Silicon Valley entrepreneur becomes a rare disease hunter and advocate for his daughter, born with NGLY1 deficiency  

In 2013, after four years of symptoms ranging from muscle weakness to developmental delays, Grace Wilsey was finally diagnosed. But that diagnosis—NGLY1 deficiency—came at a huge cost, both financial and emotional.

“When we started out, we didn’t know what Grace had,” said Matt Wilsey, who along with his wife, Kristen Wilsey, founded the Grace Science Foundation to help their daughter. “We crisscrossed the country trying to find the one clinician who had seen this particular phenotype. We couldn’t find anybody, so I persuaded two centers, Stanford University and Baylor College of Medicine, to do whole genome sequencing independently.”

The whole genome sequencing itself was incredibly expensive, but it gave Matt and Kristen their answer. Unfortunately, that answer came with a universe of new questions.

The Parents’ Will

The Grace Science Foundation, this year’s winner of Charles River’s Research Models in Drug Discovery Award, was born of the Wilseys’ determination to help their daughter. At first the grieving couple supported researchers using their own funds. No one was looking directly at NGLY1 as a disease gene, and Grace’s condition was completely new. This meant they had to approach the issue from a unique angle.

“Once we had a diagnosis, it was like okay, now we know something and we have a target,” Wilsey said. “And a lot of family and friends were asking what they could do to help.”

Wilsey decided to funnel interest from family and friends into a foundation where scale and coordination could move science faster. They would search for scientists working in related areas and cold call them to spark a focus on NGLY1 in return for research funding. Since orphan diseases like NGLY1 deficiency have a limited pool of patients, treatments have a very limited potential for profit and don’t attract the attention of large pharma companies. Smaller ventures like the Grace Science Foundation have begun popping up to fill in that gap and save those patients who fall through the cracks. The Wilseys’ foundation, while a common solution for this problem, was at a disadvantage from the beginning due to the extremely limited patient pool and lack of meaningful research. A parent’s will, however, can achieve wonders.

The Science of Saving Grace

“Initially we thought [NGLY1] was just sort of a housekeeping gene,” said Wilsey. “It was involved in cleaving off glycan structures and getting rid of junk. But really it’s about misfolded proteins and how cells respond to stress.”

Researchers know that symptoms of the disease are caused by deglycosylation errors, or a failure to remove sugars from glycoproteins. In fact, NGLY1 deficiency is the first identified deglycosylation disorder. It is not yet understood how those errors cause Grace’s symptoms, but scientists are getting close.

“Matt is drumming up interest in this and raising money for it in order to solve Grace’s problem,” said Dr. Charlie Boone, one of the foundation’s researchers and a professor at the University of Toronto. “It’s a hero move, and it’s time dependent. We need a solution now, not tomorrow.”

Boone and other foundation researchers are approaching the problem from many angles. According to Wilsey, the foundation is not looking to fill up a room full of glycobiologists. Instead, they want to create a Manhattan Project for this one disease. To that end they have animal researchers, cell and systems biologists, chemists, geneticists, and scientists from many other fields working simultaneously on the foundation’s one goal: cure Grace and patients like her. Like all science, however, the impact of their research will certainly radiate out to help other patients.

“We do have support that it’s tied to larger neurodegenerative diseases like Parkinson’s,” Wilsey said. “This is so much bigger than we ever expected. Can it help with diabetes? Can it help with Hashimoto’s, or lupus, or being able to make better vaccines? It’s a little bit daunting, because at the end of the day we want to cure the 60 people that have the primary disease.”

Bringing Patients Together

In 2017 the foundation gathered researchers, patients, and patients’ families together in Palo Alto, California for a conference. One of the guiding missions of the foundation is to foster collaboration between scientists, so that part of the conference was routine. The addition of patients, however, added an emotional and humbling wrinkle to the proceedings.

“It was strange for me – I am not a doctor,” said Gary Ruvkun, who heads his own lab at the Simches Research Center in Boston, Massachusetts. “I don’t see a lot of people with genetic disease, and it was sobering. The parents get a lot of hope from it, because they see that these people who seem wicked smart are working on their kids’ disease.”

Wilsey called the 2017 conference the “UN on steroids for rare disease.” Nine languages were spoken, and some families who came had never been on a plane. Samples were taken from each patient, including stool, skin, urine, and saliva, which were used to build a biobank of infinite value to researchers.

Wilsey is proud of the collaborative atmosphere of the conference, which reflects the values of the foundation itself. Although he is quick to shuffle funding when one research avenue seems to be exhausted, he admires the dedication of all the scientists who have chosen to pitch in, calling them “A+ people.”

Matt will accept the Charles River Research Models in Drug Discovery Award at the World Congress: Delivering Therapies to the Clinic Faster in Cambridge, MA on September 23-24. Register now to join us!