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Diabetes Reversing Implants with enhanced Viability and long-term Efficacy

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

Diabetes is a disease characterised by high blood sugar due to a shortage of insulin, that affects 415 million people worldwide. Pancreatic islet transplant is an extremely promising therapy, with the potential to cure insulin-dependent diabetes. Transplant of insulin-producing cells restores natural control of blood sugar, eliminating the need for insulin, blood glucose monitoring and the risk of dangerous hypoglycaemic (low blood sugar) episodes, all of which greatly affects diabetes patients’ quality of life. Islet transplant involves purifying islets from donor pancreases and infusing them into the patient’s liver. Limitations of the therapy include:

(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
M1-18: Development and testing the β-gel, β-shell, and β-cath; Design of the drug delivery systems for the sustained local delivery of immunosuppressants. Dose-response studies have been performed with human islets; Development of a protocol for islet harvesting with bio-engineered collagenases in rodents and human. Investigation of Induced Pluripotent Stem Cells (iPSC) derived islets. First Patient Panel
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
all the beneficiaries benefited from networking and collaborations. In particular, the transdisciplinary dialogue between academia, industry and medical determined DRIVE course of action.
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.
the DRIVE logo
DRIVE's Beta-Gel: an injectible support matrix to enhance pancreatic islet transplantation
The DRIVE Consortium at the 12 Month General Assembly in Venice, Italy