Using DNA Nanoplasmids as a Diagnostic Tool in Cancer

David Suhy, PhD

Thus far, DNA vectors have largely been thought of as tools for directly treating disease in the form of gene therapy or cell therapy. Other useful applications may be possible, however.

Biotech company Earli is currently working on such an application: the use of DNA nanoplasmids as a diagnostic tool for cancer. Notably, David Suhy, PhD, the cofounder and chief scientific officer of Earli, presented about the company's approach at the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting, held May 7 to 10, 2024, in Baltimore, MD. At the conference, CGTLive® sat down with Suhy to learn more.

CGTLive: Can you give some background about Earli?

David Suhy, PhD: Earli is a company that has taken a slightly different approach to cancer diagnostics and therapeutics. The secret sauce of what Earli does as a company is that we develop exquisite DNA vectors that have the ability to detect dysregulated transcription factors largely present within the context of cancer cells, and are at more appropriate background levels in normal cells or benign tumor lesions. By designing the synthetic promoters that recognize this dysregulated transcription factor status within these cells, it gives us the ability to turn on gene expression preferentially within the context of malignant cells and remain essentially transcriptionally silent in normal adjacent tissues or benign lesions. By doing so, it gives us the opportunity to express a wide variety of payloads, including engineered epitopes, for diagnostic purposes to be used with commercially available radio tracers, where it gives us the ability to express therapeutics within the context of being able to kill the cancer cells themselves.

What is Earli presenting at ASGCT this year?

The key point of this presentation is it's fundamentally different than what most typical applications of gene therapy are... We're using it within the context of a diagnostic as one of our products. This is very atypical because essentially people have thought about using nucleic acids and cell therapy based approaches as therapeutics, but this is really one of the first scenarios where the nucleic acids themselves are being used in a diagnostic concept. The second novel concept is that most therapeutics worry about transfecting as many cells as possible within the context of a target organ or target tissue. For a diagnostic purpose, we don't need 90% to 100% transfection efficiency. In fact, we've shown that as little as anywhere between .1% and a few percentage transfection efficiency is more than sufficient to generate a signal to noise ratio which makes it applicable for diagnostic use.

How would you summarize the key takeaways for doctors and the broader healthcare community?

I think the big implication is twofold. One is that cell and gene approaches don't necessarily always need to be used for therapeutics. The second is that creating really exquisite synthetic promoters gives you the ability to preferentially turn on gene expression within the context of certain cells. Now the field has evolved in gene therapy over the last 20 years or so, so that no longer are people using strong general promoters such as CAG to drive gene expression. There's really been an effort to focus on the interior of what's being expressed through promoters, through tissue activation, or even cell-specific activation in certain cases for retinal diseases. What we've done is we've taken a very bioinformatics-driven approach, where we've taken tens of thousands of cancer samples and taking the information contained within those samples for RNA protein levels as well as phosphoprotein levels were able to identify these dysregulated transcription factors and really create this new version of synthetic promoters which have much higher specificity, as well as sensitivity.

I think that the lessons that conference attendees and doctors can take away from this is that the next generation of transcription regulation is here. It's driven largely by bioinformatics and AI-driven approaches to be able to add more sensitivity and more exquisite control behind what we're expressing from these gene therapy products, or diagnostic products, as it suits early.

Are there ongoing challenges or any specific areas of interest for future research for this approach that you can discuss?

I think one of the biggest challenges for us is that we are delivering DNA because we take advantage of transcriptional activation and that brings its own set of unique challenges. If you think about most nonviral delivery approaches, it's simply about dumping the mRNA into the cytoplasm. I think that the areas that we need to focus on as a company and the field needs to focus on for DNA approaches to become much more applicable to many types of diseases and patients, is focusing on how to get the DNA across the nuclear pore and into the nucleus where it serves as a transcriptional template. I think that is the next level hurdle that as a field we'll all be facing to make these types of approaches successful.

Is there anything we didn't cover with the previous questions that you just want to share?

Earli is an early stage company—the joke is, we'll always be early—but we really look for really great collaborators to work with. I think we bring some unique technology to the table and what we're talking about is transcriptional-driven activation within the context of cancer to express some sort of payload. Now, what we're talking about can be applicable to almost any area where there's a genetic dysregulation at the transcription level so this is an approach that could certainly be tailored to other disease areas and we're always looking forward to working with really great groups or collaborators to push that forward, as well.

This transcript has been edited for clarity.

Click here to view more coverage of the 2024 ASGCT Annual Meeting.

REFERENCE
1. Goryawala M, Lee HYH, Tong L, et al. Hostile takeover: diagnosing cancer from within using a cancer-activated genetic construct as a novel imaging platform for NSCLC detection. Presented at: ASGCT Annual Meeting 2024, May 7-10; Baltimore, Maryland. Abstract #417