[Note: after I initially released this, Dr. Abdueva spotted some glitches; I pulled it back for editing & then got swept into London Calling; this revised version is finally emerging]
Liquid biopsies - the idea of peering into the disease state somewhere in the body by looking at “cell-free DNA” in the blood - is quite the rage these days. There are a host of companies and approaches, and I haven’t quite found the discipline to start trying to build a census of all of them. The field started with Non-Invasive Prenatal Testing (NIPT), and then some early NIPT cases had odd DNA that looked like oncogenic in healthy mothers - who turned out to actually have the cancer. Oncology has been the primary focus, but there’s been many hints that liquid biopsies may be valuable in a wide range of diseases. A bit over a week ago, Dr. Diana Abdueva founder and CEO of AQTUAL, walked me through (over Zoom) that company’s liquid biopsy approach to inflammatory disease management.
Abdueva has a very interesting personal history. Abdueva studied physics at the Moscow Institute of Physics and Technology, focusing on DNA alignment. She connected with Pavel Pevzner, leading to her joining Michael Waterman's group in the Department of Mathematics at UCS. This group laid the groundwork for The Department of Quantitative and Computational Biology. Her PhD advisor was Simon Tavare. At Children’s Hospital of LA she first brushed up with modern highly parallel sequencing, as a floor was being reinforced to support the geological wonder known as Helicos. Next came Affymetrix and array technology for DNA copy number measurement. Later she went to the early NIPT startup Verinata, where the accidental cancer via NIPT discovery was made and she connected with Dr. Rich Rava - who would later be a co-founder of AQTUAL. After a stops at Ion Torrent and Gardant Health, she took a year collecting rocks at California National Parks (I’m jealous; my first childhood science exposure was rock collecting). Then she reconnected with Rava to found AQTUAL.
Abdueva gave me a quick tutorial on “cell-free DNA”, which as she emphasized (and I heard back at the Ultima bash) really should be thought of as “cell-free chromatin” - what is in the blood is not naked DNA but bits of shed chromatin, with a size distribution showing the same periodicity as the size of a nucleosome. This is released via apoptosis, but Abdueva pointed out that if apoptosis works in textbook fashion, The Wolf of the body - macrophages - should fully clean up the debris. But local inflammation can interfere with complete consumption of the apoptotic debris, resulting in blebs of cells which carry loops of chromatin escaping into the bloodstream. So, in this model (I’m certainly not equipped to argue against it), cell-free chromatin is a signal of where inflammation is occurring in the body.
AQTUAL aims to read this signal with high specificity. Many liquid biopsy companies use methylation profiles to identify the tissue of origin of the detected chromatin; the wide range of specific technologies used is a fascinating space I won’t dive into here. Some are looking for specific mutations, but this is probably only practical in Minimal Residual Disease (MRD) monitoring as then you know what mutation to enrich for - though a view presented at the Ultima event was with sufficient read depth one could scan healthy individuals for oncogenic mutations. AQTUAL is enriching, using an unspecified but antibody-free approach, for specific types of chromatin elements such as chromatin-bound RNA polymerases, enhancers, promoters and insulators. In many cases, they can zero so far that the assay can be reduced to a qPCR or digital PCR assay - which I can admire even as it ruffles my NGS chauvinist feathers. In early work, they could differentiate Osteoarthritis (OA) from Rheumatoid Arthritis (RA) by looking at a signature specific to synovial tissue. To find more applications of this technology, AQTUAL is partnering with pharmaceutical companies. In discovery mode, sequencing readouts are the norm (yea!)
AQTUAL has stayed small - only 22 employees - and focused, recognizing early the poor funding environment the biological tools industry is now mired in. Their key effort is to create a therapy selection test for rheumatoid arthritis (RA) - a field which has the bittersweet bounty of many expensive but effective therapies - but not every therapy is effective in every patient. The current semi-random guessing (aka trial-and-error or treat-to-target) for therapy selection benefits nobody, except maybe the drug manufacturers - patients don’t get relief and payers spend on ineffectual treatments. As Abdueva puts it, ‘it’s the biggest pain point for any chronic disease”. AQTUAL hopes to have clinical trial results by end of the year, with commercialization of the test in 2025 as a Laboratory Developed Test (LDT). The test modality will be simple enough to run in a basic pathology lab without NGS
AQTUAL should be interesting to watch. The cell-free liquid biopsy space is crowded overall, but the inflammation subspace much less so. If assays in qPCR or other well-established, non-NGS formats can really have sufficient information to deliver actionable information at low cost, AQTUAL should have a much lower bar to obtaining reimbursement - and they are already working with payers in designing the trials. I always try to be a realist when it comes to the clinic - many a beautiful concept has run aground in the clinic - so we must all await the verdict of the trial data.
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