NEW YORK – Molecular diagnostics startup Circular Genomics sees a more direct way to predict patient response to psychiatric medications by analyzing circular RNA (circRNA) molecules that brain cells shed into the bloodstream.
The University of New Mexico spinout is focusing its efforts first on major depressive disorder (MDD), then it plans to develop diagnostics for other psychiatric disorders such as bipolar disorder and Alzheimer's.
Unlike standard pharmacogenomic tests such as Myriad's GeneSight, which assess single nucleotide polymorphisms (SNPs) in DNA to estimate the liver's ability to metabolize drugs, circRNA provides a more direct readout of how a drug affects gene expression in the brain, according to the firm.
"We're looking at what's actually changing in the patient," said Alexander Hafez, cofounder of Circular Genomics and the company's VP of operations and corporate development.
Molecular circRNA profiles, he explained, can be used to describe what a patient's MDD-related gene expression looks like before treatment, enabling physicians to determine which antidepressant they're most likely to respond to and how that profile changes in response to therapy. "We're going straight to the source of the problem," Hafez said, whereas traditional pharmacogenomics assays take "a very indirect approach."
Although GeneSight and similar tests, such as Tempus' Genetic Test, would be direct competitors for the assay that Circular Genomics hopes to soft launch in the first quarter of next year, the science of DNA SNP-based tests and a circRNA test could be complementary, in that each measures a different aspect of drug-gene interaction, predicting therapy response through distinct biological processes.
PGx testing in general has yet to be adopted as routine practice in clinical care, and Hafez thinks that the indirect approach of SNP-based tests is a key barrier, one that makes clinical validity difficult to demonstrate and therefore leads to slow payor adoption.
"We're solving the problem that [those tests] are having with clinical and payor adoption," he said, "by showing that [an] antidepressant is directly changing part of the brain [through] circular RNA expression."
Circular RNA crosses the blood-brain barrier where it enters into circulation and can be purified from a standard blood draw. Unlike linear RNA, circRNA is significantly more resistant to degradation and persists in the bloodstream for days to weeks.
"Circular RNAs have great promise as biomarkers for brain disorders and diseases," said Mriganka Sur, professor of neuroscience at the Massachusetts Institute of Technology, who has collaborated with Nikolaos Mellios, Circular Genomics' cofounder and CSO, but is otherwise unrelated to the company. In addition to their greater stability in the bloodstream, Sur noted that they are expressed more highly in the brain than in other tissue. In addition, circRNA biogenesis generally correlates well with production of linear RNAs, such that circRNA presence and abundance closely reflects gene transcription.
This, Mellios said, provides "a window into the current processes in the brain."
Circular Genomics appears to be the only firm currently pursuing commercialization of circRNA in the PGx field. Other companies, however, have been actively developing therapeutic circRNA products.
Orna Therapeutics, for instance, is developing a chimeric antigen receptor (CAR) product that delivers CARs via circRNA molecules combined with lipid nanoparticles. Ginkgo Bioworks and Esperovax, meanwhile, are collaborating to design synthetic circRNAs highly specific for colorectal cancer cells.
Circular Genomics' assay uses qPCR to measure the expression of known brain-derived circRNAs and predicts therapy response through a proprietary data analysis algorithm. The company aims to launch it next year as a lab-developed test, although Hafez said that there is a "high likelihood" that the company will subsequently pursue FDA approval via either the breakthrough device designation or 510(k) pathways.
For next year's planned soft launch, Circular Genomics anticipates targeting concierge care and primary practices, where services are predominantly self-paid, as the company seeks payor adoption for reimbursement.
The firm anticipates a full launch of a larger depression product capable of predicting responses to a broader set of antidepressants in early 2025.
The company is currently conducting one prospective study evaluating the predictive power of its product and is conducting several basic science studies aimed at teasing apart the mechanisms behind how antidepressants interact with circRNAs.
Hafez said that the firm is close to finalizing the full dataset from its prospective study that will be used to justify the commercial launch. "That's why we're shooting for next year," he said.
The Albuquerque-based firm is also exploring the possibility of using circRNA profiles to improve the diagnosis of psychiatric depression.
"Not just the diagnosis, but also differential diagnosis," Hafez said. "Is it depression versus bipolar, for instance?"
"Bipolar disorder typically manifests as a depressive state," he said, "so it's hard to tell what [patients] really are when they first go in to the physician." This makes finding a way to clearly distinguish the two a significant unmet need, and developing the means to do so currently exists in "a very wide open space."
Circular Genomics raised $4.5 million in a seed round in late 2021 and recently opened a Series A funding round, which it expects will carry the firm through both soft launch and full launch of its depression assay. It plans to subsequently build out other psychiatric and neurological products.