Endsulin’s developing an innovative yet simple therapy to treat Type 1 diabetes mellitus (T1DM) by engineering a vector containing a novel transgene for glucose- dependent insulin secretion from the liver.

About 50,000 Wisconsin residents and 1.5 million Americans are afflicted with T1DM (1-3). Experts agree that a treatment which would precisely control blood glucose, will revolutionize T1DM management by preventing secondary complications. We have spent the past 20 years incrementally reaching our goal of more accurately controlling glucose levels by developing a novel insulin gene construct, called TA1m (Diatagene, patented by WARF: # US7425443 B2;)

Our goal is to provide long-term benefit by utilizing gene therapy. Current treatment protocols do not adequately control blood glucose levels resulting in retinopathy, renal failure, cardiovascular complications and to this end, we have engineered TA1.

After nearly 20 years of experimentation testing Adeno virus, Lenti Virus, Mini Circles and Adeno Associated Virus (AAV) we have arrived at the conclusion that AAV is the optimal vector to achieve our goals. The safety of the vector and relative ease of production are obvious advantages. The fact that to date the only FDA approved gene therapy application are based on AAV is an indicator that this vector, at least for the immediate, has the best chance to pass regulatory hurdles. Our own work using AAV began four years ago when we were challenged by the production process. In an attempt to expedite production, we collaborated with the laboratories and production facilities of Jean Bennett (Penn), Samulski (UNC) and Genenthon in France. In addition, we consulted with several commercial production facilities.  The products of these highly experienced centers were compared to the quality of the vector produced in our own lab. After four years it has become clear to us that our production methods were superior in terms of restoring normoglycemia. We realized that the insertion of GIRE causes unexpected molecular changes which other labs had not anticipated. As a result, we made proprietary changes in our vector production resulting in a robust and reproducible construct. In fact, at the end of the testing period we had four leading candidates. At the current time we are working with the UW Waisman Center in testing which of the leading candidates is optimal in upscaling. This work is in progress and final tests will be completed by fall of 2020. In the meantime, a proven batch has been allocated for the treatment of naturally diabetic dogs as first proof-of concept in our preclinical model. Experts concur that this preclinical model is ideal to study the effect of gene therapy on glucose metabolism.

The incidence of T1DM in humans has now reached epidemic proportions and is predicted to rise. More than 20 years ago we initiated research in our laboratory to find a simple, affordable and non-invasive method to treat T1DM which would be available for all T1DM patients. The creation of an insulin gene with glucose-sensitive-response element in our laboratory brought us closer to this goal; the proof-of- principle has been achieved and published. 

All experts accept that for any T1DM therapy to be meaningful, it must be evaluated in an autoimmune large animal model (10). It is estimated that about 1% of all pet dogs will develop autoimmune diabetes, which is identical to human T1DM in its clinical, metabolic and autoimmune aspects. animals from insulin injections. expertise. Our team approach supplies the synergy required to move this novel T1DM therapeutic approach forward to application in man. 

In summary, we propose a novel T1DM treatment using an ideal pre-clinical T1DM model. Successful completion of the overall endeavor is likely to yield a therapy for human T1DM patients with glucose control far superior to other available treatments.

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