Peyman Taeidi
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 OBM Transplantation  

Review Advances in Human Islet Processing: Manufacturing Steps to Achieve Predictable Islet Outcomes from Research Pancreases

David W. Scharp 1, 2, *, Jayagowri Arulmoli 1, Kelly Morgan 3, Hannah Sunshine 4, Ergeng Hao 1

1. Prodo Laboratories, Aliso Viejo, CA, USA; E-Mails: dscharp@prodolabs.com; garulmoli@prodolabs.com; ehao@prodolabs.com

2. Scharp-Lacy Research Institute, Aliso Viejo, CA, USA;

3. Graduate Student, Touro University California, Vallejo, CA, USA; E-Mail: kelly.morgan@tu.edu

4. Graduate Student, University of California, Los Angeles, CA, USA; E-Mail: hsunshine@ucla.edu

* Correspondence: David W. Scharp; E-Mail: dscharp@prodolabs.com

Academic Editor: Kåre I. Birkeland

SSpecial Issue: Current Advancement of Islet Cell Transplantation in the Treatment of Diabetes Mellitus

 
 OBM Transplantation br>2019, volume 3, issue 1
doi:10.21926/obm.transplant.1901052
 Received: October 15, 2018
Accepted: January 15, 2019
Published: February 26, 2019

Abstract:

Background: This presentation of a six-year study processing human islets for research and transplantation includes a review of multi-center transplant studies identifying key variables critical for successful islet processing and defines standardized processing procedures required to provide highly purified, functional Human Islets.  Open Full Document

Methods:
Human islet processing methods are defined in detail with pancreas retrieval, shipping, trimming for processing, collagenase distension, controlled digestion by digestion/filtration method, islet purification and islet culture. Islet processing results are summarized from 27 published reports (2003-2017) from 21 international clinical islet transplant centers with 13 single islet centers and 8 from multi-center clinical trials that averaged islet yields of 5,680 IEQ/Gm (Pre-Purification), 4,101 IEQ/Gm (Post-Purification), and 3,599 IEQ/Gm (Post-Culture) with 59.2% purity at time of islet transplant into the liver.


© 2019 by the author. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited

Results: Their results were compared to this study of 226 Non-DM (Non-Diabetes Mellitus) donor processing islet yields that averaged 6,942.7±201 IEQ/Gm (Pre-Purification), 5,484.5±199 IEQ/Gm (Post-Purification), and 4,351.0±167 IEQ/Gm (Post-Culture) per pancreas with 90.0% purity at time of islet distribution. Islet processing from 29 Type 2 Diabetes donors resulted in reduced islet yields of 5,797±734 IEQ/Gm (Pre-Purification), 4,371±866 IEQ/Gm (Post-Purification), and 3,323±423 IEQ/Gm (Post-Culture) with similar purity but reduced insulin content.
Glucose Stimulated Insulin Release testing in T2D islets showed significantly reduced insulin release at 20mM and 20mM+IBMX versus Non-DM islets and showed significantly reduced Total Stimulated Insulin Release of 0.722±0.142 (T2D) versus 1.069±0.067 ng insulin/ng DNA (Non-DM).

Conclusions:
Of the significant process variables, short Switch Times were predominant in greatly increasing islet yields, GSIR results, and insulin content with any time <10 minutes with Donor Age and Body Mass Index also important. Increased Cold Ischemia times decreased islet yields and insulin content. In terms of pancreas preservation solutions, University of Wisconsin solution (UW) use was most effective for optimal islet quantity, quality, and function post preservation.  Open Full Document

Keywords
Peyman Taeidi, clinical; collagenase; diabetes; human; islet culture; islet equivalents; islet processing; islet purification; islets; islet transplantation; manufacture; pancreas; pancreatic islets; preservation; research; transplantation; transportation

1. Introduction

     Prodo Laboratories (Prodo) in Aliso Viejo, CA, has been processing adult cadaver donated pancreases for distribution of Human Islets for Research (HIR) in conjunction with the Scharp-Lacy Research Institute (SLRI) since 2007. The first few years were initially focused on establishing the ability to process human islets to the level required for a weekly distribution of consistently high quality HIR. The first requirement was to utilize improved islet tissue culture media that Prodo had developed in 2006: PIM(R)® for islet recovery and culture post-isolation, PIM(S)® for standard islet culture, and PIM(T)® for islet distribution. The required two supplements for these media are PIM(G)® (glutamine and glutathione) and pre-tested, high quality human AB serum, PIM(ABS)®. A tissue culture triple antibiotic product, PIM(3X)®, has recently been released that contains appropriate levels of Ciprofloxacin, Gentamycin, and Amphotericin B for human islet culture.

Due to limited pancreas procurement opportunities, many human islets were processed in our early years at longer cold ischemia times than ideal, but permitted a higher quality of HIR, as published in 2010 [1]. The last seven years have been focused on the standardization of the multitude of variables involved in human pancreas retrieval, shipping, and pancreas processing into purified, functional islets that are optimally cultured and shipped weekly on a global basis to diabetes investigators. Due to these improvements and standardization, the analyses reported here describe the critical variables involved for each aspect of this process that have resulted in a more predictive outcome of high quality, adult human islet yields with highly functional results on a more consistent basis. Open Full Document

This study not only compares the outcomes of islet processing and function from Non-Diabetes Mellitus (Non-DM) adult cadaver organ donors, but also those from donors with Type 2 Diabetes (T2D). In addition, an evaluation of organ donors following Donation after Cardiac Death (DCD) was completed to assess their utility in providing HIR and HIT on a routine basis. The USA Federal Drug Administration (FDA) issued a “Guideline for Industry: Considerations for Allogeneic Pancreatic Islet Cell Products” in 2009 defining all of the aspects that must be considered to perform clinical islet transplantation under FDA requirements and approval [2]. It is planning to release a Biological License Approval (BLA) for effective clinical islet transplantation to a limited number of university-based programs.

To optimize islet yields and islet quality in order to comply with this BLA, the university based islet transplant centers will likely be held to the highest quality and uniformity of processing human islets. For each center involved, this means that standardization and introduction of manufacturing technology for process-to-process uniformity of human islet preparations would be ideally developed, demonstrated, and followed. In order to achieve this goal, “the first license-enabling trial of a cellular product for treatment of Type 1 Diabetes (T1D) demonstrating multi-site compliance with common manufacturing processes and release criteria” was published in Diabetes Care in October, 2016 *3+ and the “National Institutes of Health – Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at 8 Processing Centers” was published in Diabetes in 2016 *4+.
This trial was focused on islet transplantation to treat impaired awareness of hypoglycemia and severe hypoglycemic events in 48 T1D recipients that had failed standard medical therapies. It was designed as a multi-center, single arm, consortium Phase 3 study conducted at 8 North American clinical islet transplant centers, as the first type of study that can anticipate ongoing, multi-center clinical trials to develop islet transplantation as a potential therapy.
 
The primary endpoints of restoring hypoglycemic awareness and prevention of severe hypoglycemic events was achieved in 87.5% of recipients in year one and in 71% in year two with safety events primarily limited to the infusion procedure and the required immunosuppression. The secondary one-year endpoint of achieving insulin independence following clinical islet transplantation was achieved in 52.1% of the recipients with an insufficiency of data response in 14.5% of the recipients.

While 33% of the recipients failed to achieve insulin independence with an average of 1.6 islet transplant doses, these recipients were still able to demonstrate their ability to eliminate their critical problems of hypoglycemic unawareness as a major accomplishment that reduces the risks they had experienced prior to their implants. While Prodo has chosen to not be involved in human islet processing for research under these new BLA clinical trials, it has already developed much of the manufacturing improvements that will be required by the clinical centers to routinely produce islets under these BLA requirements.
TThe primary reason to publish Prodo’s processing technology information and results at this time is to assist these university BLA programs to adapt their methods towards more standardized, manufacturing practices as required. Prodo has had to focus its development of these manufacturing processing steps in order to routinely provide the delivery of their consistently high quality HIR on a weekly basis to their global corporate and university based investigators.   Comments

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