DRC & Research News

Published 2 weeks ago by Albert McKeon in Diabetes, Donor Recognition, and Medical Research. Click here to read original article.

After nearly 20 years of research, Massachusetts General Hospital researcher Denise Faustman, MD, PhD, has made a promising advance in her quest to cure type 1 diabetes.

Her team recently passed a major threshold by receiving FDA clearance to test a large group of long-term diabetics with an old tuberculosis vaccine that could also combat type 1 diabetes. The phase 2 trial of the bacillus Calmette-Guérin (BCG) vaccine was announced last month at an American Diabetes Association conference in Boston, an exciting next step in Dr. Faustman’s pursuit of a therapy to reverse the disease.

While thrilled about receiving the FDA’s blessing, Dr. Faustman and her staff didn’t celebrate for long. They’re already accepting applications for patients who want to participate in the five-year trial that starts this summer.

We’re in full action mode. The phones are ringing off the hook,” Dr. Faustman says. As many as 100,000 diabetics are expected to volunteer for the clinical trial, but the MGH Immunobiology Laboratory will winnow the number of participants to 150 adults, with some receiving BCG and others taking a placebo.

Old Vaccine, New Promise

The FDA approved the phase 2 trial essentially by certifying MGH’s use of BCG that will be produced by the Japanese government. Academics usually don’t have to look around the world to find a drug supply chain, Dr. Faustman says, but her lab – in collaboration with the Bill & Melinda Gates Foundation and the World Health Organization – searched as far as Japan because it couldn’t land enough BCG from a U.S. drug manufacturer.

BCG was first used as a vaccine against tuberculosis, and it more recently targeted bladder cancer. Dr. Faustman started experimenting with the vaccine in the early 1990s. She was interested in how BCG triggers the immune system to make a protein that kills the abnormal T-cells which hinder the pancreas’ ability to produce insulin.

Her recent advance might not have happened without the insistence and generosity of former Chrysler CEO Lee Iacocca. After losing his wife, Mary, to complications from diabetes, Iacocca’s charitable foundation began supporting Dr. Faustman’s research, and in 1999 he urged her to expand her testing to mice, with the promise of continued funding.

Deserving Diabetes Patients

“We cured a late-stage diabetic mouse and saw pancreatic regeneration. No one had seen that before,” Dr. Faustman recalls. That led to a small phase 1 study in people to see if BCG could destroy the bad T-cells and prompt the good ones to produce a small amount of insulin. That phase succeeded, leading to this next stage: a longer trial on a larger number of people who have had type 1 diabetes for years.

“All type 1 diabetes intervention trials have been only in new onset cases, people only a year out from diagnosis,” Faustman says. Her team’s phase 2 trial will be “remarkable because we’re picking people who are the most deserving to receive this novel therapy. These are the people who’ve had diabetes for years. If there’s a way to see if it works, you have to go for the people who’ve had it the longest.”

Dr. Faustman’s team will administer, four weeks apart, two injections of BCG or a placebo, on top of annual injections over the remaining four years. Trial participants – ages 18 to 60 – need to have low but detectable levels of insulin secretion from the pancreas to qualify for testing. If the trial succeeds, Dr. Faustman’s team will conduct a third trial with a larger group of people.

Extremely Broad Support

“We’ve worked on this for 20 years,” Dr. Faustman says. “We understand the pathway and mechanism of the disease…the tools are in hand. We’ve done the homework.”

The Iacocca Family Foundation and many individual donors contributed to the more than $19 million that has been raised to finance the phase 2 trial; another $6 million is still needed. Dr. Faustman appreciates the support she’s received over the years and hopes donors recognize the importance of moving testing forward.

“We have kids raising money with lemonade stands and other people having large fundraisers. We’ve benefitted from small and big philanthropic programs, from the U.S. and Canada. We’ve had extremely broad support and we’ve been fortunate.”

Published on July 28, 2015 via The Lancet. Click here to read original article.

Background

Traditional genetic testing focusses on analysis of one or a few genes according to clinical features; this approach is changing as improved sequencing methods enable simultaneous analysis of several genes. Neonatal diabetes is the presenting feature of many discrete clinical phenotypes defined by different genetic causes. Genetic subtype defines treatment, with improved glycaemic control on sulfonylurea treatment for most patients with potassium channel mutations. We investigated the effect of early, comprehensive testing of all known genetic causes of neonatal diabetes.

Methods

In this large, international, cohort study, we studied patients with neonatal diabetes diagnosed with diabetes before 6 months of age who were referred from 79 countries. We identified mutations by comprehensive genetic testing including Sanger sequencing, 6q24 methylation analysis, and targeted next-generation sequencing of all known neonatal diabetes genes.

Findings

Between January, 2000, and August, 2013, genetic testing was done in 1020 patients (571 boys, 449 girls). Mutations in the potassium channel genes were the most common cause (n=390) of neonatal diabetes, but were identified less frequently in consanguineous families (12% in consanguineous families vs 46% in non-consanguineous families; p<0·0001). Median duration of diabetes at the time of genetic testing decreased from more than 4 years before 2005 to less than 3 months after 2012. Earlier referral for genetic testing affected the clinical phenotype. In patients with genetically diagnosed Wolcott-Rallison syndrome, 23 (88%) of 26 patients tested within 3 months from diagnosis had isolated diabetes, compared with three (17%) of 18 patients referred later (>4 years; p<0·0001), in whom skeletal and liver involvement was common. Similarly, for patients with genetically diagnosed transient neonatal diabetes, the diabetes had remitted in only ten (10%) of 101 patients tested early (<3 months) compared with 60 (100%) of the 60 later referrals (p<0·0001).

Interpretation

Patients are now referred for genetic testing closer to their presentation with neonatal diabetes. Comprehensive testing of all causes identified causal mutations in more than 80% of cases. The genetic result predicts the best diabetes treatment and development of related features. This model represents a new framework for clinical care with genetic diagnosis preceding development of clinical features and guiding clinical management.

Written by Serena Gordon on July 21, 2015 via HealthDay News. Click here to read original article.

Taking two 12-week courses of alefacept — a drug already approved to treat the skin condition psoriasis — may help people with newly diagnosed type 1 diabetes preserve some function in the beta cells in the pancreas, a new study suggests.

People taking the drug needed about 25 percent less insulin, and they had about half the rate of major low blood sugar episodes (hypoglycemia) compared to those who took a placebo, the study revealed.

“This is the first time that documented rates of hypoglycemia — using standardized home glucometers in all patients — have shown a reduction in major hypoglycemia events following an immune intervention in new-onset [type 1 diabetes] patients,” lead researcher Dr. Mario Ehlers, of the Immune Tolerance Network, said in a network news release.

“This is important because frequent hypoglycemia is a common and serious complication in this disease,” Ehlers added.

Type 1 diabetes is an autoimmune disease that causes the body’s immune system to mistakenly attack the insulin-producing beta cells in the pancreas. Specifically, certain T-cells in the immune system lead the attack. When enough beta cells have been destroyed, a person can no longer produce enough insulin. Insulin is necessary to help the sugars in foods get into the body’s cells to be used as fuel.

When used early after diagnosis, alefacept may interfere with the action of the destructive T-cells. And the drug appears to do this without affecting another type of T-cell that is protective, the researchers noted.

The current clinical trial — the second of three required for approval — included 49 people between the ages of 12 and 35 who were newly diagnosed with type 1 diabetes. Patients were randomly selected to receive the drug or a placebo. Thirty-three people were given the drug for two 12-week courses, with a 12-week gap in between the courses.

Over two years of follow-up, the group that received the drug had a lower decline in a marker of beta cell function known as C-peptide. Moreover, nine out of 30 patients evaluated for C-peptide function showed no decline in C-peptide production, compared to just one of 12 people evaluated in the placebo group. Preservation of C-peptide lasted as long as 15 months after treatment stopped, Ehlers noted.

“Achieving long-term benefit following a short course of therapy is a challenging goal,” Dr. Gerald Nepom, director of the Immune Tolerance Network, said in the news release.

“Detailed analysis of the T-cell types present in the blood of those who responded to the treatment will help us identify the best way to improve this type of immune therapy for patients with type 1 diabetes and potentially other autoimmune diseases,” he added.

The study results were published July 20 in the Journal of Clinical Investigation.

Published on July 8, 2015 via The Journal of Pediatrics. Click here to read original article.

Young people with type 1 diabetes are increasingly likely to be obese, according to new research.

The study, which was conducted by researchers from T1D Exchange, suggested that excessive consumption of processed foods was to blame, and urged people with type 1 diabetes to maintain a healthy diet and plenty of exercise.

The study does not suggest that obesity is a cause. In fact a dramatic loss of weight is one of the key symptoms of type 1 diabetes. Rather the problem of weight gain and obesity can develop in some people with type 1 diabetes following theirdiagnosis.

Traditionally, people with type 1 diabetes have tended to be underweight. This is because insulin and blood glucosemanagement technologies were less advanced, and as a result, more glucose – and therefore calories – pass out of the body through the urine.

However, as diabetes management has improved, more glucose and calories have been retained. Coupled with the same over-consumption of unhealthy foods that affects many people in society, it has meant that people with type 1 diabetes have been affected by the obesity crisis.

Obesity in people with type 1 diabetes increases their risk ofinsulin resistance, severe hypoglycemia and cardiovascular disease.

The research was conducted by examining the data of 33,000 pediatric diabetes patients aged to between two and 18, using their height and weight to judge their Body Mass Index (BMI.) Of those patients, nearly 40 per cent were classed as “overweight.”

The study, which was the first to compare data of young type 1 patients from a variety of countries, also found that higher BMI in people with type 1 diabetes was closely linked to higher HbA1c levels.

The researchers blamed unhealthy diets for the rise in type 1 obesity, and urged young people to develop healthy eating habits from a young age. Not only does a healthy diet reduce the risk of obesity, it makes it easier to control blood glucose levels.

“Type 1 diabetes is extremely difficult to manage even under the best circumstances,” said corresponding author Stephanie DuBose, of the Jaeb Centre for Health Research.

“Thus, the number of young people with the disease who have the added burden of excessive weight is disconcerting to say the least. These patients are at risk for serious complications, especially as they get older.

“This research underscores the need for physicians to educate their patients about the importance of maintaining a healthy weight as part of overall diabetes management.”

David M. Maahs, associate professor of pediatrics at the Barbara Davis Centre for Diabetes at the University of Colorado, said: “The obesity problem in the US is well-known, but obesity’s effect on adolescents with type 1 diabetes is overlooked. These patients need to avoid excessive calories and get more physical activity. Addressing these issues as early as possible in a pediatric patient’s life will make healthy behaviours more likely to become lifelong habits, adopted well before the damage is done.”

Dr. Maahs suggests that more research should be done to explore the potential weight loss benefits of various treatments, including metformin and GLP-1 receptor agonists, medications traditionally used to lower blood glucose levels in people with type 2 diabetes.

The research was published in The Journal of Pediatrics.

Written on July 8, 2015 via Nature Communications. Click here to read original article.

Reprogramming an already specialised cell into a stem cell is a scientific feat coveted by many researchers. In 2006, the Japanese scientist Shinya Yamanaka first succeeded in producing these “induced pluripotent cells,” known as iPS cells, capable of becoming any type of cell from the human body, by a process requiring the introduction of a cocktail of four genes into differentiated cells. Until now, only embryonic human cells possessed such a characteristic. iPS cells represent a promising advance. With their help, it should ultimately become possible to replace diseased organs with new organs derived from the patient’s own cells, thereby eliminating all risks of rejection. They would also circumvent the ethical problems raised by the use of cells from human embryos.

Despite this success, cell reprogramming is not yet fully controlled. It is limited by certain constraints, including the phenomenon of programmed cell death, which restricts the number of cells produced. In this context, Fabrice Lavial’s team, in collaboration with Patrick Mehlen’s team, sought to identify new regulators of the genesis of iPS cells.

With this objective, the researchers directed their attention to the factors affected by the four inducing genes involved in the initiation of reprogramming. They then selected from this list those known to have a role in programmed cell death, and with a level of expression that varies over the course of reprogramming. After this screening process, one molecule emerged: netrin-1.

Netrin-1 is a protein naturally secreted by the body. Interestingly, it is able to prevent programmed cell death, among other things. In the first days of reprogramming mouse cells, the researchers observed that their production of netrin-1 was strongly reduced. This deficit limited the efficacy of the process. The researchers then tested the artificial addition of netrin-1 to compensate for its insufficiency in the early phases of reprogramming.

This time, the quantity of iPS cells produced from mouse cells was much more greater. An observation repeated during study of human cells, from which fifteen times more iPS cells were produced by adding netrin-1.

From a therapeutic point of view, it was important to determine whether this treatment affected the quality of cell reprogramming.

“According to several verifications, netrin-1 treatment does not seem to have any impact on the genomic stability the iPS cells or on their ability to differentiate into other tissues,”says Fabrice Lavial, Inserm Research Fellow.

The team continues to test the effect of netrin-1 on the reprogramming of other types of cells, and is endeavouring to gain a better understanding of the mode of action of this molecule in stem cell physiology.