Learning from Rare Diseases

October 30, 2017

Matt Wilsey has liked to make the case that one justification for investing in rare disease research is that through it, we can unlock an understanding of common diseases.

Wilsey, chairman, president, and co-founder of the Grace Science Foundation (and a member of the Global Genes’ board) has good reason to make that case. In 2013, his daughter Grace was diagnosed with a rare genetic disorder called NGLY1 deficiency. At the time, she was one of only six known patients with the condition worldwide. Even today, only 37 people have been identified with the condition, which has devastating affects including developmental delays, life-threating liver complications, tremors, and more.
But it’s not just the case of a father looking to find justification for research spending in an ultra-rare disease few would seem to have reason to care too much about. Wilsey is in good company making such an argument. The same case has been made by researchers ranging from the English Renaissance physician William Harvey to National Institutes of Health Director Francis Collins.
Examples of how rare disease research has shed light and more common diseases include new insights that have emerged from rare disease research into such things as heart disease, Alzheimer’s disease, diabetes, and osteoporosis. Now, Wilsey can add to this list with work funded in part through the Grace Science Foundation.

Last week Stanford University reported that Carolyn Bertozzi, a Stanford professor of chemistry and member of the Grace Science research team, along with graduate student Frederick Tomlin and postdoctoral fellow Ulla Gerling-Driessen, gained an important insight into why some cancer patients develop resistance to a promising new class of cancer therapies known as proteasome inhibitors.  

It’s long been known that the NGLY1 gene is responsible for producing the enzyme N-glycanase 1, which is produced by the NGLY1 gene. In the 1990s, Japanese researchers found that the enzyme the strips sugars off of proteins, a process called deglycosylation.

In March 2016 Bertozzi was attending a conference when she learned about a molecule called Nrf1. Nrf1is a regulatory protein within cell and plays a critical role in the health of neurons. It is also the culprit in cases where cancer patients turn resistant to proteasome inhibitors.

For Nrf1 to take its active form, sugars on its surface must be stripped away through deglycosylation. Bertozzi and her associates showed NGLY1 does that. In the absence of NGLY1, Nrf1does not become active and protect neurons and other cells. In the case of patients like Grace Wilsey, the absence of NGLY1 leads to a disastrous range of symptoms, but Bertozzi’s research suggest by muting the protein a tad, they might be able to counteract the effects of Nrf1 to allow proteasome inhibitors to be effective in patients who are otherwise resistant.

That new insights may help researchers better understand the problems of NGLY1 deficiency, but also many cancer patients who might eventually benefit from protease inhibitors that otherwise not have been able to help them.

On the homepage of the Grace Science Foundation, there’s a video that makes the pitch that helping that research into NGLY1 deficiency will benefit millions of patients with countless other diseases. Bertozzi and her colleagues just added to that case.

October 30, 2017



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