The “Reverse” Vaccine: Stopping Type 1 Diabetes
Three million Americans are living with type 1 diabetes, once known as juvenile diabetes. These patients need to inject themselves with insulin every day to stay alive. Now, for the first time, a promising therapy may stop the disease in its tracks.
Every second of every day, Spike Loy has to think about his blood sugar. He was diagnosed with type 1 diabetes when he was 7.
“My mom tested me for years,” Loy told Ivanhoe.
Now, he tests himself up to 10 times a day and has to worry about potential complications like nerve damage, blindness, and stroke. However, Stanford researchers are now studying a vaccine that could reverse the disease.
“We saw some very exciting outcome measures,” Larry Steinman, MD Professor of Pediatrics and Neurology, Stanford University, told Ivanhoe.
In type 1 diabetes, the immune system stops beta cells from making insulin. The vaccine uses DNA to attract and attack the bad cells that destroy insulin, while leaving the good beta cells alone.
“We bait the bad cells, kill them, and leave the beta cells in the pancreas to survive and function as insulin-producing cells,” Dr. Steinman said.
Researchers gave 80 patients the vaccine once a week for 12 weeks. Those who received it had more beta cells. It essentially reversed the effects of the disease, which could lower the risk of complications.
Spike says it’s a step closer to what he wants most, a cure.
Steinman says future studies of the vaccine will test whether patients can reduce or maybe even one day eliminate their daily insulin doses. There were no significant side effects observed in the study. To date, no DNA vaccine has ever been approved for human use. This could be the first one.
BACKGROUND: Type 1 diabetes when the body is not producing enough insulin. This disease is commonly diagnosed to children and young adults, previously named juvenile diabetes. Type I diabetes involves constant pricking to measure blood sugar levels and continuously injecting yourself with insulin because the pancreas is not producing enough. There is no cure for type I or type II diabetes yet, but there are ways to keep healthy and stable. (Source: http://www.diabetes.org/diabetes-basics/type-1/)
SYMPTOMS: Most symptoms for type I diabetes consists of:
· Weight loss
· Unusual hunger
· Increased thirst and urinating often
TREATMENT: Because there is not a cure for diabetes, patients need to take insulin every day for the rest of their lives. Commonly, insulin is administered through a pump, needle or pen depending on the patient. A few ways that patients can help with type I diabetes is to maintain a healthy diet, exercise often and monitor blood sugar regularly. Doctors suggest that patients keep blood sugar levels between 80 and 120 before meals during the day and 100 and 140 before bed.
NEW TREATMENT: A new vaccine is being studied to potentially reverse type I diabetes with just a simple shot. This vaccine manipulates bad cells that ruin insulin with DNA while preserving the good cells in the pancreas. This will reduce or get rid of patients’ complications with the disease and will free individuals of injecting themselves with insulin. This treatment is still being researched and will be the first DNA vaccine on the market. (Source: http://www.nlm.nih.gov/medlineplus/news/fullstory_138189.html)
Larry Steinman, MD, Professor of Pediatrics and Neurology at Stanford University, talks about a possible vaccine for type 1 diabetes.
So, we are talking about what used to be called juvenile diabetes. There’s really no cure for these people. Is that correct?
Dr. Steinman: That’s correct. Over 100 years ago, researchers in Toronto made one of the most stunning discoveries in medicine, insulin. Insulin saves the lives of people who can’t make it. Since that huge discovery, there has not been further advance in turning off this disease. We have meters, nicer needles, and blood sticks to monitor; however, we don’t have a single therapy for the disease.
Is Juvenile Diabetes caused by lifestyle?
Dr. Steinman: Juvenile diabetes is in large part a genetic predisposition for the immune system to attack for reasons that were trying to understand. The only cell in the body that makes insulin is the beta cell in our pancreas. So, juvenile diabetes, or type I diabetes as we now call it, is not a lifestyle disease, but it can change your life. It is not the disease of the overeating obesity epidemic that sweeps the industrialized world.
Now, with good control we can get through most of the crises that are caused by type I diabetes, namely having either too high or too low blood sugar. The complications that can come 20, 30, 40, or 50 years down the road are still devastating. They include blindness, disease of your peripheral nerve so that your sensation goes away, stroke, eye disease, and blindness. Those are all the long-term complications. If we could do something to modulate the disease or even to cure it someday, then we wouldn’t have to face those downstream problems.
So, what are you looking at now? Is it manipulating DNA?
Dr. Steinman: Well, what we’re trying to do is to use DNA itself as a vaccine to shut off that immune response that goes on that wrecks and kills the cells that are making insulin.
So, how do you use your own DNA as a vaccine?
Dr. Steinman: DNA is a very versatile molecule. It’s easy to replicate. We are creating a vaccine that has in its coding region, so it actually a protein called pro-insulin. Pro-insulin is the main target of attack in the autoimmune part of type I diabetes, autoimmune meaning that it is the part of the disease where your immune system mistakenly decides to attack itself. Pro-insulin is a protein molecule that is the precursor of insulin, which is life-saving in the disease. So, we use the DNA vaccine in the following way, we have a circular piece of DNA and part of it codes for pro-insulin and part of it that does not do any coding for a protein is actually part of the solution to the problem. We engineer into the DNA a series of sequences that turns down the immune response. It is a two-pronged missile. It is a smart way to do it. We bate the immune system by saying here’s pro-insulin come get it. So, the cells that are attacking pro-insulin and insulin are drawn to the vaccine. It is a bait and switch, if you will. We bate the bad cells, kill them, and then leave the beta cells in the pancreas to survive and function as insulin producing cells.
So, when I think of a vaccine, I think of a shot or a drop on your tongue. This wouldn’t be that way, correct?
Dr. Steinman: Well, it’s a shot. We inject the DNA into the muscle, but there are probably other ways to do it.
Do you take the DNA out of the patient first?
Dr. Steinman: We do it all in a test tube. We don’t have to take out an individual’s DNA. It’s a standard piece of DNA that is so engineered to do the things that I mentioned. We are not manipulating the individual’s DNA; we are actually using DNA itself as an intelligent vaccine to specifically shoot down the unwanted immune responses.
Now, you have put this through Phase II clinical trials?
Dr. Steinman: Yes. First, we spent a lot of time curing mice, but the good news here is that it worked very well in mice and looked safe in mice. So, we’ve now taken it into an early Phase II trial in humans, 80 patients. The safety looks very good and unexpectedly because the trial was really small and we were mainly looking for signals of danger. We did not see them, it’s safe. Also, we saw some very exciting outcome measures that look like this may be very helpful for people suffering from type I diabetes.
What did you see?
Dr. Steinman: We saw the preservation of beta cells that make insulin and not only did we see preservation, but we saw a small increase in the number of beta cells while we were giving the DNA vaccine. We gave the DNA vaccine for a period of three months and during that period, and for a few months thereafter, the beta cell numbers actually increased. So, the idea in the next trial, which will be bigger, is to give this for longer, maybe for their entire lives, on a weekly basis or a monthly basis; we’ll have to learn about that.
Did the eighty people in the trial have type 1 diabetes?
Dr. Steinman: They all had type I diabetes. It was a safety trial, but done in people with the disease.
Did they have to keep taking their insulin then or were they able to come off of it?
Dr. Steinman: They did keep taking their insulin and we’ll see as the treatment improves and as we give it for longer, whether we can influence that. The second thing we saw implications were for those horrible complications that I mentioned. The other thing that we saw that was the most exciting was that we were removing from those immune cells that attack pro-insulin and that kill the beta cells in the pancreas. So, the good news is they were dying and we can detect that their levels were being significantly lowered. Also, we were not affecting other aspects of the immune system because we still need our immune system, with or without type I diabetes, to fight viruses and other forms of infection. This was specific immune targeting of only the cells that cause the autoimmune disease. Now, the other thing that we did see of course was the first part of the two exciting findings, namely that we were showing that the beta cells were stabilized and were even increasing. We feel as does the research community in type I diabetes, as well as the Food and Drug Administration, that if you can do that there is a very good chance that you will lower the incidence rate of all the horrible complications that occurred decades later. Whether or not we can take away the need for giving insulin shots, just the fact that we can preserve those beta cells will hold up well in the future for protecting individuals with type I diabetes from these complications.
Would you have to keep taking your insulin?
Dr. Steinman: We don’t know the answer to that. In a perfect world, we would continue this vaccination program and you stop requiring insulin because your own body will start making more insulin at physiological quantities, just like when you need it after a meal. However, it’s hard to say whether or not we would be able to stop the need for insulin shots.
How often would you have to take this vaccine if you’re a type 1 diabetic?
Dr. Steinman: Well, the way we are giving it now is on a weekly basis. We may learn that we can give it less frequently as we continue the program, but this is a work in progress. We are very excited about what has been accomplished so far in 80 humans with the disease, but we have a lot more to learn. I estimate that it will take another 2 to 3 years of testing before we can give the answers to those very important questions.
The immune system seems to be very tricky and it adapts to things and learns ways around them; is that a concern?
Dr. Steinman: It is a great question and we already have some answers. First, the major immune response in type I diabetes targets pro-insulin and we’re covering all the different aspects of that immune response to pro-insulin. The second thing is what if there is some kind of escape mechanism in these individuals, that they start making an immune response to some other component of the beta cell. Well, there’s not that many other components of the beta cell that are only made in the beta cell and the thing is that insulin is only made in one cell in our body and that’s the beta cell. So the main thing you want to target is pro-insulin. Another thing we can do with this versatile vaccine, is if other unwanted responses come up we can easily program the DNA to take care of them. We are actually watching to see if there are escape mechanisms just as you mentioned that one sees in chemotherapy and in other types of treatments for severe diseases.
On the more optimistic side, with a lot of the vaccines we use there are not escape mechanisms. If a child gest immunized to polio, he or she essentially would be immunized the rest of my life even though polio is a virus. Now, many vaccines need booster shots, our tetanus shots should get replenished every 10 years or so, according to our public health service. So, I think we’re working more in the domain of a vaccination that requires boosting and actually more frequently perhaps. Then that example I gave with tetanus, that’s once every 10 years because as I said, we think we’ll have to give this maybe weekly or monthly. We may come up with a pleasant surprise and find out that it is much like tetanus.
Are there any downsides or any side effects that came out in your trial?
Dr. Steinman: No, it looks very safe and I have to mention that many people would like to solve the problem of type I diabetes and cure it. Many of the procedures that are being tried have been taken from the realm of cancer therapy, transplantation therapy, and I refer to them as big hammers. If you have a cancer or you need to protect yourself from rejecting a transplant I don’t care if I have to take down a big hunk of the immune system to do so and that’s what these drugs do. For an autoimmune disease, like type I diabetes, where you can live essentially a normal lifespan though you have the risk of some severe complications decades down the road, I think the balance of efficacy and safety is switched way over to let’s do something that’s safe and efficacious, not something that’s a big hammer and efficacious. So, unlike our competing approaches, we feel that this is a targeted approach that will have the benefits of both efficacy and safety.
Could the people suffering from type II diabetes benefit from this at all?
Dr. Steinman: Well, I’d like to hope that’s true, but type II diabetes appears not to have as much of a specific immune response as we know from type I diabetes. I think that for type II diabetes lifestyle changes are the first line of action. For type I diabetes, or so called juvenile diabetes, changing your lifestyle isn’t going to help you have to stop that immune attack.
Would you say this could be a cure for type I diabetes?
Dr. Steinman: Well I hope so, but there’s a long way to go and I don’t want to hold out false hopes now. If we could maintain the level of beta cells and help to lower the long-term complications of the disease, it would be a great step forward. Could this be a cure? Well, let’s see where the data take us.
FOR MORE INFORMATION, PLEASE CONTACT:
Larry Steinman, MD
Professor of Pediatrics and Neurology
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