This past summer was a rare disease conference-palooza. In July, I attended the 2018 NGLY1 Conference, hosted by Grace Science Foundation (GSF) in Palo Alto. It was the 5th gathering of families and scientists from around the world, united behind one goal: to find a cure for NGLY1 deficiency. This post recaps my time at the 2018 NGLY1 Conference, as well as my take on how the conference has changed since its inception in 2015, and the path that lies ahead.
The arc of progress
At a lunch during the conference, I remarked to Kristen Wilsey, Grace’s mom, that I was fortunate to have been present at all four previous conferences. I could clearly discern the arc of progress from where the tiny NGLY1 knowledgebase stood in April 2014, when I first met Matt Wilsey, Grace’s dad, until now.
At the beginning, it was personified by Dr Tadashi Suzuki, the brilliant scientist who discovered NGLY1 in the 1990’s, and who has devotedly studied the gene since. A biochemist by training, Tadashi was the seed around which the GSF has crystallized a large and engaged community of researchers working on NGLY1. The first yeast and fly models of NGLY1 were published by Tadashi’s group in the pre-CRISPR era. Four years later, it’s 2018, and we’re standing atop a rapidly expanding NGLY1 knowledgebase, taking aim at the clinic.
Growth of the NGLY1 community
I remember the first gathering, held in March 2015, in downtown Palo Alto. There was a group dinner, followed by a full-day meeting the next day.
The second meeting was held in December 2015, on UCSF’s Mission Bay campus. It was a smaller meeting, with roughly 30 participants. Whereas the March 2015 meeting included everyone, this meeting primarily focused on PIs. (The pattern – alternating between a large meeting and a smaller, more focused meeting – is one that the GSF has maintained since.)
Grace Science Foundation (then named the Grace Wilsey Foundation) held its first NGLY1 meeting in March 2015
By then, Dr. Kevin Lee had also joined GSF as Chief Scientific Officer, and Dr Carolyn Bertozzi of Stanford had started working on NGLY1. One of the roadblocks at that time was not having a good specific antibody against NGLY1. It’s a rate-limiting step for basic, translational and clinical research for most, if not all, rare disease foundations that are eager, but struggling, to score easy therapeutic wins in the early days post diagnosis.
The third gathering, in October 2016, was a two-day conference in Palo Alto. Two highlights for me that year were Drs. Gary Ruvkun’s and Nic Lehrbach’s paper showing, in worms, that PNG-1/NGLY1 regulates the function of SKN-1A/NRF1/2 by removing its N-linked glycans, a novel mechanism of post-translationally modification. Dr. Bertozzi presented data from her lab that confirmed the conservation of NGLY1 regulation of NRF1/2 in patient and mouse cells.
2017 NGLY1 Conference families and researchers
The fourth conference – another 2-day event – was held in July 2017. NGLY1 families from all over the world converged on Palo Alto for a long weekend to hear the scientific talks and to participate in “biohackathon” of sorts. Blood, urine, stool and other biosamples were collected from the NGLY1 families, followed by biomarker/metabolite analysis in Dr. Mike Snyder’s lab at Stanford and whole-genome sequencing by the Broad Institute. Remarkably, a little boy from Hong Kong who is homozygous for nonsense mutations – in theory a severe genotype – could walk and talk. To the trained eye of any NGLY1 parent, the symptoms of the disease were unmistakably present, though extremely muted. What this means is that this boy is being protected by one or more variants in a gene, or genes, other than NGLY1 – so-called disease modifiers. If we could determine which modifiers are protective, it could be the opening of a therapeutic avenue.
2018 NGLY1 Conference researchers
2018 NGLY1 Conference
That brings me, finally, to the GSF 2018 NGLY1 Conference. Only the GSF-funded researchers attended and presented data during the 2 conference days. But it wasn’t just all science, science, science. GSF tried something new this year: several breakout sessions led by experts in industrial design thinking. These impromptu brainstorms got our creative juices flowing, and reminded everyone of the big picture, i.e., curing NGLY1 as fast as scientifically possible.
Next goal: the clinic
As we conclude Stage 3 of our NGLY1 PerlQuest with GSF and take the next steps toward commercializing the drug repurposing assets we discovered to the clinic, I look forward, with great anticipation, to next year’s GSF conference. A natural history study is underway at Stanford to lay the groundwork for the first clinical trials. Can we get into the clinic by 2020? We’re doing everything we can to make that ambition a reality!
Learn more about Perlara’s work in developing and screening disease models of NGLY1!
Group images courtesy of the Grace Science Foundation
