Smarter insulin?

insulinInsulin was the first hormone to be genetically engineered for human use, and synthetic insulins now control blood glucose levels for almost everyone with type 1 diabetes and millions of those with type 2 diabetes. Many variants of the molecule have been designed to act quickly or slowly or in between, but the Holy Grail is smart insulin—which would not only work over many hours but automatically adjust its own release to keep blood glucose levels in a good range.

Many labs have taken a stab at smart insulin since the first attempt in 1979. New approaches keep cropping up, and a few show particular promise in animal tests. A “nanoparticle network” reported in 2013 is one of the more interesting. These nanoparticles combine insulin, dextran (a complex sugar often employed to slow down glucose effects) and enzymes that target glucose. Given opposite electrical charges, the nanoparticles are thought to clump together in the body rather than wander off in the bloodstream, doing their duty like a tiny pancreas.

The current commercial champion for smart insulin, though, began back in 1999 with research by Todd Zion, then an MIT graduate student in chemical engineering. Zion came up with a design that combined modified insulin with a sugar gel, and worked dramatically well in rats. He and his colleagues spun out a startup firm called SmartCells in 2003 and honed the technology well enough to get the attention of Merck, which snapped up SmartCells in 2010. Last spring, Merck remarked that it would bring a L-490 smart insulin based on the company’s technology into a clinical trial this year.

But there’s been no news from Merck since, and the National Institutes of Health’s site doesn’t mention a trial for L-490.

So we’re still in the animal labs.

But I’m still encouraged by last month’s paper in the journal PNAS on a different approach to smart insulin, developed by a team led by MIT’s Daniel Anderson and Robert Langer. This group found that an engineered insulin with the sprightly name of Ins-PBA-F performed very well, maintaining good glucose levels in the blood of mice without functioning pancreases over more than 12 hours and also behaving itself in normal mice.

Which sounds like L-490. But the researchers suggest that the approach Ins-PBA-F spearheads may offer better control and safety in the long run than L-490 because it’s more like normal insulin.

Ins-PBA-F starts with a molecular structure of a long-acting synthetic insulin, and adds a chemical group called “phenylboronic acid” (PBA) that binds to glucose and other sugars. When the surrounding glucose levels climb high enough to occupy the PBA group, the insulin itself is released for action. (Curiously, though PBA is often used to sense sugars and other carbohydrates, the PNAS paper acknowledged that the exact mechanism by which Ins-PBA-F responds to higher glucose levels in the blood isn’t yet clear.)

In theory, such a directly modified insulin molecule may be safer from immune reactions and other side effects than smart insulins that add gels or other types of protein barriers for glucose, as do L-490 and most other approaches. If so, that benefit will appeal mightily to the FDA, which will give extremely tight scrutiny to a radical new drug that could be used around the clock by many millions of people.

A successful smart insulin will be very far from a niche product. Anderson and Langer (who may well hold the world record for co-founding biomedical startups) have the attention of the venture capital community. I hope that successors to Ins-PBA-F will indeed move toward clinical trials, and eventually the clinic. That might be a very smart bet.

Update: Merck actually but very quietly moved its smart insulin into a two-part clinical trial in fall 2014.

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s