UCSF researchers block molecular pathway to diabetes, blindness

2005 Career Award for Biomedical Science Recipient Feroz Papa
When Feroz Papa was an internal medicine resident at the University of California, San Francisco he treated many patients with diabetes, giving them insulin and other treatments designed to restore the body’s balance of glucose. But he always knew he wasn’t treating the root of the problem.

“There really weren’t any disease-modifying therapies aimed at the beta cell itself,” said Papa, who had always been interested in the molecular basis of diseases. “That sparked an interest to try to work in that arena,” he said.

In people with diabetes, the insulin-secreting beta cells in the pancreas are destroyed. Wanting to better understand this process, Papa focused his postdoctoral work at UCSF on the pathway that secretes proteins such as insulin out of the cell. He sought to understand how this pathway functions in health and what happens when it goes awry in disease.

With this goal in mind, Papa decided to tackle the complex unfolded protein response, a cellular quality-control mechanism. The cell’s endoplasmic reticulum, where proteins fold and assemble, has the ability to sense when protein folding has gone wrong. If a cell is malfunctioning and deformed proteins accumulate, the unfolded protein response jumps into action. Its cascade of signals equips the cell to either fix or get rid of misfolded proteins.

But if too many malformed proteins are present, and the cell can’t cope, the once adaptive quality-control machinery kicks into overdrive. Instead of saving cells, it programs them to die. This process destroys beta cells when insulin is misfolded in the case of diabetes. Other conditions, especially degenerative diseases, have similar origins.

Papa focused specifically on one of the molecular sensors of unfolded proteins: IRE1α. In studies involving yeast, Papa discovered that this sensor not only promotes the expression of genes related to cell survival but can also foster cell death. If too many unfolded proteins accumulate, IRE1α acts like a “life-death switch,” changing its molecular shape to induce cell death, Papa said.

As Papa wrapped up his postdoctoral work and sought out faculty positions, he hoped to apply what he found in yeast to mammals. He wondered if he could design a small molecule to inhibit the switch function of IRE1α, forcing it to stay in the off state. This would prevent the unnecessary cell death that occurs in diseases like diabetes. But these complex ideas had not yet been tested.

In 2005, Papa accepted a faculty position at UCSF and received what he described as a “lifeline,” a Burroughs Wellcome Fund Career Award in the Biomedical Sciences.

“Having that grant initially made me take risks,” he said. Instead of spending time at the beginning of his career gathering pilot data for a governmental grant proposal, Papa was able to pose the big research questions he’d been aiming for.

In a series of more than a hundred experiments, Papa and his collaborators explored ways to inhibit IRE1α and validated their approach in animal studies. For Papa, the resulting paper, published in Cell in July, was the most satisfying of his career. With 24 authors, the paper is also the result of an enormous interdisciplinary collaboration involving experts in fields ranging from medicinal chemistry to ophthalmology.

First, the researchers replicated Papa’s previous work examining the function of IRE1α. When it senses too many unfolded proteins, IRE1α sticks to itself, forming rod-like sections of protein that allow it to promote cell death. Papa and his colleagues then developed and optimized a small molecular inhibitor of IRE1α, called KIRA6, which breaks these rods apart and prevents cells from dying.

After several experiments, Papa and his colleagues wanted to further explore this process “not just in cells but in animals,” he said. “That was always the standard we held ourselves to.” The researchers turned to two seemingly unrelated diseases that are both driven by an overactive unfolded protein response.

They tested the effects of KIRA6 in mutant rats designed to model retinitis pigmentosa, a degenerative disease that eventually leads to blindness. In this condition, an important protein in the eye’s light-sensing cells becomes misfolded, causing the cells to undergo programmed cell death. But when the researchers injected KIRA6 into the rats’ eyes, they found that less of the light-sensing cells were dying.

Then Papa returned to his original interest: diabetes. The researchers injected KIRA6 into mice with a mutation that causes misfolded insulin and found that it improved insulin production and blood sugar balance in these mice. Surprisingly, these benefits were maintained even after the mice stopped receiving the small molecule treatment.

“That’s when we knew we were there,” said Papa. Instead of just treating the diabetes-like symptoms in these animals, the researchers were able to change their underlying biology, just as Papa had envisioned during his residency.

But the pathway to disease Papa has proposed is likely more complicated, said Randal Kaufman, director of the degenerative diseases program at Sanford-Burnham Medical Research Institute.

“There are really a lot of ways to interpret these findings,” said Kaufman, who also studies the unfolded protein response. He thinks more data is needed to show exactly how KIRA6 is inhibiting cell death and which pathway it’s acting on.

In future studies, Papa hopes to explore the role of the unfolded protein response in type 2 diabetes, in which factors like obesity play a role. He also wants to make KIRA6 even smaller in size, which would allow it to enter the brain to treat neurodegenerative conditions, such as Alzheimer’s disease. And he will further explore potential toxic effects of the drug, including disrupted growth. This work will eventually lead to clinical trials in humans, he said.

But Papa is quick to remember a time when his ideas were “pie in the sky” before he received the BWF award. “Having the ability to do big science, to dream, and ask big questions really was enabled by having the types of mechanisms that Burroughs has done really so well,” he said.