The study co-author, Lawrence Chan, MD, DSc, chief of Baylor’s diabetes, endocrinology and metabolism division, had already managed to develop a gene therapy that stimulated the development of new beta cells in the liver, restoring insulin production and normal blood sugar levels in more than 100 mice with chemically induced diabetes. But in non-obese diabetic mice, they had found that the treatment failed after the mouse’s immune system killed the newly formed beta cells.

The team combined the gene therapy with interleukin-10 and then injected the therapy intravenously. During more than 20 months of follow-up, the treatment completely reversed Type 1 diabetes in half of the mice. While the therapy did not reverse autoimmunity throughout the body, it protected the new beta cells from the “local destructive effect of autoimmunity.”

“We developed a protective ‘moat’ around the new beta cells,” said Chan. “We are now developing other strategies to try to fortify the newly formed beta cells and give them better weapons in addition to the moat, in order to increase the treatment’s cure rate.”

Source: FierceBiotech

CD3 is a molecule found on the surface of T-cells and is important in stimulating the them into action. Otelixuzumab works by latching onto the T-cells, potentially switching them off and increasing regulatory cells that control inflammation. Researchers are betting that otelixizumab will be as effective in reducing symptoms as the current standard therapy for severe RA, but will have a more sustained effect from just a one-off one course of treatment.

“Everything we know about this drug suggests that it has the potential to be a powerful treatment,” Professor John Isaacs from Newcastle University’s Musculoskeletal Research Group who will lead the study says in an Arthritis UK statement. He adds that the researchers hope to demonstrate the safety of the drug with the study. If the drug was shown to be safe and effective in subsequent Phase II and III trials, it could be available for RA patients in eight to 10 years, Isaacs says.

In an important aspect of the study, researchers from Newcastle University and King’s College London, will also be performing laboratory studies aimed at identifying and analyzing potential biomarkers in the blood that might predict whether or not a patient will have a sustained response to the therapy.

Source: FierceBiotech

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The research was led by Jerry Nadler, M.D., professor and chair of internal medicine and director of the center. It is published in the February issue of The Journal of Clinical Endocrinology and Metabolism.

Prior research has established that 12-LO, a protein-based enzyme found in beta cells, produces specific lipids that cause inflammation and can lead to the death of beta cells in laboratory models. Yet, little is known about the differential effect of the various hydroxyeicosatetraenoic acids (HETEs) that result from LO activity in human islets, the EVMS team explains. Their study thus focused on comparing the effects of 12-LO products on human islet viability and function.

One challenge has been to validate that 12-LO and its pro-inflammatory lipid products have a role in human diabetes. Gaining access to human beta cells can be difficult, but the school was able to leverage resources from JDRF’s Islet Resource Center Consortium, Dr. Nadler explains.

Human islets were treated with stable compounds derived from LOs: 12(S)-HETE, 15HETE, 12HPETE, and 12RHETE. The islets were then examined for insulin secretion and islet viability. The p38-MAPK and JNK stress-activated pathways were investigated as mechanisms of 12-LO-mediated islet inhibition in rodent and human islets.

They found that insulin secretion was consistently reduced by 12(S)-HETE and 12HPETE. 12(S)-HETE at 1 nM reduced viability activity by 32% and increased cell death by 50% at 100 nM in human islets. These effects were partially reversed with lisofylline, a small molecule anti-inflammatory compound that protects mitochondrial function.

Additionally, 12(S)-HETE increased phosphorylated p38-MAPK protein activity in human islets, the scientists report. Injecting 12-LO siRNA into C57BL/6 mice reduced 12-LO and phosphorylated p38-MAPK protein levels in mouse islets. The addition of pro-inflammatory cytokines increased phosphorylated p38 levels in normal mouse islets but not in siRNA-treated islets.

“We are currently working with investigators in California and the National Institutes of Health to identify ideal medications that would target 12-LO as a new treatment to halt immune damage to human insulin-producing cells,” says David A. Taylor-Fishwick, Ph.D., associate professor.

Source: GEN News

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The studies, by the Meta-Analyses of Glucose and Insulin Related Traits Consortium (MAGIC), identified a total of 13 genetic variants that seem to influence blood glucose regulation, insulin resistance, and the function of insulin-secreting beta cells in people of European descent. The research is published in two papers in Nature Genetics titled “New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk” and “Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge.”

In the first study the researchers, led by Jose Florez, Ph.D., M.D., from Massachusetts General Hospital and Harvard Medical School, investigated genetic variations linked with fasting glucose and insulin levels as well as with beta-cell function and insulin resistance. Their meta-analysis evaluated about 2.5 million genetic variants in 21 genome-wide association studies that had included some 46,186 individuals who did not have type 2 diabetes and who had been tested for measures of glucose and insulin regulation.

Of 25 candidate SNPS identified in the initial analysis, further testing of genetic samples from about 77,000 additional individuals led to the identification of 16 SNPS that appeared to be clearly associated with fasting glucose and beta-cell function as well as another two SNPS associated with fasting insulin and insulin resistance. Of them, five were found to increase type 2 diabetes risk.

One is located in the ADCY5 region, which influences fasting and postprandial glucose levels. Another is in region FADS1, which is linked with fasting glucose and lipid traits. None of the variants were associated with type 1 diabetes.

“Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing, and circadian regulation,” the authors conclude. “Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.”

One of the interesting findings, according to Dr. Florez, is that glucose elevation in itself does not appear sufficient to increase the risk of type 2 diabetes. Rather, it is how the glucose is raised that determines risk. “The hallmarks of type 2 diabetes are insulin resistance and impaired beta-cell function,” notes lead author, Ins Barroso, Ph.D., from the Wellcome Trust Sanger Institute. “We were intrigued to find that most of the newly found variants influence insulin secretion rather than insulin resistance. Only one variant, near IGF1, is associated with insulin resistance.”

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The second paper evaluated the genetic basis of glucose levels two hours after an oral glucose challenge in a subset of 15,234 participants. The authors claim the discovery that a variant of the GIPR gene influences blood glucose levels after glucose challenge highlights the role of incretin hormones in type 2 diabetes. “Our association results suggest a role for GIPR in the incretin effect and in early pathophysiologic pathways that could lead to impaired glucose tolerance and type 2 diabetes in humans,” they conclude.

The paper’s senior author, Richard Watanabe, Ph.D., from the University of Southern California, suggests the findings add to a growing body of evidence implicating the incretin pathway in type 2 diabetes risk. “These pathways, which stimulate insulin secretion in response to digestion of food, may offer a potential avenue for therapeutic intervention.”

Although the two studies focused on populations of European descent, the MAGIC researchers believe a number of the genetic variants will have similar effects in other populations. Nevertheless, as Dr. Florez concludes, “Even with the discovery of these variants, we’ve only explained about 10 percent of the genetic contribution to fasting glucose in people who do not have diabetes.”

Source: GEN News

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Researchers compared overall rates of eye, kidney and cardiovascular complications in patients diagnosed with type 1 diabetes an average of 30 years earlier. The study included two groups of patients from the randomised, 1441-patient Diabetes Control and Complications Trial (DCCT), which began in 1983, who researchers have continued to monitor since the study became observational in 1993. The intensive treatment group aimed to maintain near-normal A1C levels with at least three insulin injections per day, while the conventional treatment arm had no specific A1C targets and took one to two daily injections of insulin.

Results indicated that after 30 years of diabetes, the cumulative rates of complications in the intensive treatment arm compared with the conventional treatment arm were 21 percent versus 50 percent for eye damage; 9 percent versus 25 percent for kidney damage; and 9 percent versus 14 percent for cardiovascular disease. Furthermore, researchers said data showed that fewer than 1 percent of those in the intensive therapy group became blind, required kidney replacement or had an amputation because of diabetes during that time.

DCCT co-chair David Nathan commented that “when intensive therapy, now the standard of care, is implemented early in the course of diabetes, most patients with type 1 diabetes should be able to avoid the disastrous long-term complications that were so common in the past.” He said the long-term outcomes “should encourage clinicians and patients alike to implement intensive therapy as early in the course of type 1 diabetes as possible.”

Source: FirstWord

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The $350 million agreement with Bayhill covers a mid-stage DNA-based, antigen-specific immunomodulatory drug candidate for type 1 diabetes. The deal also marks the company’s first deal since being acquired by Roche. Until now Genentech’s technology franchise has rested firmly on partially or fully human mAbs aimed at specific immune-cell surface receptors to treat a variety of cancers.

Drawbacks of mAbs in Autoimmune Diseases
Genentech, now owned by Roche, also develops its antibodies to treat autoimmune diseases. It is currently seeking FDA approval for Rituxan® in DMARD-unresponsive rheumatoid arthritis, and for Xolair®, an anti-IgE antibody currently marketed to adults and adolescents, for pediatric asthma.

Ocrelizumab, a second generation anti-CD20 humanized mAb, is being developed with Biogen IDEC. It is currently in Phase III trials in rheumatoid arthritis and lupus nephritis. Said to be less immunogenic and cause less complement activation than Rituxan, this antibody may reduce the development of drug-neutralizing antibodies and infusion reactions.

mAbs, however, require regular IV infusions and can have serious side effects in some settings, because they compromise normal immune function. These may be acceptable therapeutics in an acute life-threatening disease setting such as cancer but can pose significant problems for use in chronic illnesses such as autoimmune diseases.

Avastin’s Potential?
Besides this limited setting for mAbs in chronic diseases, Genentech’s mAb-based cancer franchise is seeing some setbacks. The company’s strategy of finding additional applications for marketed products recently backfired with Avastin as an adjuvant therapeutic in early-stage colorectal cancer patients failing a late-stage study.

The drug, currently approved for patients with cancers that have spread beyond the breast, colon, and lung, already has blockbuster status. So far attempts to further expand this anti-VEGF antibody’s reach has not been successful. Such potential label expansions definitely played a role in Roche’s $95 per share, or $46.8 billion, takeover of Genentech.

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Following the announcement of the Avastin trial results, Roche’s stock plummeted to a 19-year low. The company had hoped that the drug, used in the adjuvant setting, would prevent tumor return and increase U.S. sales to $10 billion by 2015, according to some analysts’ projections.

Avastin now generates $4.8 billion globally in annual sales. U.S. sales of Avastin, considered the most important barometer of Genentech’s growth, rose 18% to $704 million toward the end of 2008 likely due to its increased use in treating breast cancer.

Fresh Approach: DNA-Based Antigen-Specific Drugs
Thus, while Genentech has profited handsomely in the past from the strategy of finding new uses for marketed drugs, its post-Avastin investment in Bayhill may represent a fundamental strategic change by taking a stake in a novel approach to autoimmune disease treatment. Genentech paid $25 million in cash and equity up front and agreed to pay development and sales milestones exceeding $325 million.

The terms of the exclusive, worldwide license cover development and commercialization of BHT-3021, a therapy based on Bayhill’s BHT-DNA antigen-specific immunomodulatory platform. The compound is intended to reduce or eliminate immune system attacks on insulin-producing pancreatic islet cells that result in type 1 diabetes.

“The BHT-DNA platform is based on plasmid DNA,” explains Bayhill CEO, Mark Schwartz, Ph.D. “We insert the gene for the protein that is the target of an autoimmune response, for example, proinsulin in the case of type 1 diabetes or myelin basic protein (MBP) in the case of multiple sclerosis, into a plasmid. Upon injection, the plasmid is taken up by antigen-presenting dendritic cells, which migrate to lymph nodes where they bind to the antiproinsulin T cells, thereby inactivating them and preventing them from attacking pancreatic islet cells.

“Preservation of C-peptide is what we want to see in treated patients,” Dr. Schwartz continues. “Placebo-treated patients experience a decline in C-peptide production over time as the insulin-producing cells of the pancreas are destroyed by the autoimmune response. C-protein is produced in a 50-50 ratio with insulin as proinsulin produced by pancreatic islet cells is enzymatically cleaved. The FDA accepts C-peptide as a marker of efficacy for type 1 diabetes therapeutics.”

Interim results of a Phase I/II trial testing this DNA-based, antigen-specific immunotherapy in patients with type 1 diabetes showed a preservation of C-peptide in treated patients compared to placebo and that BHT-3021 was safe and well tolerated among 42 patients who received one of four different doses of the drug over 12 weeks.

Understanding immune system mechanisms has evolved enough in the last few years to allow the development of antigen-specific, tolerance-inducing drugs. Dr. Schwartz notes that treatment of autoimmune diseases needs to be antigen specific. He characterizes the effects of general immunosuppressive agents as difficult for patients and physicians saying, “All antibody companies recognize that, in the end, antibodies and other immunosuppressants are bridges to antigen-specific approaches to treat these chronic diseases.”

Source: GEN News

The researchers, from Ireland and Hungary, warn cases in older children will also rise substantially.

Writing in The Lancet, they say genetics alone cannot account for the rapid rise, and suggest lifestyle factors are likely to play a role.

The study is based on 29,311 cases of type 1 diabetes recorded in 20 European countries between 1989 and 2003.

Type 1 diabetes is caused by insulin deficiency, and must be treated with regular injections of the hormone.

In the general population it accounts for only 10% of total diabetes cases, but is much more common than the type 2 version in children.

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The researchers, from Queen’s University, Belfast, and Pecs University, Hungary, found the overall incidence of type 1 diabetes rose by 3.9% per year.

However, among the under-fives it was 5.4% per year, and in the five to nine age group it was 4.3% per year.

They calculated that, on present trends, 24,400 new cases will be diagnosed in children under 15 in 2020, including 7,142 cases in the under-fives.

The total number of cases of type 1 diabetes among European children under 15 is predicted to rise from 93,584 in 2005 to 159,767 in 2020 – a 70% increase.

Among the under-fives, the total number of cases is predicted to double, from 9,955 in 2005 to 20,113 in 2020.

In the UK, where type 1 diabetes appears to be more common than elsewhere in Europe, the predicted rises are bigger still.

The researchers predict the total number of cases in the under-15s will rise by nearly 80% from 18,622 in 2005 to 33,289 in 2020.

And among the under-fives, they expect to see a 123% rise, from 1,975 in 2005 to 4,402 in 2020.

Lifestyle factors

The researchers say the increase in type 1 diabetes has been so rapid that it cannot be blamed on genetic factors alone.

They also point out that the highest increases have been seen in Eastern Europe, where lifestyle habits are changing more rapidly than in richer Western European nations.

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Researcher Dr Chris Patterson said: “The children of older mums are at slightly increased risk of type 1 diabetes as are children born by Caesarean section and children with rapid weight gain early in life, while breast-fed children are at slightly decreased risk.

“Infections and viruses may also play a role. But currently none of these risk factors can be said to be responsible for the increase, the cause of which remains largely unknown.”

The researchers warn that it is likely that hospitals will see more patients with severe diabetes complications presenting at a younger age.

These can include the potentially life-threatening condition ketoacidosis, in which the acidity of the blood is raised by the unregulated breakdown of fats and proteins by the liver.

Not only do young children with type 1 diabetes tend to be diagnosed late, and so have a higher risk of complications, they potentially face a lifetime of problems – bad news for them, and for the health care systems who must look after them.

Writing in the journal, the researchers said: “In the absence of any effective means to prevent type 1 diabetes, European countries need to ensure appropriate planning of services and that resources are in place to provide high-quality care for the increased numbers of children who will be diagnosed with diabetes in future years.”

Dr Iain Frame, director of research at the charity Diabetes UK, described the research as “worrying”.

“Many people live full and healthy lives, however, the longer the person has diabetes the higher the risk of complications such as heart disease, kidney failure and blindness.

“However, a lot more research is needed before we can come to any concrete conclusions about the causes of this rise in type 1 diabetes in younger children.”

Source: BBC NEWS