Type 1 Diabetes Vaccine Shows Promise In Small Trial

Date: Jun-27-2013A new type of "reverse" vaccine for type 1 diabetes has shown some promising results in a small trial. The DNA-based
vaccine is designed to switch off the part of the immune system responsible for destroying the pancreatic cells that produce
insulin. Its novelty lies in the fact it does the opposite of conventional vaccines, which are designed to boost immune
responses.

The researchers who carried out the trial, led by Stanford University School of Medicine in the US, write about their findings in a
paper published in the 26 June online issue of Science Translational Medicine.

Richard Insel, chief scientific officer of JDRF, formerly known as the Juvenile Diabetes Research Foundation, says in a
statement:

"This is the first demonstration of a DNA vaccine targeting type-1 diabetes in humans."

Lawrence Steinman, one of the paper's senior authors and a professor of pediatrics and of neurology and neurological sciences at
Stanford, adds:

"We're very excited by these results, which suggest that the immunologist's dream of shutting down just a single subset of
dysfunctional immune cells without wrecking the whole immune system may be attainable."
Type 1 Diabetes Is An Autoimmune Disease that Destroys Insulin-Producing Cells
Some 3 million Americans have type 1 diabetes, an autoimmune disease, where for reasons that aren't completely understood, a
part of the immune system attacks the beta cells in the islets of Langerhans in the pancreas, where insulin is produced and
released. The body needs insulin to help regulate blood sugar.

Researchers have long been seeking a therapy that targets just this part of the immune system while leaving the rest
intact.

The CD8 cells of the immune system are like patrolling inspectors that go around the body checking if the cells or materials they
come across are "healthy" and to be left untouched, or suspicious (such as a bacterium or virus that causes disease) and should
be destroyed.

All cells make proteins, and they display bits of the proteins they make on their cell surfaces. These are what the patrolling CD8
cells inspect. If they find any bits of protein that look "foreign" or altered in some way, they mount an attack on the
cell.

So in the case of type 1 diabetes, the CD8 cells are mistakenly attacking the pancreatic cells that produce insulin. But what is the
protein on the surface of the beta cells that triggers them?

Beta cells are the only cells in the body that produce insulin. The hormone starts out as precursor protein called
proinsulin.

Immunologists suspect that it is bits of proinsulin on the surface of the beta cells that triggers attacks by misdirected CD8 cells.
Vaccine that Shuts Down Rather than Boosts An Immune Response
So for their study, Steinman and colleagues tested a vaccine designed to reduce attacks by misdirected CD8 cells on the insulin-
producing beta cells of the pancreas.

There are two features of the "reverse" vaccine they developed that make it a novel approach compared to conventional
vaccines.

Conventional vaccines typically deliver proteins or bits of proteins that boost the immune response against those organisms that
produce them.

But instead of carrying the protein itself, this new vaccine contains some DNA of the gene that codes for the proinsulin
protein.

And secondly, the vaccine is not designed to boost the immune response to the protein but to shut it down.

Adapting an approach they were already working on, Steinman and colleagues inserted a piece of DNA from the proinsulin gene
that they suspected would cause the immune system to launch an anti-inflammatory signal only to the CD8 cells targeting
proinsulin.

In other words, they designed a vaccine that makes the immune system attack the bit of itself that is attacking the beta
cells.
Trial's Key Findings: Beta Cells Likely Preserved, CD8 Count Fell
The trial they carried out to test the vaccine was a multicenter, randomized, double-blind trial involving 80 patients diagnosed with
type 1 diabetes who were receiving insulin replacement injections.

The vaccine contained modified genetic material incorporated into rings of DNA and was administered with weekly intramuscular
injections for 12 weeks.

They gave four different doses of the vaccine to four patient groups and placebo injections to a fifth group.

The researchers chose not to test blood levels of insulin, because these can vary widely and lead to spurious results. Instead,
they measured levels of C-peptide, a piece of proinsulin that is chopped off in the process of making insulin.

C-peptide stays in the blood much longer than insulin, so it is an excellent "proxy" measure for insulin production by the beta
cells.

The trial yielded at least two important findings.

First, levels of C-peptide were maintained, and in some cases increased, over the 12-week period.

This suggests the patients who received the vaccine suffered less ongoing destruction of beta cells than those who received the
placebo.

Second, blood levels of the proinsulin-primed CD8 cells targeting the beta cells fell in the patients receiving the vaccine.

The beneficial effect of the DNA vaccine appeared to fall a few weeks after the 12 week dosing schedule stopped.

There appeared to be no serious side effects.
Very Early Days
Steinman warns that these are early results from a small trial and now need to be confirmed in larger trials that last
longer.

And it looks like it will be years before such a vaccine is ready for human use. To date, no DNA vaccine has been approved for
use in human patients.

Steinman and two other authors have an interest in the trial sponsors, Bayhill Therapeutics. Bayhill has now been acquired by
Tolerion, who are seeking funding for a larger, one-year-long efficacy trial of the new vaccine.

Tolerion and Stanford University hold the intellectual property associated with the vaccine.

Earlier this year, Diabetes UK announced a big research program to develop a new vaccine for type 1 diabetes within the next two decades.

Written by Catharine Paddock PhD

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