This story has been updated to include Nir Friedman's association with Senseera.
NEW YORK – Precision medicine startup Aqtual is combining transcriptomic and epigenetic information to develop molecular profiles for therapy selection across a wide range of chronic disorders.
The Hayward, California-based company, which recently emerged from stealth mode, presented data on its first assay, a blood-based test for rheumatoid arthritis, at the American College of Rheumatology's annual conference earlier this month.
The company showed early data that its platform accurately identified a gene expression signature specific to the synovial compartment of rheumatoid arthritis patients, distinct from both healthy controls and patients with other chronic inflammatory conditions, including ankylosing spondylitis, osteoarthritis, and psoriatic arthritis.
"All of those conditions have very similar profiles and represent challenge in clinical diagnosis," Diana Abdueva, Aqtual's founder and CEO, said.
The inclusion of those conditions, Abdueva said, "allowed us to find a classifier that is unique to rheumatoid arthritis, rather than targeting generic inflammation profiles."
In contrast to more standard cell-free DNA (cfDNA) liquid biopsies, Aqtual focuses on longer DNA fragments — cell-free chromatin — that include regulatory sequences and often retain proteins related to transcription and gene regulation.
"What Aqtual has learned," Abdueva said, "is that these larger DNAs are actually most informative in terms of regulatory activity of a cell at the time of its death."
Although many specifics of Aqtual's process are proprietary, Abdueva explained that the key differentiator of its technology lies in its proprietary protocol for selectively isolating membrane-bound regulatory-active chromatin fragments from the detritus of dying cells.
When a cell dies through apoptosis, Abdueva explained, the nucleus is broken up and "mercilessly shoved around the cell."
"Then large chunks of DNA bound to protein start blebbing on the surface of the cell and those blebs come apart," she said.
Aqtual's protocol frees those chromatin fragments from the bleb membranes and captures them via nanoparticles targeted to DNA-protein complexes. Captured chromatin fragments are sequenced via Illumina whole-genome sequencing and quantified, and bound regulatory proteins are identified and quantified, for a combined transcriptional and epigenetic readout.
Abdueva is named as the inventor on several US patents and applications assigned to Aqtual for methods of characterizing and profiling the pattern of cell-free nucleic acid fragments. These involve hybridization to cfDNA fragments with up to two oligonucleotides used as bait, followed by genomic sequencing and fragmentation analysis.
Aqtual's approach allows it to examine aspects of gene regulatory architecture beyond protein coding sequences, including enhancers, promoters, transcription factors, chromatin remodeling complexes, and chromatin boundary elements.
"This technology greatly enhances our understanding of cellular processes and disease mechanisms, paving the way for innovative diagnostic and therapeutic strategies targeting the epigenome," said Abdueva, who previously served as director of bioinformatics and R&D at liquid biopsy developer Guardant Health.
Aqtual's leadership team includes other alumni of Guardant, Grail, and Gilead, among others.
Still, the lack of details provided in company presentations has left some researchers unsure of what exactly to think of it.
Nir Friedman, a professor of computer science and medicine at the Hebrew University of Jerusalem, and cofounder and chairman of Senseera, which is developing its own epigenetic-based blood test for early cancer detection and monitoring, said that he found the company's presentations at the recent annual meeting of the American College of Rheumatology "almost contentless."
"Nanoparticle binding and 'adjusting parameters like lysis and binding conditions' can mean many things," he said via email. "I am not sure to what extent regulatory proteins (non-histones) are associated with cell-free DNA. This is a somewhat open question. I do hope their investors got better information before making their decision."
The company recently raised $16 million in a Series A financing round.
While the specifics of Aqtual's method for epigenome and transcriptome co-profiling remain secret, that methodology in general is a topic of active research.
Spatial epigenome and transcriptome co-profiling, for instance, could expand our understanding of tissue-specific cellular function, cell differentiation, and gene regulation in ways that other single-cell multiomic approaches can't. Recent advances in that field include spatial ATAC RNA-seq and spatial CUT&TAG RNA-seq.
The Chromium Single-Cell Multiome ATAC + Gene Expression assay from 10X Genomics is one commercial application of ATAC-seq, which enables analysis of both the epigenome and transcriptome.
Similarly, researchers at the New York Genome Center developed a way of combining oligonucleotide-tagged antibodies with ATAC-seq to simultaneously profile chromatin accessibility, mRNA expression, and protein levels.
Abdueva said that, as with the methods described above, tissue specificity is a key advantage of the company's combined transcriptomic and epigenetic readouts, enabling downstream applications such as tumor profiling.
The research that the company presented at ACR was a pilot study of some 100 patients. Aqtual is now enrolling participants into a slightly larger clinical study called PRIMA-102 aimed at evaluating the assay's potential for helping physicians make therapy selection decisions.
That observational, case-only study seeks to enroll 150 individuals with rheumatoid arthritis, who have shown intolerance or poor response to previous disease-modifying antirheumatic drugs and who are planning to begin therapy with new ones. Following initial screening and baseline measurements, PRIMA-102 will evaluate treatment response and disease activity at a 12-week follow-up visit.
Abdueva said that it is currently about 93 percent enrolled and expects to complete the study in mid-December.
Aqtual intends to launch its rheumatoid arthritis assay as a lab-developed test in the first quarter of 2025.
"Rheumatoid arthritis is just the beginning," Abdueva said. "We already have proof-of-concept work across autoimmune disorders like [irritable bowel disorder], as well as chronic conditions like cancer."
The company currently employs approximately 20 full-time individuals. Abdueva said that the firm's recent fundraising provides it with enough of a cash runway to carry it through planned assay commercialization in Q1 2025. However, the company is also in the early stages of a Series B funding round.
In anticipation of commercialization, Aqtual is in talks with private payors regarding reimbursement, with which the results of the upcoming study are expected to help.
"We're very excited about our ability to generate evidence to review with our largest healthcare providers," Abdueva said.
Aqtual is also exploring strategic opportunities beyond rheumatoid arthritis and cancer. Abdueva said that the company has some "exciting collaborations" with pharmaceutical partners in the works, which will be announced over the coming months, with news of which other indications it might be pursuing next coming out early next year.