Type1 Study's Update.....THE SURPRISE...SURPRISE.. .
This is huge!!!
Even with Type2 Db as Transitions focus the R&D for Type1 soldiers on. Transition has 3 Partners. Elan., Eli Lilly and the Junior Diabetes Research Foundation ( The JDRF ) . The JDRF's focus is 100% directed toward Type1. They started out a long time ago to try to help the children that Type1 afflicts. The founders thought it unfair that little children that can't even read or write were being stuck with needles full of Insulin just to stay alive. Simply put JDRF wants a Cure. They have grown into a huge entity with a whack of cash and they spend it all on research into Type1. Type1 is an autoimmune disease and all Type1's are Insulin dependant.. Type2 is more of a Panreatic beta-cell exhaustion that can eventually lead to Insulin dependance not unlike Type1
Dr. Cruz has stated that they and Lilly will persue a Type1 Db indication in the future with a LY-GLP1/TT223. Unlike Type2 that can be controlled with just one analogue, Type1 Db will require both TT-223 ( a Modified Gastrin Analogue) and another Analogue such as a GLP1--EGF--Prolactin---etc...........
.........TT223 can differentiate pancreatic precurser cells into beta cells. GLP1 has regenerative properties in beta cells. Tests in Type1 have shown that the combination of the 2 is way more effective than just one of the analogues alone. TT223 as well has some regenerative properties but it is believed that increasing TT223 signals an increase in endogenous GLP1.
Transition and the JDRF have been working behind the scenes on Type1 study's. The findings coming out of Rabinovitch's Lab are nothing short of Astounding! The combination of TT223 and GLP1 not only reverses the disease but it does it without any immuno suppressives. That is a huge surprise. It actually reduces the AutoImmune Response. This is in the same mouse model that TT223-EGF was tested in for Type1 and Transition has theHuman Phasella Trials showing the Translational Success of going from animal study's to Human.... Proof of Concept in Humans showing the Mechanism of Action.
The study that Rabinovitch did was performed from a grants coming from the Transition/JDRF Partnership. The partnership agreement was a 50/50 match funding so Transition would have contributed as well in direct grant or equal supporting lab work from out of one of Transitions labs or a combination........
In light of these recently announced findings it comes as no surprise that 2 weeks ago another Patent was applied for for Transitions proprietary and trade marked "INT" (Islet Neogenisis Therapy) in Diabetes. INT is the combination of TT223 with any one of many other Analogues.
https://www.freshpatents.com/-dt20090205ptan20090036381.php========================================================================================
New Regeneration Therapy Reverses Diabetes in Mice
JDRF's Research Frontline E-Newsletter, February 2009
A short treatment with two drugs partially restores the number of insulin-producing beta cells in the diabetic mouse pancreas and also slows their autoimmune destruction-enough to restore normal blood-sugar levels and reverse the disease.
The study, published in the journal Diabetes, was funded by grants from JDRF and Transition Therapeutics, Inc., one of JDRF's Industry Discovery and Development Partners.
According to the investigators, led by Alex Rabinovitch, M.D., at the University of Alberta in Edmonton, the findings suggest that the two drugs work together to target both the cellular mechanisms that promote beta-cell growth and survival, as well as the immunologic mechanisms that destroy beta cells in type 1 diabetes. As a result, the use of both drugs offers a "promising strategy" for reversing beta-cell loss in people with the disease.
Patricia Kilian, Ph.D., director of the Regeneration Program at JDRF, described the study results as "exciting and unexpected," in that the combination therapy produced positive effects related to both regeneration and autoimmunity. The study is unique, she said, because it is the first to test the two-drug combination (gastrin and glucagon-like peptide 1, or GLP-1) in mice with diabetes, and to show that it reverses diabetes, not just prevents it.
"While much more needs to be determined," Dr. Kilian said, "the study supports, at the preclinical level, the use of gastrin combination therapy in a human clinical trial, making it highly relevant to JDRF's mission."
GLP-1 and gastrin are among the most promising beta-cell growth factors being tested for therapeutic use in people with diabetes. GLP-1 is a protein produced by intestinal cells after food is ingested; one of the things it does is stimulate insulin production by the pancreas. In mice, it has been shown to promote beta-cell function, survival, and growth. Gastrin, also a protein produced by the gastrointestinal tract, also stimulates insulin production, but it causes new insulin-producing cells to form from pancreatic duct cells.
Within three to six days after the onset of diabetes, Dr. Rabinovitch and colleagues treated the mice with GLP-1 and gastrin, administered alone or together. They measured blood-sugar levels once a week during the treatment period and for five weeks after treatment ended. At the end of eight weeks, the researchers measured pancreatic insulin content and assessed whether insulin-producing cells had grown or declined in quantity.
The two-drug combination restored normal blood sugar levels in 11 of 13 mice, and as a result, the mice gained weight as they aged at rates similar to what one would see in non-diabetic mice. In contrast, neither drug alone restored normal blood sugars in a significant number of mice. "The surprise," Dr. Rabinovitch said, "was that no immunosuppressive drugs were required. The GLP-1 and gastrin were sufficient, in combination, to restore pancreatic beta-cell mass and stop the autoimmune destruction of beta cells in the diabetic mice."
Combination therapy had a pronounced effect on the amount of insulin produced by the pancreas. For example, low doses of GLP-1 plus gastrin increased insulin content threefold. In mice given high doses of GLP-1 plus gastrin, pancreatic insulin content was fivefold higher-about 74 percent of normal.
The combination therapy also increased beta-cell mass. Examination the pancreas revealed that the islets were abundant with insulin-containing beta cells. These changes, however, were found to be less about replication of existing insulin-producing cells, and more about decreased beta-cell death (attributed to GLP-1) and increased production of new beta cells from pancreatic duct cells (attributed to gastrin).
Other findings suggested that the combination therapy had altered the autoimmune response against the beta cells. For instance, autoantibodies directed at insulin were undetectable in mice receiving GLP-1 and gastrin, whereas these antibodies were present before treatment and rose to very high levels in the control mice. In an "adoptive transfer" experiment, the researchers combined diabetes-causing immune cells with immune cells from the mice given the two-drug treatment, and then transferred both cell types into mice that were expected to quickly develop diabetes. What they found was that onset of diabetes was delayed by as much as 107 days. "This suggested," the scientists said, an "activation of immunoregulatory cells" in the mice treated with the two drugs.
In another set of experiments in which insulin-producing cells were transplanted into mice, even when those transplants were set up to fail, they did not do so in the majority of mice (seven of eight) that received the two-drug combination immediately following transplantation. This again suggests that the treatment is somehow regulating the autoimmune response against the beta cells.
Especially important, according to the researchers, was the finding that although white blood cells had infiltrated the transplanted islets in the mice treated with the two-drug therapy, beta cells were not destroyed. The researchers will need to determine the basis of this effect to establish the combination treatment's full therapeutic potential.
The clear application of this intervention within regeneration is to treat type 1 patients with gastrin combination therapy to promote new beta-cell growth within the patient and to restore functional beta-cell mass.
JDRF is also working with Dr. Rabinovitch to develop alternative strategies leading to beta-cell regeneration. One such approach, for which Dr. Rabinovitch was awarded a two-year project grant, is to elevate the body's natural gastrin and GLP-1 levels using next-generation regenerative products.
"Instead of giving the large protein gastrin," Dr. Kilian said, "another possible strategy to achieve the same endpoint is through the small molecule approach," elevating GLP-1 and gastrin indirectly through next generation compounds. Preclinical data presented by Dr. Rabinovitch last year showed that diabetic mice could be cured by a combination of two newer drugs, both of which "are safe for human consumption and can be taken in pill form," he said.
Next steps will be to advance these observations to proof-of-concept clinical trials in type 1 patients.
There are also several theoretical applications of these findings, with a number of them supporting JDRF efforts in replacement. For instance, one might incubate the two growth factors in vitro with isolated human islets, with pancreatic duct cells that might otherwise be discarded, or both, in order to increase the total number of beta cells available for islet transplantation; one could also administer the two agents to islet transplant recipients after islet transplantation to promote new beta-cell growth in the graft.
Gastrin's potential as a regenerative agent continues to be investigated on other fronts as well. Transition Therapeutics' exploratory phase IIa clinical trial of gastrin in combination with the growth factor EGF showed improvements in important measures of blood-sugar control in both type 1 and type 2 patients. Transition Therapeutics has subsequently partnered with the pharmaceutical company Eli Lilly to develop gastrin-based therapies using Transition's proprietary technology.
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