Hartford Courant: Rebecca Lurye, August 1, 2017

Yale Chemist’s Upcoming Trial Could Open Doors For New Medical Treatments

A Yale chemistry professor is closing in on a medical breakthrough that could help cure a rare genetic disorder as well as pioneer a novel way of treating disease.

Yale University Sterling professor Alanna Schepartz is working to send protein-based therapies into hard-to-reach areas of the cell. It’s an incredibly difficult task, one that has stumped the numerous scientists who’ve tried to apply it to treatments for cancer, HIV and other diseases. But this summer, with a new Yale grant in hand, Schepartz is beginning preclinical trials that could prove she’s done it.

If her treatment is successful, it would be a first for the long-studied drug-delivery method —based on what are called cell-penetrating miniature proteins — and a potential model for other therapies. Other researchers have sought to treat cancer, cardiac diseases, pain, and strokes with the method.

“Frankly, that’s pretty remarkable,” said Jon Soderstrom, director of Yale’s Office of Cooperative Research. It could be, he said, “like another arrow in the quiver for potentially developing new therapies.”

Beyond the vital medical research, Schepartz’s progress toward animal trials also illustrates how major universities are aggressively seeking markets for their faculty’s work.

Schepartz will soon begin mouse trials on a potential cure for Type 1 Citrullinemia, a rare genetic disorder in which ammonia and other toxins build up in the blood, causing lethargy, seizures, loss of consciousness and vomiting. It affects 1 in 56,000 people worldwide, and often presents itself in newborns.

For more than a decade, Schepartz has been studying the chemistry behind this treatment method, which involves understanding and then manipulating the traffic patterns of molecules in and out of and within cells. Her first major breakthrough came in 2012 with her lab’s discovery of a protein that traveled where she needed it to go.

By the summer of 2019, Schepartz hopes to know whether she can successfully hitch a therapy to that protein, called ZF5.3, and treat the disease.

But Schepartz’s research goes back much further, and she once had something different in mind for its application. In 2012, she was one of three professors awarded $2.5 million from the National Cancer Institute to study ways to prevent cells from becoming cancerous.

Her attention expanded to Type 1 Citrullinemia when she applied to Yale’s new $10 million Blavatnik Fund for Innovation, established in August 2016 to help move research out of labs and into the market. The fund’s advisory board thought — and Schepartz agreed — that a breakthrough in treating an incurable genetic disorder would be highly attractive to investors.

There are treatments for this disorder’s symptoms, but they’re inconvenient, required in high doses and don’t prevent ammonia from building up in the body again.

“The buildup of ammonia is especially damaging to the brain,” Schepartz said. “A big reason this disease was chosen is that no disease-modifying treatments currently exist.”

In May, she won a $300,000 Development Grant from the Yale Blavatnik Fund.

While it’s not a huge windfall by medical research standards, it will help fund one more study — one tailored to the questions and concerns of real industry members, the ones with the capital to take her research to the next level.

This is how the Blavatnik Fund helps remove barriers to commercializing research, Soderstrom said.

“We’ve spent a lot of time talking to potential investors about exactly what data they want to see before they make that investment so when we show it to them, it’s not a ‘So what?’ it’s an ‘Oh, finally!'” Soderstrom said.

The key to Schepartz’s work has been the protein her lab discovered in 2012.

Cells are full of compartments, and it’s hard to predictably move large molecules — like those designed to treat disease — from one compartment to another, Schepartz said.

But this special protein “magically” seems to make this movement happen easily and predictably. That may allow her to send treatment to regions of the cell it otherwise couldn’t go.

The “why” is still a mystery. That’s another goal of her upcoming trials, to learn more about how the machines of the cell work so she can rewire them to heal people.

Her work is a bit like a novice trying to repair an automobile engine. They may not know how it works to start, but they will by the time they’re done. But what would be foolish in a garage is necessary in Schepartz’s lab, where there are no manuals and mechanics to turn to.

“The truth is, she tackles the most difficult questions in biology and chemistry,” said Rebecca Wissner, a post-doctoral researcher who joined Schepartz’s team in 2015. “This is a problem that medicine has not really overcome yet. It’s exciting, but a little bit daunting too.”

Wissner, like Schepartz, is quick to say that the trial may not succeed — and that it’s too early to talk about the way their research could change a patient’s life. But even a failed experiment helps push science forward, she said.

“Just because something works well in a dish doesn’t mean it will work well in an animal, but we need to know that,” Wissner said.

It helps to work in a lab where “never give up,” is the constant refrain, and with a woman who hasn’t stopped working to solve the same problem in more than 15 years.

“I’m an eternal optimist,” said Schepartz.

 http://www.courant.com/health/hc-yale-schepartz-breakthrough-20170726-story.html