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Molecular Stethoscope Early R&D Efforts Aimed at Future Circulating RNA-Based Diagnostics

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NEW YORK (GenomeWeb) – Protective of its IP stance and conscious of a long road to commercialization, liquid biopsy startup Molecular Stethoscope has shared few details so far of its plans to develop a suite of diagnostic tests.

The basic premise behind the assays Molecular Stethoscope intends to deliver is the ability to link signatures detected amongst circulating RNA molecules with a particular origin in the body, or more specifically, with the diseased-versus-healthy state of that organ.

This week, the San Diego-based company said that it has organized collaborations with 23 academic and medical institutions and has so far received over 700 plasma and serum patient samples from these partners to support the validation of its eventual commercial tests.

Founded a little more than six months ago by Stanford University's Stephen Quake and the Scripps Translational Science Institute's Eric Topol, the company's research backbone is a 2014 study led by Quake and published in Proceedings of the National Academy of Sciences is the backbone for the company's commercial path forward.

In that study, Quake and coauthors were able to identify the relative contributions of different tissues to circulating RNA, and to monitor changes in tissue development and health.

As one application of the approach, the researchers showed they could distinguish between fetal and maternal contributions to circulating RNA, as well as measure changes in the levels of different gene transcripts over the course of a pregnancy.

More relevant to Molecular Stethoscope's commercial aims, the Quake team also looked neuron-specific transcripts in the blood of healthy adults and those suffering from Alzheimer’s disease, and showed that disease-specific neural transcripts present at increased levels in the blood of individuals affected with the disorder could be detected using qPCR.

Speaking with GenomeWeb this week, Tina Nova, Molecular Stethoscope's CEO, and Mike Nerenberg, its chief medical officer, said that with the support of its newly announced academic and medical collaborators, the company hopes to commercialize its first assays based on this fundamental concept within a few years.

According to Molecular Stethoscope, its nascent diagnostics research program covers a spectrum of diseases, including Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease, ALS, and nonalcoholic fatty liver disease.

In essence, the company plans to study patient samples provided by its new slate of academic collaborators to determine how these various disorders alter or affect the cell-free transcriptome.

With that information in hand, the firm believes it will be able to develop specific assays to detect disease-associated RNA signatures in blood.  "Some will move quicker than others depending on disease state," Nova said. 

Though she said that Molecular Stethoscope considers the number of samples it's collected so far to be "remarkable to have for a company at this stage," Nova added that the firm's relationships with its academic partners are ongoing, and will also support the growth of these sample cohorts as the company finalizes and validates its tests.

According to Nerenberg, although Quake's landmark PNAS paper showed that a comprehensive RNA-seq approach can simultaneously detect molecules from sites throughout the body, Molecular Stethoscope is focusing its commercial development on individual signatures for individual sites and diseases, rather than developing a broad, total-body approach.

"It won't be one integrated total-body assay, even though that's what the PNAS paper showed," he said. "There are ways of homing in so we have different assays depending on the condition."

Nova and Nerenberg declined to discuss technical details of how Molecular Stethoscope anticipates each test will function, if not by RNA-seq, but they were clear that broad sequencing is not necessary in the context of the assay they are developing.

Although RNA degrades even more rapidly than DNA in circulation, making it a challenging analyte, Nerenberg said that Quake's PNAS paper shows clearly that it's possible with sensitive enough technology to detect organ- or disease-specific transcripts in blood.

Molecular Stethoscope is not alone in its interest in a method to use circulating nucleic acids to detect or monitor disease states in the body.

Recently, several approaches based on detecting DNA alterations have also been described in the literature, including one using cell type-specific methylation signatures to trace the origin of circulating cell-free DNA, and another that inferred nucleosome patterns from sequenced cfDNA that could be linked to a particular tissue of origin.

Nova said that Molecular Stethoscope is following advances in the scientific literature, but the company feels overall that what it's doing is unique, both because of its focus on RNA and its proprietary IP position.

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