Why is TMEM175 an interesting drug target?

This is a great question; the reason I think that many people/companies are interested in TMEM175 as a drug target is that it checks most of the boxes for something you would want to go after sporadic disease.  First off, the genetic data on this are from GWAS studies on the sporadic/common form of the disease.  While I think the pharmaceutical industry has agreed on the value of pursuing targets with genetic data linking them to the disease of interest, there’s always a concern with genes linked only to rare familial forms of disease that you may not be hitting the pathway that drives the disease in the majority of patients.  The TMEM175 M393T variant is relatively common in the general population, and it has been tied to the common form of the disease.  Similarly it has been tied to lysosomal and mitochondrial function, both of which have strong genetic support as being critical to Parkinson disease pathophysiology - again that suggests modulating gene function could be beneficial in a large percentage of PD patients.

All of that would make TMEM175 worth pursuing, but there is an additional piece that makes it stand out - bidirectionality of effect.  Many risk variants for disease have clear evidence for pushing in one direction (risk), but it isn’t clear that they can also have a protective effect.  As an analogy, consider a car driving down the highway too fast - perhaps this is the highway to Parkinson disease.  A risk variant in a gene causes you to push down harder on the gas pedal.  Modulating the gene - making the foot go off of the gas pedal is great, but it only gets you so far - if you start to pull up on the gas pedal, the car doesn’t slow down.  That’s an analogy for a gene with a unidirectional association with disease.

TMEM175 has a second relatively common variant - the Q65P variant, that has a protective effect, reducing disease risk.  Similarly, which knocking out the gene increases the level of pathologic synuclein, we also showed that overexpression of the TMEM175 reduces pathologic synuclein.  Hence TMEM175 appears to have both “gas pedal” and “brake pedal” function. I think the combination of these two pieces of evidence - strong genetic evidence in a central pathway of PD and bidirectionality - is what makes it so interesting.

From your perspective – considering TMEM175 as a druggable target – what are the lessons learned since the PNAS publication in 2017? What were the challenges? 

Challenges have never been lacking with this target!  When the initial publication came out (and the following one in 2019) ^1,2 and I spoke to other researchers in pharma and academia, one of the main questions that came up was “How can we ever screen this thing?”  Running an HTS on TMEM175 seemed a Herculean task at best, and the fear was that we were years away from the necessary technology being available.  I remember speaking to one colleague in big pharma who said the reason his company hadn’t screened this was that they had no idea where to begin.  Since the gene was so new, virtually none of the tools necessary were out there, and running an HTS on a lysosomal ion channel seemed almost impossible.  But as a colleague of mine once told me “almost impossible = possible”.  I’m glad this team knows that and was willing to tackle the almost impossible!

In what way, do you think the recent manuscript is a contribution to potentially revealing more about TMEM175 function and/or accelerating the drug discovery process?

I think it’s worth noting two things about the manuscript and the methods described; how this has moved the field forward, and importantly also acted as a lesson in drug discovery.³  The first thing to remember is that the reason we do this is to find a therapeutic that can help patients - that always has to be at the top of our algorithm and our ultimate goal.  It’s great to examine the effect of a gene by knocking it out or increasing its expression, but in the end we want to know what happens when we pharmacologically manipulate the protein’s activity. This manuscript has demonstrated that it is in fact possible to screen this channel, giving us the ability to both make tool molecules to understand the basic biology of the protein, and more importantly to find lead molecule for developing candidate therapeutics.

Equally important is the lesson for drug discovery in general: this was considered to be a difficult, if not impossible target to work on, but this research has shown that with tenacity, perseverance, and careful science, the problem could be cracked.  The only way we will ever make therapeutics for these areas of unmet medical need is to never shy away from a problem just because it is hard; in fact, finding a cure for diseases like PD is supposed to be hard.  For that reason I think this manuscript demonstrates one of the most important lessons in drug discovery.³

References

1. Jinn S, Drolet RE, Cramer PE, Wong AH, Toolan DM, Gretzula CA, Voleti B, Vassileva G, Disa J, Tadin-Strapps M, Stone DJ. TMEM175 deficiency impairs lysosomal and mitochondrial function and increases α-synuclein aggregation. Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):2389-2394. doi: 10.1073/pnas.1616332114. Epub 2017 Feb 13.
2. Jinn S, Blauwendraat C, Toolan D, Gretzula CA, Drolet RE, Smith S, Nalls MA, Marcus J, Singleton AB, Stone DJ. Functionalization of the TMEM175 p.M393T variant as a risk factor for Parkinson disease. Hum Mol Genet. 2019 Oct 1;28(19):3244-3254. doi: 10.1093/hmg/ddz136.
3. Bazzone A, Barthmes M, George C, Brinkwirth N, Zerlotti R, Prinz V, Cole K, Friis S, Dickson A, Rice S, Lim J, Fern Toh M, Mohammadi M, Pau D, Stone DJ, Renger JJ, Fertig N. A Comparative Study on the Lysosomal Cation Channel TMEM175 Using Automated Whole-Cell Patch-Clamp, Lysosomal Patch-Clamp, and Solid Supported Membrane-Based Electrophysiology: Functional Characterization and High-Throughput Screening Assay Development. Int J Mol Sci. 2023 Aug 14;24(16):12788. doi: 10.3390/ijms241612788.