Naz News, Gappers and FLE's

[mcmike]

Novocell's attempts at Encapsulated Islet Cell Implantation

Novocell, Inc.
Novocell is a leader in the research and development of encapsulated cellular transplants for the treatment of diabetes and other diseases. The Company believes that cellular transplant technology will bring the control of blood glucose to patients with insulin-dependent diabetes, without requiring the chronic use of immunosuppressive drugs. Achieving such control could be expected to decrease or eliminate the need for insulin injections and delay or prevent the downstream medical complications from the disease. It is hoped that this technology will benefit people with Type I diabetes and late-onset Type II diabetes who must use insulin regularly.
http://www.assetman.com/portfolio/current_portfolio.php

Cell encapsulation: Promise and progress
In cell encapsulation, transplanted cells are protected from immune rejection by an artificial, semipermeable membrane, potentially allowing transplantation (allo- or xenotransplantation) without the need for immunosuppression. Yet, despite some promising results in animal studies, the field has not lived up to expectations, and clinical products based on encapsulated cell technology continue to elude the scientific community. This commentary discusses the reasons for this, summarizes recent progress in the field and outlines what is needed to bring this technology closer to clinical application
http://www.nature.com/nm/journal/v9/n1/full/nm0103-104.html

Surmodics' relationship with Novocell:
What is the significance of the Novocell agreement regarding a revolutionary treatment for diabetes?
Answer: Finding a cure for diabetes would represent a significant advancement in healthcare with an estimated 120-140 million diabetics worldwide. Diabetes is estimated to cost this country $44 billion annually in direct medical costs and $54 billion in productivity losses. The use of islet cell encapsulation technology—islets are the pancreatic cells that produce insulin in the body—could reduce or eliminate daily insulin injection therapy for many diabetic patients.

It has already been demonstrated that transplanting insulin-producing islets has the potential to dramatically reduce the harmful side effects of diabetes, but it would also require the life-long administration of immune-suppression drugs. Using SurModics technology, Novocell is encapsulating islet cells with a polymeric coating that protects the islets from the body’s immune system yet allows the insulin to pass through. This approach provides the same potential cure without the need for immune-suppressive drug therapy, thereby making this therapy attractive to all insulin-dependent diabetics.

Novocell has demonstrated success with encapsulated islet cell implants in diabetic primates, and is preparing to request approval from the FDA to begin clinical trials of encapsulated islet cell implants in human diabetics. If this islet encapsulation therapy proves to be successful in humans, it should be quickly accepted by the diabetic community, and soon after its introduction to the vast insulin-dependent market, the potential revenue stream would be significant.
http://www.corporate-ir.net/ireye/ir_site.zhtml?ticker=SRDX&script=2100

7/9/2003
"The potential to normalize blood glucose with islet cell implantation without the need for the dangerous immunosuppressant drugs lifelong would be a major advance in therapy for diabetic patients. There is evidence that normalizing blood glucose can reverse and/or prevent the complications of the disease. At Novocell, we are also working on expanding the number of insulin producing cells available for implantation with our proprietary cell growth technology. This is necessary because there are not nearly enough organ donors available to acquire the billions of islet cells it will take to treat millions of diabetic patients."
http://islet.org/forum030/messages/27502.htm

6/14/2005
Encapsulated islet cell transplants avoid host immune rejection
results of a study of implantation in 16 diabetic baboons
http://transplantliving.org/community/news.aspx?id=453

11/2005 Phase I/II trial description
Safety and Efficacy of PEG-Encapsulated Islet Allografts Implanted in Type I Diabetic Recipients
a combination biologic and device product in which the pharmacologically active agent is human insulin that is released from the functional islet cells by natural production and release, stimulated by control mechanisms in response to blood glucose concentrations.
The primary outcome is demonstration that encapsulated islet allografts can be implanted safely in the subcutaneous tissues without the use of long-term immunosuppression. The expected functional outcomes from the implantation of the encapsulated islets are significant reductions in the average blood glucose daily glycemic excursions and in insulin requirements as well as significant increases in C-peptide levels in response to meal challenges. The ultimate expected outcome is that patients who receive these implants will have reduced hemoglobin A1c levels that may be associated with reduced long-term diabetic complications. An important outcome should be reduction in hypoglycemic episodes and crises with significantly functioning grafts without having the risks associated with hepatic portal vein infusion and long-term immunosuppression.
http://www.clinicaltrials.gov/ct/gui/show/NCT00260234

Even if successful, Novocell will need to find a source for islet cells beyond the few that are harvestable from organ donors. This will be another challenge. In 2001 at hte NY Diabetes Association's Annual Scientific meeting:

David Scharp, Irvine, CA, Chief Scientific Officer of Novocell, Inc., pointed out the immense discrepancy between the 5,000 organ donors in the U.S. annually and the 750,000 patients in U.S. with type 1 diabetes who would potentially benefit from islet transplantation. Although it may be possible to grow islets or genetically engineer islets, he stated that consideration must be given to the use of xenografts. Primates are endangered species and have a higher insulin requirement than humans; therefore, they would not be a good source. The mature cow makes insulin in response to fatty acids rather than glucose, and, therefore, also may not show optimal characteristics. Scharp suggested that porcine and human [beta]-cells respond in a similar fashion, making this a feasible source. Interestingly, islets from fish can be genetically engineered to make human insulin, and may also be suitable. However, preformed antibodies exist in humans to antigens present in many other vertebrates, having potential for an immune response to all species other than primates. Immune rejection mechan isms for xenografts are complex and not well understood. Furthermore, they vary from species to species, so that effective immunosuppression regimens are difficult to formulate, These regimens can be categorized into hyperacute rejection due to preformed antibodies to blood vessels not seen with islets, which are nonvascular; accelerated and acute rejection involving cell-mediated immune responses occurring over 2- to 3-day and 7- to 10-day periods; and chronic rejection, with a variety of poorly characterized mechanisms.

When unencapsulated porcine islets are administered to diabetic SpragueDawley rats, there is a several-day period of restoration of euglycemia, followed by acute rejection. The T-cells causing allograft rejection are CD3/4, CD3/8, and Th-1 type-positive, whereas for xenografts, acute rejection involves CD3/4 but not CD8 Th-2 T-lymphocytes and involves many more cytokines and other cells, such as eosinophils. Rather than involving interleukin (IL)-1 and IL-2 alone, IL-4 and IL-S are also involved in xenograft rejection. Complex immunosuppressive regimens are presently required to prevent xenograft rejection. Genetic engineering may offer an approach allowing replacement of pig antibody targets with human proteins to prevent acute rejection. An alternative a pproach is the creation of an immunoisolation barrier around transplanted islets. Scharp's company, Novocell, has used polyethylene glycol for the encapsulation process to allow a very thin coating around each islet with control of pore size. Encapsulated porcine islets placed intraperitoneally in diabetic Sprague-Dawley rats can produce lasting maintenance of euglycemia without evidence of immune rejection. Similar studies in diabetic primates have shown that euglycemia can be maintained for a several-week period. An important hallenge for encapsulation is the biocompatibility of the polymer with the host for prevention of rejection while allowing islet nutrition and function. Clinical trials are being planned for transplantation of encapsulated human I slets into patients with type 1 diabetes by using donor-specific bone marrow for tolerance induction.

An important risk concems the transference of zoonoses, such as swine influenza, vesicular stomatitis, encephalomyocarditis, and the prion-based illness bovine spongiform encephalitis. Beyond these known illnesses, there is the risk of a recombinant virus that could lead to the development of new diseases. Such viruses may be controllable and definable by donor surveillance. The porcine endogenous retrovirus (ERV) is a single RNA strand enclosed in a glycoprotein envelope derived in part from the infected host cell, Inside the host cell, the RNA is copied into the host DNA as a permanent insertion. ERV in host DNA may direct a cell to make copies, which then can circulate within the host. Most species, including human, have such ERVs. Each porcine cell in nature has 50-100 viral genome copies, some only partially complete, which are passed to all daughter cells. Scharp described the potential problem that the porcine ERV may combine with human ERV to form a new virus capable of both causing new human disease and transmitting to other humans. This scenario occurred in the development of feline leukemia virus, derived from a bird ERV combined with that of cats.
http://www.med-articles.com/med/marticles/atenolol/atenolol-article-74246-4.html

need to find out if progress has been made since.

Islet Cell Transplants Offer Best Chance
A businessman, Gordon also has type 1 diabetes and started The Islet Foundation three years ago. It has an extensive Web site at www.islet.org . The industry's four leading companies, he believes, are:

● Islet Sheet Medical LLC of San Francisco, Scott R. King, president

● Diatranz Ltd. of Auckland, New Zealand, David Collinson, managing director

● Encelle Inc. of Raleigh, North Carolina, James D. Woodward, president and CEO

● BetaGene Inc. of Dallas, Christopher Newgard, founding scientist and chief consultant.
Likely to be the first into clinical trials, Gordon believes, is Diatranz Gordon either unaware of Novocell...or wrong

http://www.mendosa.com/islets.htm