The GBA1 Meeting and the State of Science in Parkinson’s Disease

Last week I went to Montreal to attend the GBA1 meeting at the Montreal Neurological Institute. I left more optimistic about the state of neuroscience than I have been for some time. While things are still not perfect, and I’ll highlight some of the more glaring imperfections soon, there was a palpable sense that we may finally be on the cusp of a turning point in the science of PD. One that just might finally deliver on the long-sought after disease modifying therapies for sub-groups of people with PD within the next few years!  

But before I get into all that cause for optimism, a note first on what drives science forward. Science is the product of the collective efforts of individuals. Thus that is how I plan to tell the bulk of this story, by profiling the individuals that made it memorable for me. From debates on Loss of Function vs. Gain of Function to brilliant talks on lipidomics and immunology to lively conversations had in the hallways and over meals, it is through the steadfast work of individuals acting for the betterment of the whole that science moves forward. Though I cannot here pay homage to all that deserve, know that I feel indebted to each and every one of you for choosing to pursue the careers you have. And so, from the bottom of my heart, thank you.

Various depictions of the GBA1 protein and lysosomal dysfunction, thanks to Meta.ai for these. For anyone in need of a primer on GBA-PD before we get a little lost in the weeds here I’d recommend reading two blog posts from The Science of Parkinson’s found here and here.

Having said that, I need to start with the most glaring downfall of meetings such as these, the lack of patients. There were none invited to speak and only a scant few in attendance, including myself and Jonathan Silverstein, who was one of the principal funders of this event. I was saddened to see how little regard the patient voice is still given in meetings such as these. I’ve been attending conferences like it for over eight years now and outside of the WPC and a few bespoke events there is very little progress that has been made in making a seat for the patient voice to be heard.

Why this is I think boils down to an incomplete understanding of the value that comes when patients are given a voice. So let me put forth an argument for doing so, again.

It is vital that at conferences such as these everyone in attendance is grounded in reality. Again and again I heard scientists speaking about PD or even GBA-PD as if it were a monolith. You’ve likely heard the phrase before, ‘if you’ve met one person with PD you’ve met one person with PD’. I believe the same is true among GBA carriers. We seem just as varied in our symptomology as those with idiopathic PD. I for one am still not convinced that that my own N370s variant of my GBA gene really has that much to do with my own version of PD.

Also in the same vein I was very disappointed that there was so little talk of the variety and breadth of symptoms that patients with PD and GBA-PD experience. I tried to bring this up in a comment early on in the conference but was rather quickly muffled. So I again say here that for us carriers there is no disease, only symptoms we clump together and label a disease. No one has ever gone to their doctor complaining about their lysosomes, they go to get help with their abnormal movements which have only ever been loosely tied to aberrant cellular processes like lysosomal dysfunction which are still only presumed, yet never proven, to be linked to our GBA mutations.

(I’ll stop myself there before I veer to far into that rant. For more, click to read my take on symptoms vs. disease. Also check below for a more up to date listing of the various symptoms of PD.)

Before I delve into the meat of this article, the talks and the individuals that gave them, a few words on trying to understand the lingo of science. I have always viewed science as just another language and I believe that has really helped me better understand my own form of PD, while also enabling me the ability to speak with and understand, for the most part, the people who speak about it.

For anyone out there hoping to learn any branch of science the first thing one would need to do is pick up the vocabulary the individuals in that branch use. When I started out I would go to lectures or read the literature and write down every single word I did not know and test myself on them later.

And so, the best tip I can give for how to understand any domain of science is by making vocab lists. Thankfully there’s now a much easier way to make them. Below is a sampling of some of the words one would need to know to better understand the talks that took place at this past GBA1 Meeting. Hope someone out there finds them helpful.

I have many many more, if anybody thinks they might be useful just let me know and I’d be happy to give.

But enough preamble, on with the show. And I’ll begin with one of the more lively talks I have heard from one of the most remarkable individuals in the field. Dr. Peter Lansbury who I will affectionately title, The Skeptic…

The Skeptic

Every good science conference needs a vocal skeptic and I was happy to see that they put one as a speaker at the outset of this meeting. Though I have known Dr. Lansbury for a number of years now, first in his role as CSO of Lysosomal Therapeutics (here is our interview from back then) and then at Bial, I have never actually been present to hear him speak at a meeting such as this before. And so, I was eagerly awaiting his talk, and boy did he deliver.

He was tasked with giving an overview of the lysosomal glycosphingolipid metabolism pathway and turned what could have been a very dry talk into one of the most riveting journeys of the entire meeting while also touching on the perils the field faces in its attempts to make sense of it all. I shouldn’t have really been that surprised at Peter’s story telling prowess, after all he was the one who first convinced me that all trials in PD can only be responsibly done in individuals whom we can confidently measure and demonstrate marked changes to specific biomarkers in question. In the case of GBA-PD trials, this can be done through assays he helped establish which can now reliably measure an individual’s Gcase activity. (Gcase is an essential enzyme that lysosomes need in order to break down a crucial lipid called a glycolipid.)

Now, if you are asking yourself what the hell does any of that mean and what does it have to do with a patient’s symptoms you are not alone and I can vouch for Dr. Lansbury and say that is exactly the question he has been trying to answer. And though we cannot say anything definitive quite yet, there is reason to believe we might be on the cusp of doing so for some individuals diagnosed thanks in large part to the tireless work of people like Dr. Lansbury. I won’t spoil what he is working on next, but will say I am very excited to follow him as he pushes the field ever closer to its goals of developing disease modifying therapies for subtypes of PD. Exciting times.

A final note on another crucial lesson I have learned from Peter over the years. As science evolves and ostensibly gets us closer to its goals, it desperately needs to be repeatedly kicked and pruned along the way. I am very grateful to Dr. Lansbury for being one of those prickly prunes who is unafraid to challenge those who need challenging, allowing patients like myself to do one of the most important tasks there is in our lives, more easily sort out what is true from what is not, so that we can better tell what might work for each of us from what will not.  

The Immunologist

Dr. Malu Tansey is truly one of a kind. Something that came through the first time I interviewed her almost exactly 6 years ago is her knack for using words to paint moving images in the minds of her audience. As a result, more than probably anyone else she is responsible for teaching the PD field about the role the immune system plays in both health and disease.

In the talk she gave in Montreal she took us a step further when she said, and I’m paraphrasing here, ‘We need to look at cells, the cells that make up our immune systems, not fluids.’ This in my opinion is a critical message that we must take to heart. For too long we have been ignoring the crosstalk between the central and peripheral compartments of ourselves that are critical to brain health because we have been too narrowly focused on the liquids that cells live in and not the cells themselves. This is especially true now that we have the tools needed to collect and analyze those cells that are so important to our well being.

So, instead of just collecting fluids from patients and analyzing their blood, serum or cerebral spinal fluid, which the vast majority of trials currently do, we must begin to look at patients cells if we are going to make progress in understanding what cellular dysfunctions might be taking place within each of us.

This message rings especially true to me having gone through deep brain stimulation surgery. I can’t help but think about all the benefit that could have come if while my surgeon was implanting the electrodes deep inside my brain, he had also had the liberty and ability to take some of the cells that would invariably have been removed for further study later on. (Apparently some stick right to the apparatus that is put in patients during the surgery and can now be rather easily collected.)

A note on showing vs. telling: Malu, like Peter above and the others I will highlight below, in addition to being fantastic scientists also happen to be master story tellers. In my humble opinion, the skills needed to be both are intertwined. And it is critical in these times we live that scientists are able to communicate clearly their findings to a wide range of different audiences. One of the best ways to do so is to keep in mind an old trick of all great story tellers, show do not tell. Do not ever get up in front of any audience and read to them words from a slide deck. When in doubt, follow Malu’s lead and paint images in the minds of the audience, show them what they need to know to understand the basics and fill in the rest through your verbiage.

Though the images below cannot even begin to capture the rapture with which Malu was able to hold her audience, I hope it gives some indication of the prowess her voice caried for all who were in attendance.

The Lipidologist

Prof. Steffany Bennett’s talk was a veritable symphony of science. I’m not sure if she remembers, but I visited her lab about six years ago. I was really glad to see her able to communicate the same level of excitement for all things lipids to the scientists in attendance at this conference that she imparted to me the first time we met.

It is a rare thing to meet someone who exudes that level of passion about the most minute of details. But her message is essential to understanding our brains, after all, almost 60% of our brains, the most important organ we have, is made of lipids, the main constituents of fatty tissue. In other words, what makes us what we are is mostly fats and we should be doing more to celebrate individuals like Dr. Bennett who have devoted so much of themselves to trying to understand what role the composition of those fats play in both health and disease.

Now, coming to her talk itself, I really doubt if many of the world experts who were in attendance could really understand more than half of the wisdom she shared in it, I certainly could not. But I could tell that it was an unflappable polemic on so many of the problems that patients have been shouting from the rooftops about for decades. From sex differences between men and women and what role those differences might play in the development and progression of an individual’s disease, to the role of specific nutrients and how vital some can be to how our diseases change over time, to why there is so much variety in our symptoms that leads these diseases to appear so heterogeneous. And so so so much more.

Just taking a glimpse at the image she walked us through in the top right of the images shown below is enough to make almost anyone’s head spin. While I will not dare to try and walk anyone else through every step of it, there is one thing I do want to emphasize, that is Dr. Bennett’s unbridled joy with which she revealed to us the wonderful world of lipids and their numerous effects on what we are in both health and disease. It was truly a rare delight to witness.

The Dam Builder 

Also about six years ago I met for the first time Dr. Pablo Sardi at a conference in Lisbon. Dr. Sardi is the global head for Rare and Neurological Diseases at Sanofi, one of the ten largest pharma companies on earth. He struck me as being surprisingly forthcoming so I asked him questions about what it was like to work at Sanofi as well as his take on the role big pharma plays in getting us closer to treatments for PD. He sat me down and gave me one of the best answers I have ever heard.

He explained to me that his job at Sanofi is analogous to a builder of dams. You see, in this analogy, patients are similar to swimmers being pushed relentlessly down river by ever stronger currents, doctors are like lifeguards trying hard to rescue those that occasionally go under, while scientists/engineers try to invent better whistles, flotation devices and other tools that can help any one of the parties involved save even more people. He saw himself in his role at pharma as that of a person trying to stop the river from swallowing up so many people by designing ever better dams. 

I thought that was about as apt an analogy I have ever heard for the system we patients, doctors, scientists/engineers and pharma companies find ourselves in. And so, I was really glad to see that one of the speakers at the GBA1 conference would be that same Dr. Pablo Sardi. At the time when we first met Sanofi was recruiting for a drug called Venglustat, which much of the field had pinned their hopes to as having the potential to be the first disease modifying drug for a subpopulation of those diagnosed with Parkinson’s disease. However, earlier this year Dr. Sardi and his colleagues reported that the MOVES-PD trial did not meet its endpoint as, “No beneficial treatment effect of venglustat was shown compared with placebo and, therefore, the hypothesis was refuted.” (Source)   

Dr. Sardi’s presentation at the GBA1 Meeting was a masterclass in how to walk an audience through the trials and tribulations involved in running a clinical trial over years and across continents. I encourage readers to go through the images below as I believe they tell the story better than I ever could. I just really wanted to thank him and his team at Sanofi for embracing the clarity and conviction needed to honestly report on the findings from the trial. The truth is a rare commodity these days, especially when that truth comes at such a steep cost for the companies that sponsor these trials and for the patients all around the world that pin their hopes to them. You Dr. Sardi are the model that I’d hope all drug developers follow. All of us in the audience learned something from all that you had to teach about the importance of not shying away from failure and why it is crucial that companies be as transparent as possible throughout. Thank you for that.

Btw, we were told that many of these talks should be available for all soon, so hang tight.

The Rockstar

Dr. Ziv Gan-Or, for those unaware, is a die hard heavy metal fan who has travelled the world to see some of his favorite bands. So it seems somewhat reciprocal that so many leading scientists and researchers would travel to Montreal to come to this conference which he was the primary driver of. His talk definitely delivered, even if it was missing the loud distorted heavy metal guitar rifts and pink hair one might have expected from a rockstar such as him.

Before I get into the talks he gave, I want to thank Dr. Gan-Or for his leadership and courage he showed to me over 5 years ago when he invited me to come talk to his students at McGill and endure the entirety of my 4-hour long lecture on all things PD. It was one of the strongest signals I have ever been given that perhaps I could make difference in the field. Also want to thank him and his colleagues at the MNI for championing Open Science and their steadfast belief that it will speed up the delivery of better therapies for patients like me.

What he gave in his seminal talk that the field of GBA-PD (and frankly the entire PD field) has needed is clear and logical guidelines for others to follow and build on. The field has long been in need of methods to organize all the information it produces and do so in a systematic way. Geneticists have made some valiant efforts to organize genetic data, but that has yet to be presented in the larger context for what it means to PD as a whole.

Though I have some quibbles, mainly over the lack of patient involvement and the need to push for symptom specific outcome measures, I will say that over the course of his two talks, he convinced me that his system for molecular classification of GBA1 variants is the one the field should adopt. As he pointed out to me in our first interview, and something he reiterated in his talks, it’s one thing to just collect data, but figuring out what to do with all that information is what will enable the breakthroughs of tomorrow.

So what was his classification system that he proposed for GBA PD field? Here it is in the picture presented below. My only addition to it would be to add one more bullet to the bottom of that framework labelled something like, “what the hell does any of this have to do with the various symptoms patients experience?” Though I can see how to some that may seem like a bridge too far at the moment, allowing patients to better control our symptoms should be the NorthStar we point towards to let us know that we are not simply drifting around in circles.

What I picked out above is just my own subjective highlights from what was, and I do not say this lightly, the best conference I have yet attended on Parkinson’s disease. There were many other standout talks including Dr. Simon Stott who demonstrated once again why he is the leading hedgehog this field has through his brilliant presentation looking at the landscape of clinical trials targeting GBA PD, or Dr. Ron Postuma’s incredibly insightful talk on RBD and its ties to GBA and PD, or Drs Ari Zimran and Stephen Mullin’s respective overviews of the exciting potential of ambroxyl to perhaps change the course of PD in some, or Dr. Oluwadamilola Ojo and the terrific overview she presented on the importance of the intronic GBA1 variant identified in people of African origin, or Dr. Jia Nee Foo who gave a brilliant review of SMPD1 and its potential contributions to PD while also highlighting the unmet needs throughout Asia, or Dr. Konstantin Senkevich and the birds eye view he was able to describe of the lysosomal glycosphingolipid metabolism pathway in PD, or Dr. Lorna Chebon-Bore’s excellent overview of the exciting new G-CAN program being launched by the Montreal Neurological Institute, or Dr. Lorraine Kalia’s talk describing the latest finding that pathologists have given us and its relevance to GBA-1 associated PD and dementias, or the industry talks from Drs Kimberly McDowell and Sebastian Boland on the exciting developments taking place in clinical trials for gene therapy in GBA1 PD from Capsida Biotherapeutics and Prevail Therapeutics respectively. On and on the conference went with one exceptional talk after another.

To answer a question Dr. Lorraine Kalia put to me during this conference, it is weird coming to a place where you are a walking contradiction. For three days all I heard was how bad GBA PD can be, and how closely tied it is to developing very severe impairments and how interventions like DBS can accelerate the course of one’s disease, all the while I felt great. Meanwhile, if some of the talks were to be taken literally, I have presumably had a GBA-PD variant eating away at my brain for over 20 years now (assuming a 10 year prodrome.) If nothing else, I hope my presence staring at so many in the face as they talked about the perils of GBA-PD served as a reminder to all of them that no two of us are alike and that nothing can be so easily predetermined. And though we do seem to be on the cusp of better therapies, there is still so much that we do not know about each individual patient that we cannot pre-prescribe with enough certainty any one of the therapies discussed to any one of the people in need of them. Having said all of that, it is also important for patients to remember that science is not there to better understand or treat them as an individual. That is just not how this works, which makes understanding all of this ever more important for individuals diagnosed because in the end, it will be you and your doctor that have to make a decision about which of the available therapies, and there may be many available soon, best fits your individual makeup.

Now, despite that rants above about no one in the scientific community trying to understand individuals, and the lack of symptom specific outcome measures, those are also not entirely true as there was one poster that did explicitly mention them and drew a fair bit of attention. Though I should mention that the poster was from the company that sponsored my attendance and one that I have been working with for over 2 years now as the Chair of their Patient Advisory Board, Rune Labs. That said, they are the first group that has managed to “characterize GBA PwP in relation to age and gender matched controls, with wearable technology to benchmark symptom progression compared to the wider Parkinson’s Disease (PD) population”. In other words, by looking at actual symptoms that individual patients both experience and report we can now see if there are any noticeable differences between GBA carriers and the rest of the PD population, so long as they have StrivePD (a free app) downloaded onto their Apple devices. Props to Dr. Ro’ee Gilron et al. for recognizing the need and putting this all together…

I should also emphasize that while I have acknowledged above a few of the individuals that made this event so special, it is important to remember something that Dr. Malu Tansey often says, science is a team sport. It takes a huge number of inspired individuals to come up with a therapy that works for any one person. And so, once again from the bottom of my heart I say thank you to all for demonstrating what team science is capable of for patients like me.

Finally, below is an image from Dr. Simon Stott’s presentation showing all the trials in development just for GBA-PD. No doubt that this field will continue to flourish thanks in no small part to last week’s meeting. Special thanks as well to all of the sponsors named below for their generous support of this groundbreaking meeting. Hope to see even more of you at the next one where we will hopefully have grown the numbers in the charts read below and where I also hope many more patients will also be invited to speak and take in all that there was.

Artistic images above created using meta.ai. Special thanks as well to Dr. Lorna Chebon-Bore for organizing much of this event and to the Silverstein Foundation for spearheading this initiative. For more info and to keep up to date on all things GBA1 go to gba1can.org