For more than 20 years, Dr. Mary Ann Comunale has studied glycomics and glycoproteomics to understand how sugars generated by proteins could give insights into disease. Drawing upon experience in diagnostics of early liver cancer, she and her lab team began working with researchers and clinicians to apply these learnings to Lyme disease diagnostics. Now, the team is one of 10 Phase 1 winners that have advanced to Phase 2 of the LymeX Diagnostics Prize, a prize competition to accelerate the development of Lyme disease diagnostics.

Through September 2023, the Phase 2 cohort is participating in a virtual accelerator designed to help them refine their concepts for detecting active Lyme disease infections in people. The goal of the multiphase LymeX Innovation Accelerator (LymeX) competition is to nurture the development of diagnostics toward Food and Drug Administration (FDA) review.

We spoke with Drexel University College of Medicine Assistant Professor Dr. Mary Ann Comunale, graduate research student Ben Haslund-Gourley, and East Hampton Family Medicine’s Dr. George Dempsey to understand how the team is using complex sugar molecules to understand disease progression, applying clinician and patient insights to test design, and looking ahead to the future of glycomics and glycoproteomics.

Prior to your participation in the LymeX Diagnostics Prize, you worked on diagnostics for several different diseases. How did you apply these learnings to diagnostics innovation for Lyme disease?
Comunale: “I was previously doing viral hepatitis research for several decades. Right now there are no tests that can screen for early diagnosis of liver cancer or hepatocellular carcinoma. We developed a test that’s now in clinical trials that is going to hopefully make it so that you don’t have to get biopsies to screen for early diagnosis of liver cancer. 

Lyme disease has always been on my radar. It was an untapped field—nobody was looking at glycomics or glycoproteomics for Lyme disease. We know that there are changes in glycosylation on human serum proteins in the blood that indicate changes in disease state. And this is very well described in the literature for inflammatory diseases and cancers. So, because Lyme disease is an inflammatory disease I thought it would be worth it to take a look. 

People have heard of their immunoglobulins, IgG or IgM, or antibodies. Many of the typical clinical tests are based on how much of a specific antibody is present in your blood.

But we add another layer on top of that. There are sugars attached to many of these antibodies and blood proteins that help to regulate the protein’s activity. By looking at the sugar content, we can tell if there’s something changing in the sugars during a disease state. And if it is, what kind of an effect is the change in sugar having on the immune system? Is it causing you to become inflammatory? Is the activity of the antibody properly combating the infection? 

With our approach, we can see which sugars change specifically during acute Lyme disease and also observe those changes in sugars resolving to baseline levels following antibiotic therapy for acute Lyme disease. Our test can determine if the antibodies are responding to an acute Lyme infection or if the person just happened to have antibodies floating around from an infection two years previously that was already treated. So that’s how we’re looking to see if we can decipher between a previous infection and a new infection.”

Your team brings a wide array of expertise—including on the clinician side. How are you taking into consideration the provider and patient experience in developing this test?
Dempsey: “When seeing patients in the clinic, symptoms are hard to sort out, and you can feel for them, but sometimes as a clinician, you can feel helpless. Doctors like to have good tests so we can say—this is a diagnosis, and this is how we will treat our patients. Without a good test, it’s uncomfortable. And I think a lot of doctors will just empirically treat for Lyme disease without being sure, but just treat it so it’s not a problem.

So working with Lyme disease patients can be intimidating, and it’s financially not remunerating, because you spend a good amount of time with someone. So then from there springs these doctors who become Lyme disease experts. And they say, ‘Oh, I know how to take care of this, and I got all these great ideas, and all you got to do is pay me.’ It’s creating this other world that’s expensive, and people go through a lot of money and get tons of tests.

When I get those big lists of test results, go through it all, there’s not much I can find in there. A lot of times the Lyme test is negative, but every single test, it’s all normal. So it’s frustrating. 

And that’s what got me into this, too, is to try and dig in, and it’s something I could get my hands on. And what I like about glycans is the possibility that you could actually show something more than just a total antibody count, but level of activity. To me it’s a new measure that I haven’t seen in any other assay.”

Improving quality of care and transparency for patients is clearly a priority. What role do you envision your test playing in the diagnostic and treatment process?
Comunale: “We’re developing something where if the patient comes in and they get their blood drawn, we get a baseline. Then if they come in six months later, they’re still not feeling well, we can run another test and compare it back and say, ‘Yeah, I can see this looks like you’re still not feeling well.’ It would be the first time they would actually have a test to say that. 

Or does it resolve? It’s going to be beneficial to have that baseline test, and then come back if you continue to feel unwell, to see that there’s actually evidence that you are still in a very pro-inflammatory state.”

Dempsey: “If I had a test that could identify who is actively fighting an early stage of Lyme disease, and use that test to track their response to antibiotic treatment over time, to me, that’s what I’m looking for as a clinician.”

Over Phase 2, the 10 teams in the accelerator cohort have access to a range of resources from mentors and webinars to feedback sessions and networking. What has been most exciting about participating?
Haslund-Gourley: “In short, this accelerator is opening doors. It’s allowed us to have conversations with leaders in the field, initiate relationships and collaborations with a broader group of people, and foster excitement. For me, that’s great, because it elevates the research, and helps get new resources flowing toward the project.”

Dempsey: “It’s opened up some conversations with other people. It gets us going, gets people engaged talking about it. Competition’s always fun in a way.”

Comunale: “I agree that it is definitely meeting all of the different people, being able to meet with all these different experts, hearing from them what has been done. And also I think it’s interesting to see what our colleagues (I don’t want to say our competitors) are doing. Because this may end up being a collaboration between a company and a university, or two universities or two companies.

Even though it’s a competition, there’s a lot of propensity to come together. And maybe bounce ideas off each other. Maybe something that I have or somebody else is developing might actually be a good match, and would be able to be better together. And I think part of our challenge is even seeing if we can all work together in some way as well.”

There are many barriers to developing a test for active Lyme disease, which is why there have not been any major developments in diagnostics for over 25 years. If your test is validated, what implications could your research have for treatment of other infectious diseases? 
Comunale: “The approach is coming of age. When I first got into glycomics over 20 years ago now, the databases were just starting to be developed; it was a very niche field. In the past decade the field has grown immensely. It’s still something that many people don’t have on their radars, but the field as a whole is coming of age. 

Glycomics is in that evolution process and we’re starting to understand so much. Glycosylation, these sugars on the proteins, is the most abundant post-translational modification of serum proteins. And we know that they change, they’re very dynamic. The N-glycan profiles of proteins are consistent in healthy states, and they’re dynamic in disease states. And this is just exploding—we have actually developed a test for the early detection of hepatocellular carcinoma, and there are other tests that I’m sure are being developed based on glycosylation now. The blood test for diabetes now is also looking at a sugar modification.

So we’re finding that if you look at the sugars along with the protein, sometimes it’s a much better marker. A protein may not change, but if the sugars on it change, you have a marker. It’s a growing field, and we’re happy to be on the cutting edge of all of this new stuff coming out.”

Looking ahead: Expert judging panel to convene in October 2023

Following the accelerator, the cohort will submit concept papers that detail solution refinement, clinical and patient input, and a roadmap from lab to market. The competition judging panel—composed of experts across biology, clinical and technology translation, patient experience and advocacy, diagnostic science and technology, exponential innovation, and ethics—will evaluate eligible submissions according to official Phase 2 evaluation criteria. Based on the judges’ evaluations, the panel will recommend up to five Phase 2 winners of the LymeX Diagnostics Prize.

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