4 stem cell patents issued last week

Dear manoj kumar valluru,

Last week 4 patents of relevance to the area of stem cells were issued.

1. # 7,323,165 (Patent Spotlight), teaches how to make insulin in vivo by transfection with ngn3 an dother transcription factors.

2. # 7,323,190 discloses a new fibrous matrix for cell delivery.

3. # 7,323,337 covers viral transfection of ES cells using SIV.

4. # 7,323,445 blocks the use of osteochondral grafts with specific BMPs.

In The News

Breast cancer FGF-2 and VEGF calls in mesenchymal stem cells

Tuesday January 29th, 2008 @ 03:01:42 EST

Augusta, Georgia -

It is believed by many that tissue resident stem cells subsequent to accumulating DNA damage lose proliferative controls and transform into tumors. For example, there is a classical study in which mice were infected with h.pylori and gastric cancer was allowed to develop. Strikingly, the gastric cancer was derived from bone marrow stem cells which had migrated to heal the damaged stomach tissue and subsequently transformed into cancer cells _(Houghton et al Gastric cancer originating from bone marrow-derived cells.Science. 2004 Nov 26;306:1568-71)_

One interesting finding is that not only do cancer cells seem to attract various types of stem cells, but that in some situation administration of healthy stem cells can inhibit the cancer growth Evan Synder from San Diego has actually been proposing these types of approaches for targeting brain tumors. For example, in his issued US patent 7,186,409 he teaches that neural stem cells can be used as vectors to carry toxic payloads to brain tumors.

A very important question is how do tumor cells call in stem cells? Well off the top of one's head, one would imaging that since stem cells are usually attracted by injury signals similar to the ones that call in bone marrow stem cells to home into injured myocardium after a heart attack and since tumors are considered "wounds that never heal", it may be possible that signals such as SDF-1 may be chemoattracting stem cells to tumor cells.

In a recent study _(Ritter et al. Breast Cancer Cell-Derived Fibroblast Growth Factor 2 and Vascular Endothelial Growth Factor Are Chemoattractants for Bone Marrow Stromal Stem Cells. Ann Surg. 2008 Feb;247:310-314)_ the interaction between tumors and stem cells was examined. Researchers used in vitro breast cancer cell lines to determine that these cells have a chemoattracting property to bone marrow derived mesenchymal stem cells when placed in Boyden chambers.

Chemoattractants of relevance were VEGF and FGF-2. Particularly mesenchymal stem cells expressed receptors for these cytokines, and the tumor cells made these cytokines. The cytokines were found in plasma of cancer patients at high enough concentrations to induce migration of mesenchymal stem cells. Additionally, migration could be inhibited in vitro by blockade of VEGF or FGF-2.

These data provide some clues as to the molecular interaction between tumor cells and mesenchymal stem cells. Since VEGF is clinically inhibited by the anticancer drug Avastin, one wonders whether this affects the interaction of the mesenchymal stem cell with tumor cells.

An additional point of interest is whether the FGF-2 produced by the tumor has other properties besides stimulation of mesenchymal stem cell migration. For example, it is known that FGF-2 increases endothelial health So one question would be, "are the flow mediated vasodilation responses better in cancer patients?"

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This Week's Patent Spotlight

Production of pancreatic islet cells and delivery of insulin

Patent Number: 7,323,165

Assignee | Inventor

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;39:13-25)_ 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.

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