Fixing ‘Misfolded’ Proteins for New Drug Treatments

Reporting in the Proceedings of the National Academy of Sciences, researchers were able to fix “misfolded” proteins and restore their function in mice. Lead researcher Michael Conn discusses how to mend an incorrectly folded protein and what this may mean…

Reporting in the Proceedings of the National Academy of Sciences, researchers were able to fix “misfolded” proteins and restore their function in mice. Lead researcher Michael Conn discusses how to mend an incorrectly folded protein and what this may mean for developing future therapies for a variety of diseases.


This is SCIENCE FRIDAY. I’m Ira Flatow. Later in the hour, how exercise can help you fight disease, but first whenever you see a picture of proteins, they look like long chains of curled ribbons twisting and folding in on themselves. Proteins can have complicated structures. There’s even a game that crowd sources answers to figure out how they fold because proper folding is a key to making proteins function correctly.

Think of a string of tangled Christmas lights. Protein chains can get a little misfolded and that can cause illness and disease. Researchers have developed a new technique that can correct these misfolded proteins and they’ve tested it successfully in laboratory mice. It could potentially treat diseases ranging from Alzheimer’s to cystic fibrosis. Their findings are published in The Proceedings of the National Academy of Sciences.

Michael Conn is leading researcher on the study, also professor of cell biology, biochemistry, senior vice president for research and associate provost at Texas Tech University health sciences center in Lubbock, Texas. He joins us from KTTZ. Welcome to SCIENCE FRIDAY.

MICHAEL CONN: Thank you for having me, Ira.

FLATOW: I think I have some misfolded proteins in my throat this hour. Let me see if we can work through that. Excuse me. You looked at something called by various names, including a protein chaperone. Tell us about – let’s walk through what a protein is supposed to do and what happens when it doesn’t fold or unfold correctly.

CONN: Well, you know that mutations in genes cause diseases by changing the sequence of amino acids that make up the protein and your analogy of the misfolded Christmas lights is a good one. We sometimes think about it as replacing a pearl on a necklace with a marshmallow. The result just won’t be shaped right. And for years, people thought that mutations cause disease only by damaging the ability of proteins to work correctly.

And sometimes, that’s what mutations do. But we now know that cells evaluate newly made proteins for structural defects and that some mutant proteins that could work just fine are marked for destruction because they aren’t structurally perfect. What we’ve found is a way to save those perfectly good, but incorrectly folded and incorrectly rooted proteins and return them to use.

We call this process protein rescue and the drugs that rescue these proteins are what we call pharmacologic chaperones or pharmacoperones. Our recent study, done at Oregon Health Sciences University and now at Texas Tech Health Sciences University with my colleague Jody Janovick, shows that protein rescue with pharmacoperones can work in a living animal. And this, as you say, was a mouse with the same mutation that causes the human disease. We were able to reverse the course of this disease. Let me explain it a slightly different way. Suppose I asked you to give me a lift to work and you tell me that you can’t use your car. That could be because your car is broken, but it also could be because you forgot where you left it at work on the other side of town.

So what we have here are drugs that find that car and restore it to where it belongs so it becomes useful to you again. These pharmacoperone drugs correct misfolded, misrouted mutant proteins and they return them to where they need to be to function properly and reverse the course of disease.

FLATOW: And what kinds of diseases are we talking about here?

CONN: Well, the interesting thing is that proteins can be enzymes. They can be ion channels. They can be receptors, and so there is a huge range of disease to which, theoretically, this could apply. It could apply to the ion channel defect that occurs in cystic fibrosis. We’ve been working with a disease called hypogonadotropic hypogonadism. There is a disease called nephrogenic diabetes insipidus; a form of blindness, a very common form, retinitis pigmentosa; oxalosis and hyperoxaluria; hypercholesterolemia, which affects large segments of the American population.

FLATOW: So this is sort of a pathway that people have really not taken advantage of. I mean, drug-makers, people like that, as a…

CONN: Yeah, that’s correct.

FLATOW: …as a way to restore the function that these proteins could do.

CONN: It is. Most — most of drug development has been based on identification of chemicals that either activate or inhibit proteins. And here, we’re controlling the cellular location of a protein, which, as you say, is a fundamentally different approach.

FLATOW: And how soon will we know if it works in people?

CONN: It shouldn’t be too far off. I mean, the nice thing about some of the drugs that we’ve used is that they’ve already been used in clinical trials for other purposes and we know that they’re relatively safe.

FLATOW: Is this really a question of, like, tinker toys? You physically bend the protein back into the right shape?

CONN: The pharmacoperone interacts physically with the molecule and creates the shape that passes through the cell’s quality control system and because of that, even misfolded proteins can be refolded and trafficked correctly in the cell, thereby restoring them to function.

FLATOW: And so they’re sitting there, like you say, like junk cars waiting for what? To be disposed of by the cell and you can rescue that?

CONN: Well, normally the cell would dispose of them by degrading them and using the bits and pieces to make new proteins. But we’re actually able to go in and refold proteins that have been misfolded and retained in the endoplasm reticulum, which is the garbage dump of the cell.

FLATOW: And you’ve been working on this for almost two decades, right?

CONN: We’ve been working on it for almost 15 years and at the present time, we brought together a huge team of people, including our colleagues Richard Behringer and David Stewart in Houston, Darla Jacobs in Portland is a superb veterinary surgeon who helped. And so, by bringing a lot of different expertise together over the course of about eight or nine years, we were able to develop this animal and do this project.

FLATOW: Well, we’ll wait to see what happens with your human trials and anticipate that something good will happen here. Thank you very much, Dr. Conn.

CONN: Thank you.

FLATOW: Michael Conn is senior vice president for research. He’s associate provost professor of internal medicine in cell biology biochemistry at Texas Tech University Health Sciences Center that’s in Lubbock, Texas.