across laboratories to compare results.
Therefore, ARMI adapted a SC-islet fabrication protocol developed in Jeffrey Millman’s laboratory at Washington University to a scalable, automated manufacturing system to increase their yield and decrease their variability. ARMI demonstrated the production of SC-islets on its automated manufacturing system, tested their quality against strict quality control specifications provided by the Millman lab, and tested the feasibility of their distribution by shipping a production batch from its facility in New Hampshire to three laboratories in Florida, Indiana and California for implantation into a mouse model of diabetes. The SC-islets restored blood glucose control in the transplanted mice in each of the 3 labs. ARMI is now in a position to supply BT1D researchers with sufficient numbers of consistent SC-islets, generated from a single protocol on an automated system, with which to tackle the remaining challenges associated with using SC-islets as a treatment for T1D.
ARMI proposes to form a Scientific Advisory Committee (SAC) to advise it on ongoing production batches and challenges, to deploy an online SC-islet request system, to replace one of the prototype modules of the manufacturing system with an identical, but more robust module, and to test a new SC-islet shipping method by performing a second implantation study before production batches are shipped. Production will be tracked by an appropriate electronic/digital quality management system. ARMI will initially ship 4-5 production batches annually, which will facilitate at least 15 studies, and will scale up production as needed.
Anticipated Outcome
In the short-term, we will generate enough cells to supply at least 15 SC-islet studies annually. With additional automated manufacturing systems, we would be able to quadruple the output of cells. We will characterize each batch of SC-islets fully and will maintain a complete electronic record of the final disposition of SC-islets so that laboratories receiving cells from the same batch and between batches will be able to compare information and potentially learn from each other. The quality control infrastructure that we will put in place for these cells will also lay the foundation for QC for clinical and commercial products. We will improve the ability of laboratories studying SC-islet function in the laboratory and in animal models of diabetes by removing the variability associated with individual SC-islet batches in disparate labs.
Relevance to T1D
Industry is beginning to demonstrate the positive effects of SC-islets as a treatment for T1D. However, there are still challenges associated with formulation, method and route of administration, evading immune system attack and preserving SC-islets for shelf stability and transport that need to be investigated. By alleviating the need for individual researchers to generate their own SC-islets, we will allow them to focus on these remaining challenges associated with using SC-islets as a treatment of for screening new drugs as a treatment for T1D.