Periodic Reporting for period 3 - DRIVE (Diabetes Reversing Implants with enhanced Viability and long-term Efficacy)
Reporting period: 2018-06-01 to 2019-05-31
(1) poor survival and engraftment of transplanted islets
(2) shortage of donor pancreases
(3) need for lifelong immune suppressive therapy
DRIVE developed a system (β-system) to treat severe cases of Type 1 Diabetes, by implanting a bioartificial pancreas via a minimally-invasive surgical procedure. The β-system has three main componets: a macroencapsulation device (β-shell), a biocompatible hydrogel loaded with insulin-producing cells (β-gel), and a delivery system (β-cath). The β-system still requires pre-clinical validation but showed promising results in small animal models. Some of the beneficiaries are committed to continued development towards First-in-Man Clinical Trials. DRIVE produced several results in the pursuit of the β-system, which are in a separate section. In addition to the results, more conclusions can be drawn from the research activities:
• The β-system can restore normoglycemia in a preclinical model of diabetes
• β-shells have been successfully implanted in small and large preclinical models, which responded well to the implant
• Silicone and Chronoflex implantable devices allow for a better oxygen transfer, compared to PTFE
• Additive manufacturing can generate irregular surfaces that enhance integration and vascularisation in implantable devices
• The TAP is the leading candidate implant site, due to ease of access and size of potential space
• Native HA hydrogels are a viable matrix to support implantation of live and functional cells. Addition of PFD enhances the viability of the cells through oxygen delivery
• Bioactive VEGF can be successfully linked to microspheres for controlled-release
• It is possible to produce room-temperature stable VEGF out of bacterial cultures
• Collagen from R.pulmo is a viable matrix for islet preservation
• Differentiation of iPSCs into insulin-producing cells that have the ability to respond to a glucose-challenge. Nidogen-1 seems to be instrumental for the functionality of the cells
M19-36: Continued development of the the β-gel, β-shell, and β-caths; Native Hyaluronic Acid selected as lead hydrogel; Developed a scalable preparation protocol for a β-Gel unction of the islets; Studied the effect of Nidogen 1, Tacrolimus and Entanercept on the morphological and functional integrity of islets; Successful differentiation of iPSCs into insulin producing cells. Tefined the manufacturing process for the β-Shells; Developed Vascular Endothelial Growth Factor (VEGF)-loaded microspheres to facilitate vascularization of the B-Shell. Developed a system for production of room-temperature-stable VEGF. Small and Large animal trials commenced. Diabetic rat and pig models developed using Streptozotocin. Evaluation of three different implantation sites. Patient panel
M48: DRIVE generated 27 exploitable results:
01 - Chronoflex macroencapsulation device (β-shell) - exploted for research in DELIVER (812865), licensing out
02- Ropecoil macroencapsulation device (β-shell) - licensing out
03 - NUIG Macroencapsulation device(β-shell) - continue R&D with a spinoff
04 - Oxygel (β-gel) - continue R&D with a spinoff
05 - Application of Nidogen-1 for gel biofunctionalization - licensing out, continue r&D with a spinoff
06 - rHU VEGF - licensing out
07 - Multidimensional Chromatography - commercialised
08 - Formulation of VEGF + Microspheres - licensing out
09 - Delivery device I (β-cath) - licensing out
10 - Delivery device II (β-cath) - licensing out
11 - Delivery device III (β-cath) - continue R&D with a spinoff
12 - Diabetes Model (rat) - commercialised
13 - Diabetes Model (pig) - commercialised
14 - in-vitro Test System - licensing out
15 - Pancreas on-a-chip - licensing out
16 - Culturing of INS-1E spheroids - offered as service
17 - Glucose-responsive pseudo-islets - offered as service
18 - Encapsulation of pseudo-islets in 3D matrices - offered as service
19 - Oxygen diffusion model - licensing out
20 - Patent mining software - commercialised
21 - O-fold procedure - offered as service
22 - Preperitoneal procedure - offered as service
23 - TAP procedure - commercialised
24 - Extraction of pancreatic islets (rat and mouse) - offered as service
25 - Extraction of collagen - offered as service
26 - Immunoprotective Valve - licensing out
27 - Additive manufacturing technique - licensing out
DRIVE produced 8 peer-reviewed papers, and disseminated its result at ca.30 relevant scientific gatherings
The results ar have an economic impact on their owner:
• 6 results protected by patent (patent application submitted during DRIVE)
• 3 results in process of being protected (Invention Disclosure Form completed DRIVE)
• 2 results protected by Copyright
• 17 results kept as confidential Know-How
eight results (services) reached a TRL level of 8 or beyond: Three of those are currently being marketed by the respective owners. One partner has generated ca. 9000 € of income in using the foreground resulting from DRIVE, before the end of the project
Additional impacts are:
• Differentiation of iPSCs to insulin-producing cells will eventually reduce the reliance on donors for islet transplant
• The in-vitro test system and pancreas-on-a-chip developed in DRIVE are viable alternatives to animal testing
DRIVE contributed spreading information on diabetes treatment through a number of activities for the general public, people with diabetes, students and caregivers. Most relevant where three patient panels organised (Dublin, Milan, Vitoria).
The β-system must to undergo clinical validation before it can have a quantifiable impact. The foreseen impact is to
a) eliminate hypo/hyperglycaemia hospitalisation for 5 years;
b) eliminate mealtime bolusing (insulin-dependence) for 5 years;
c) have a complication rate < 1%
The majority of T1D patients undergo insulin therapy for the rest of their life, although they might be eligible for transplant. Insulin therapy in the USA costs about $ 7’900 per year. Therefore, a successful graft with the β-system would save the healthcare system at least 40000 $ per patient in insulin therapy.