Production of pancreatic islet cells and delivery of insulin

Patent Number: 7,323,165

Numerous approaches have been patented on the treatment of diabetes through regeneration. These range from bone marrow stem cell modification and administration, to generation of islets from embryonic stem cells, to creation of differentiated proliferating islet cell lines.

The current patent, belonging to the same family as 6,967,019 teaches methods of producing insulin and of delivering insulin to patients in need of. The methods actually involve stimulation or upregulation of insulin production through inducing expression of a neuroendocrine class B basic helix-loop-helix (bHLH) transcription factor. Expression of these transcription factors is covered in the lumen or duct of a pancreas, as well as the liver and gut.

What are these transcription factors? The claims cover neurogenin1, neurogenin2, NeuroD1/BETA2, neuroD2, math2, NeuroD4/Math3math1/ATOH1, mash1/ASCL1/ASH1, or mash2.

If we look on pubmed, one interesting paper (Ross et al. Basic helix-loop-helix factors in cortical development. Neuron. 2003 Jul 3;39(1):13-25) tells us that progenitor cells of the neocortex generate new neurons by upregulating activity of bHLH factors (Mash1, Neurogenin1, and Neurogenin2) and a decrease in the activity of Hes and Id factors. The paper provides a general description of what the bHLH transcription factors are. It states that these are a family of 125 member, which are classified as bHLH based on the chemical motif that allows their binding to DNA and also dimerization.

In the specification, it states that the "class B" of the bHLH genes are usually expressed during islet development. Accordingly, if one induces expression of these genes ectopically, the inventors demonstrate one can recapitulate development and start the production of insulin generating cells again. Of particular interest, the patent mentions that the Ngn3 transcription factor is not only involved in endocrine differentiation, but that it controls other islet-specific factors such as Pax4 and Nkx2.2. Interestingly there is a patent issued on the use of Pax4 to determine islet differentiation.

The inventor, Dr German, has published numerous papers demonstrating the importance of Ngn3 in pancreatic development, as well as observations that certain types of diabetics have mutations in the ngn3 gene.

The patent has some nice examples supporting the claims, for example a streptozotocin-induced diabetes model having restoration of glycemic control after in vivo viral delivery of ngn3.

Since others have transfected similar, well at least philosophically, similar transcription factors, such as pdx-1 into stem cells to enhance ability to make insulin, maybe this is an approach that will be tried with this technology.

Another interesting angle of research could involve identification of small molecules that upregulate expression of ngn3. Numerous stem cell activities have been modulated pharmacologically, for example, Velcade stimulation of bone formation, the activation of hematopoietic stem cells by valproic acid, and the use of erythropoietin to stimulate neurogenesis. An approach would be to look at DNA arrays and see which drugs that are already on the market may impact ngn3 and then see if the activities may be amplifed by other drugs or approaches.

View this patent on the USPTO website.