In order to generate an integrated protocol for transplantation, Orgenesis has completed an autologous safety study with promising results that support the concept.
So far, pre-clinical safety and efficacy studies have been conducted. The goals of this work plan are to:
- Initiate regulatory activities in Asia, Europe and USA.
- Move rapidly to clinical trials and to collaborate with clinical centers, specifically those performing Pancreatic Islet transplantations.
- Scale up Orgenesis cell production process (this activity will be carried out at a subcontracted facility of the Sheba Medical Center in Israel.
- Validate the entire manufacturing process (in certified labs).
Orgenesis has started research activity for new product advancement subject to the clinical trial results.
We have a proof of concept that demonstrates our capacity to induce a shift in the developmental fate of cells in liver and convert them into ‘pancreatic beta-cell-like’ cells. The approach of liver to pancreas trans-differentiation, and the development of a ‘self’ insulin producing tissue has been proven successful both in-vivo and in-vitro as described below.
- Ectopic expression of PDX-1, a ‘master regulator’ that governs pancreas development, in liver, resulted in induction of the otherwise silent insulin gene expression.
- Developmentally shifted liver cells produce mature and biologically active insulin. Hepatic insulin production ameliorated hyperglycemia in diabetic tests.
- The developmental shift is comprehensive and includes the induction of endocrine cells characteristics and function. Insulin is released in a glucose regulated manner.
- The therapeutic agent triggers a cascade of events, resulting in a permanent developmental shift of liver into beta cells.
- Developmentally shifted liver cells seem to resist a recurrent immune attack, characteristic to type 1 diabetes, therefore could be efficient in the cure of type 1 diabetes.
- PDX-1 induced developmental shift, maintains normal hepatic functions, no alteration in hepatic architecture is visualized in 7 months follow-up in tests.
- None of the treated mice or monkeys developed hypoglycemia or any malignancies.
Applying the therapeutic agent on primary culture of animal and most important human liver cells, results in a similar induction of liver to pancreas trans-differentiation as in the direct in-vivo gene delivery approach
- Primary culture of liver cells isolated from human liver and treated by the therapeutic agent expresses the otherwise silent insulin gene, produces the hormone process it and secretes it into the media in a glucose regulated fashion. Transdifferentiated human liver cells corrected diabetes in immunodeficient tests (Diabetic SCID-NOD mice), 60 days follow up.
- Additional growth and pancreatic transcription factors promote b-cell like maturation and increases the insulin production in these cells.
- This cellular model will allow us to analyze cellular, environmental and molecular factors that promote the liver to pancreas trans-differentiation process. It will be used in developing the optimal therapeutic agent that will give the maximal number of developmentally shifted cells, with optimal beta cells characteristics and function. Accordingly the optimal therapeutic composition of the therapeutic compound, will be established (we expect that the optimal therapeutic compound will consist pancreatic transcription and growth factors in addition to PDX-1).
- Orgenesis generated a tool that ‘tags’ PDX-1 induced developmentally shifted tissues (both in-vivo and in-vitro) this tool will be used to identify additional tissues (such as skin or bone marrow) that could serve as pancreatic progenitor tissue for the treatment of diabetes.
- The developmentally redirected human liver cells may undergo further maturation along the pancreatic lineage and function upon in-vivo implantation.
Orgenesis Feasibility Studies
Preclinical studies performed in numerous labs worldwide suggest the potential feasibility of converting liver cells to autologous insulin producing (AIP) cells. The conversion of liver cells into pancreatic endocrine cells has been described in numerous animal species and most importantly with human liver cells from about 70 different donors’ aged from 3 to 60 years old. Human insulin producing cells generated from liver cells generated processed and secreted insulin in a glucose dependent manner.
Prof. Ferber's studies were published in scientific journals such as Le Monde, Elsevier – journal of Auto Immunity, PNAS and more.
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