WORLD CONGRESS OF THE THREE UNITED SCIENTIFIC SOCIETIES IPITA (International Pancreas and Islet Transplantation Association), IXA (International Xenotransplantation Association), and CTRMS (Cell Transplantation and Regenerative Medicine Society) ON THE NEW FRONTIERS OF RESEARCH ON CELLULAR AND MOLECULAR THERAPY FOR TYPE 1 DIABETES MELLITUS AND OTHER CHRONIC DISEASES, SAN DIEGO, U.S.A., October 26-29, 2023.
Just a few days ago, a large and important world congress was held in San Diego (USA), where the three International Scientific Societies, IPITA, IXA, and CTRMS, gathered. This unique event oversees all research and related clinical applications in the field of cellular and molecular therapy for type 1 diabetes mellitus (T1D) and other chronic and degenerative diseases.
The three scientific societies decided to organize a joint congress in the post-COVID era to communicate the scientific and technical progress of research after the pandemic years, including new experimental therapies for specific morbid conditions. Over four full days of work, the covered topics included organ and tissue transplantation, both normal and biohybrid, the description of various cell types, including state-of-the-art stem cells, and innovative biomaterials for the fabrication of micro- and macro-bioartificial devices (microcapsules, scaffolds, and 3D bioprinting) used to physically support and immunoprotect transplanted cells and tissues without the need for general pharmacological immunosuppression of recipients. The latter, while ensuring prevention of host immune rejection, is burdened with significant side effects for the patient, especially considering that it should go lifetime.
The IPITA scientific mission is to achieve a radical cure for T1D and, albeit still in limited cases, type 2 diabetes (T2DM, non-insulin-dependent), through the transplantation of whole pancreatic organs or pancreatic islets extracted from donor organs. The islets contain Beta cells responsible for secreting insulin, thus automatically controlling the high blood glucose levels of diabetic patients who underwent autoimmune destruction (in the case of T1D) and/or functional inactivation (in the case of T2D). In the absence of bioartificial devices, both approaches (whole pancreas transplantation and pancreatic islet transplantation) would necessarily require, as mentioned above, regimens of generalized pharmacological immunosuppression to avoid immune rejection as well as recurrence of the autoimmune disease.
For pancreatic transplantation, the data communicated showed a significant decline in cases performed worldwide, also because, apart from the chronic shortage of organ donors, the graft of whole pancreatic organs represents a major surgical intervention, still burdened with significant side effects, including functional loss of endocrine pancreatic function over time. This approach in fact applies just to particularly serious cases of poorly controlled diabetes with conventional means, and especially those in which diabetes, is complicated by end-stage renal failure and requires a kidney transplant. In fact, the most frequent cases concern combined kidney and pancreas transplantation.
This approach has shown a decline in international caseloads in part, but not only, related to the COVID pandemic. In this context, pancreatic islet transplants extracted from donor orqans remain more active, especially in a few selected centers in North America (USA and Canada) and European. Despite the need for pharmacological immunosuppression regimens (which today benefit from more selective and less toxic agents compared to the past) administered to recipients of pancreatic islet transplants, performed alone or as for the whole pancreas, in combination with a kidney transplant, if the islet preparation is sufficiently pure and substantial in terms of functional islet mass, numerous cases have shown a good response to treatment resulting in insulin therapy suspension. However, globally, these cases remain limited to a few centers as compared to the community of patients with T1D, mainly due to the limited availability of organ donors, but also due to the cost of the procedure itself, which in most cases is not reimbursable by various healthcare systems. Nevertheless, the “proof of principle” of the system, which under the best conditions can function and thus relieve the patient from the need to self-inject various doses of insulin every day, has been stably demonstrated.
To counter at least one of the obstacles to the success of transplants of tissues and insulin-secreting cells derived from human organ donors, the IXA proposes the use of non-human tissue sources: in this sense, and especially for applications in T1D, an acceptable non-human donor tissue resource could be the pig. In fact, the pig secretes an insulin molecule that is very similar to humans, so much so that until several years ago (and still in some Countries with limited economic resources) pork insulin has been extensively used for the treatment of patients with T1D as well as those with T2D, no longer responsive to oral medications. Obviously, to avoid immune rejection of a (hyperacute) xenogeneic tissue, it is now necessary to adopt sophisticated, albeit still experimental, approaches that use advanced pharmacological immunosuppression systems, or physical devices (e.g., microcapsules and macroscopic “scaffolds”) that prevent physical contact between transplanted tissue and the host immune system, or finally, gene editing interventions capable of “humanizing” pig organs/tissues.
Humanized pigs represent an important advancement in transplant science for obvious reasons, as they would represent an almost inexhaustible source for human transplants. During the Congress, in this regard, the first clinical experience of pig-to-human heart transplantation was reported with promising results. Another characteristic that should never be missing for the use of pig organs/tissues in humans is the pig Specific Pathogen-Free (SPF) status, indicating the complete absence of microbial contaminants, obtained by breeding SPF animals in sterile environments and therefore free from any infection.
On this research front, significant advancements have been reported by the CTRMS, which studies advanced technologies for cellular and molecular therapy and tissue regeneration in the field of diabetology and other chronic disorders. Obviously, a leading role in this complex of research is played by stem cells, both embryonic and adult (among the latter, in particular, those inducible to pluripotency). It goes without saying that regenerative medicine represents the future for the replacement therapy of organs, tissues, and cells damaged by morbid processes. Particularly interesting results of organ reconstruction were presented, starting from a base that uses the “infrastructure” of an organ, i.e., the complex of membranes and linings that incorporate specific cells responsible for a selective function. For example, a lung is “decellularized,” i.e., stripped of all its active tissue components (vessels, alveolar cells, bronchi, etc.), leaving only the basic matrix.
On this, stem cells will be grafted, which will grow in a favorable 3D environment, and depending on their nature, will perform specific functional tasks. These are therefore newly reconstructed organs of which several experimental but very promising examples were presented. 3D bioprinters are on the same wavelength: briefly, like a normal inkjet printer, the 3D bioprinter is able to accept cells (preferably stem cells but not only), which are first blended in artificial or bioinks polymers. The cell/bioink complex will then be “printed” not on a sheet of paper as it happens for a normal printer, but on a polymeric bio-paper controlled by a computerized system. As a practical example that we are currently studying in our Laboratory, in collaboration with the Faculty of Engineering of our University, it is possible to print and reconstruct deep skin lesions using human adult mesenchymal stem cells that closely reproduce the morphology of the skin and subcutaneous tissue, regenerating the damaged tissue (in experimental mice with artificially induced deep wounds, we obtained complete reconstruction of skin, annexes included, and subcutaneous tissue).
A typical application of this innovative approach to “diabetic foot” could be the repair of deep diabetic ulcers typical of the “diabetic foot” due to vascular and neurological alterations associated with the disease in numerous cases. Theoretically, with such a device, it is would be possible to reconstruct entire organs, as was done at Wake Forest University in Winston Salem, USA, where a human bladder was neo-generated. Another very important result was reported by Vertex Inc., a US Biotechnology Company, which, with the permission of the US Food and Drug Administration, performed the first transplants of human embryonic cells, that have been conditioned, through particular experimental procedures, to become elements capable of producing insulin.
The first 6 patients, many months after the transplantation of human embryonic stem cells or hESC, into the liver, and under pharmacological immunosuppression to avoid immune rejection, began to produce insulin, leading in two cases to the suspension of treatment with exogenous insulin. The other cases are also showing production of endogenous insulin in ongoing follow-up studies.
This represents a promise for the future supply of insulin-secreting stem cells, albeit with two unavoidable hurdles:
1) human embryonic cells are not ethically acceptable, hence not usable, in most Countries,;
2) it is necessary to validate other strategies to immunoprotect these cell transplants other than general pharmacological immunosuppression as mentioned above.
Potential solutions, discussed at the Congress, could include:
1) use of induced adult human pluripotent stem cells (hiPSC) and subsequently conditioned to produce insulin;
2) use of microcapsules or other immunobarrier devices to avoid physical contact between the implanted cells and the host immune system, thus avoiding immune rejection.
Both of these approaches are studied in our as well as in other international laboratories.
Our Research Group represented by the Laboratory for Endocrine Cell Transplants and Biohybrid Organs (LTCEOB) of the University of Perugia (UNIPG) also participated in this very important and unique (given the presence of three United International Scientific Societies) Congress, with which the Diabetes Research Foundation (DRF) collaborates in accordance with a Memorandum of Understanding signed by the Magnificent Rector, Prof. Maurizio Oliviero for UNIG and by Prof. Riccardo Calafiore, president of DRF, less than a year ago and valid for 5 renewable years.
Calafiore, in an oral communication selected from among the hundreds received, presented the Laboratory’s data on sodium alginate and polyornithine (AG/PLO) microcapsules, generated as a prototype in 1987 by the LITCEOB and in the subsequent years implemented and perfected, especially in the formulation and purity of the polymers used. The microcapsules, by embodying cells (pancreatic islets for diabetes, stem cells, etc.), provide a highly biocompatible and selectively permeable barrier that protects the transplanted cells from the attack of the host’s immune system. After many years of in vitro and pre-clinical studies in animal models of spontaneous diabetes (NOD mice) and/or artificially induced diabetes, the Italian National Institute of Health granted our Institute permission to perform the first transplants of microencapsulated human pancreatic islets in 4 patients with long-standing T1D, not immunosuppressed in 2003.
This was the world’s first experience with microcapsules in humans with absolutely interesting results. The shortage of human pancreatic islets could envision the use of insulin producing adult stem cells that have no supply problems, as they can be collected in virtually unlimited quantities.
Pilot results were presented by Prof. Calafiore on the above-mentioned induced adult human stem cells (hiPSC). These cells have shown to mature from pluripotent and therefore undifferentiated elements into differentiated Beta-like cells, capable of producing and secreting insulin, within AG/PLO microcapsules, especially upon transplant into SCID mice.
The microcapsules have therefore shown to possess, alongside immune-protective properties, also qualities of a bioartificial micro-incubator for the development and differentiation of hiPSCs. Calafiore also presented the data of a recent prototype of microcapsules generated by the Laboratory, on which one of the members, Dr. Giuseppe Basta, has particularly worked. These AG/PLO microcapsules have been endowed with a wider permeability, able to allow the diffusion of large-caliber molecules such as Immunoglobulin M. Using microencapsulated G3C hybridoma cells, it was demonstrated the stable and controlled release, through the artificial capsule membrane, of monoclonal IgM antibodies against GITR, a protein residing in T lymphocytes capable, if bound by a ligand (IgM), of establishing a state of immune tolerance, and therefore effectively preventing autoimmune destruction.
Since T1D is an autoimmune disease, it was possible to demonstrate that the implantation of microencapsulated G3C, secreting monoclonal anti-GITR IgM, in NOD mice, a unique animal model in nature that develops a form of T1D almost identical to that of humans, completely prevented the onset of the disease. If translated to humans, this system could provide a sort of vaccine that could prevent the onset of human disease. The system could also be applied to other human autoimmune disorders.
Calafiore finally, also moderated one of the final sessions, on the last day of the Congress.
In summary, it was a great and important international scientific event that took stock of current research on various fronts of cellular and molecular therapy with stem cells and other organ-specific cells, and laid the groundwork for future projects in these relevant sectors for the treatment and prevention of serious chronic human pathologies.