Feels like the last 12 months went by in a flash! When I wrote this post a year ago, we were just getting started in the lab but we had ambitious plans for the year to come. We set two big goals for 2015. First, to complete a two-species (nematode and fruit fly), 50,000-compound HTS campaign for Niemann-Pick C in the first half of the year. Second, to begin mouse tox and efficacy validation studies in the second half of the year. I’m thrilled to say that we achieved both goals thanks to the indefatigable efforts of the PLab team.

Let’s take a stroll down recent memory lane…


Here are some plates from the first month of the NPC fly screen. It was a heroic effort by Tom and Tamy that we blogged about here and here. We had to do quite a bit of optimizing on the fly (no pun intended).


At the same time Tom and Tamy were performing the NPC fly screen, Sangeetha and Alec were hard at work on the NPC worm screen, which we blogged about here and here. While the NPC fly screen was done in 96-well plates and involved manual inspection for hits, the NPC worm screen was done in 384-well plates and involved automated image capture and analysis.



Technically, we included a yeast model of NPC but in the end we concentrated on the worm and fly screens. Here was a progress report tweet from the end of March, roughly the halfway point of the NPC HTS campaign.


Nina led the NPC patient cell validation effort, which was designed to follow the primary screens. The idea was that any hits from the worm and/or fly screens would be tested on patient cells to see if NPC disease phenotypes were affected (ideally normalized).


Right on schedule at the start of summer, we were wrapping up the HTS campaign. The primary screening phase is as the name suggests just the beginning. What follows is the most exciting part of the drug discovery process: hit-to-lead.


Midway through the year, PLab presented the results of our NPC HTS campaign for the first time to the NPC research community, which gathers annually under the auspices of the Ara Parseghian Medical Research Foundation. It was a gratifying milestone for us. A year before, I attended the Parseghian meeting by myself, with no data. In fact, we were still in the process of closing our seed round.


Tom took to the PLab blog to review a key paper from the NPC literature. It was no longer about making sure the HTS gears were turning as efficiently as possible. By this point in the summer, we were finalizing all hit retests and starting to focus like a laser on the underlying disease biology of NPC.


By the end of the summer, we had completed the hit validation phase. When the dust settled, approximately 100 compounds remained standing out of the 50,000 that went into the screen. The hit-to-lead phase was drawing to a close as we started to focus on the most promising hits. One of these compounds would come to be known as PERL101.


The autumn began with a very special occasion on the the rare disease calendar — the Global Genes Patient Advocacy Summit. This was my third Summit. When I first attended in 2013 I didn’t even have a formal business plan for PLab. At the 2014 Summit, PLab had just closed our seed round and we were brimming with excitement to get started. Each year more of us attend and we have more scientific progress to share. We expect 2016 to be no different.


Though not mentioned here by name, our lead compound for NPC, PERL101, was put through its DMPK paces. In assay after assay, PERL101 passed these preclinical “go/no-go” checkpoints with flying colors. Liver microsome stability in mouse, rat and human? Check. Human hepatocyte stability? Check. Oral bioavailability in mice? Check.


All the progress above pertains to our lead program for NPC. Our other lead program is for NGLY1 Deficiency. Alec and I started the NGLY1 HTS campaign with a yeast chemical modifier screen. Hits from this screen will be tested on NGLY1 mutant flies. One of our goals for 2016 is to complete a primary drug screen using the NGLY1 null mutant fly we generated using CRISPR, which Tom blogged about here.


We capped off the year with a huge result: PERL101 cross the blood-brain barrier! Keep in mind that at the start of this year, there was no PERL101. To give you a sense of how quickly we’ve progressed, PERL101 first came on the scene in May. By the end of the summer, we knew that PERL101 had a novel mechanism of action. But did PERL101 have the right stuff to go straight into mouse validation studies? Turns out the answer is a resounding yes.

We can’t wait to see what happens to PERL101 in the new year, and we can’t wait to find hits like it for NGLY1, and for the other diseases we plan on onboarding in 2016.

If you want to know what happens next, you know where to find us.


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