Genemo, Inc.
Monitoring Aging, Cancer, and Alzheimer's Disease from a Single Drop of Blood

Biofluids such as peripheral blood can be relatively easily obtained, making liquid biopsy a quickly expanding field for disease diagnosis and monitoring. The extracellular RNA (exRNA) in the peripheral blood reflects the gene activities of all organs and tissues including the brain. exRNA levels in the blood reflect the person’s biological age and are correlated with the functional status of all tissues. Thus, exRNA has emerged as an important type of blood-borne biomolecule for the development of disease diagnoses.

Founded by Professor Sheng Zhong, a Professor of Bioengineering at University of California San Diego (UCSD) in 2015, Genemo is a biotech company focused on developing exRNA based blood tests. Genemo developed the Small Input Liquid Volume Extracellular RNA Sequencing (SILVER-seq) technology that is sensitive enough to quantify thousands of exRNAs in one drop of blood.

“SILVER-seq can efficiently sequence both integral and fragmented exRNAs from a small droplet (5 μL to 7 μL) of liquid biopsy,” says Sheng Zhong, the CEO of Genemo, Inc. “We calibrated SILVER-seq in reference to other RNA sequencing methods based on milliliters of input blood serum and quantified droplet-to-droplet and donor-to-donor variations.”
"SILVER-seq can detect exRNA from approximately 10,000 human genes, including the RNAs transcribed from coding and noncoding genes. It takes as little as a few microliters of blood serum as input. This small input requirement provides two unique advantages. First, it significantly accelerates the speed of biomarker discovery. Without requiring a significant amount (milliliters) of blood, many ongoing clinical trials that have collected blood samples can add SILVER-seq-based exRNA measurements by using a small aliquot from their collected sample. The other technologies that require milliliters of blood as input cannot be added to ongoing trials because the collected blood samples often have planned utility and there is not enough (milliliters of) blood to spare. Thus, testing any biomarker based on other technologies often requires prospective blood collection, which can take many years to complete. Second, this small input volume makes it possible to develop biomarkers from finger-prick blood, avoiding painful vein punctures.

Measuring biological age

Genemo has completed analyses of more than 2,000 blood samples and released two sets of clinical data. These released clinical data demonstrate that the SILVER-seq technology can accurately quantify a person’s biological age. A biological age greater than this person's chronological age implies that this person experienced faster aging than the average population. Monitoring the changes in exRNA levels over time can indicate whether any preventative measures such as exercise, diet, or meditation slow down biological aging.

Genemo in collaboration with researchers at UCSD published a subset of their clinical data in the journal Proceedings of the National Academy of Sciences (PNAS) in 2019 (DOI: 10.1073/pnas.190825211).

Monitoring cancer recurrence

Applying SILVER-seq to the blood samples collected from a breast cancer trial (ClinicalTrials.gov ID: NCT01197456), researchers from Genemo and UCSD identified significant differences in exRNA between cancer patients and control blood donors. The exRNAs of several oncogenes including KRAS are significantly more abundant in cancer samples than the control blood samples. A simple classification model using the exRNA levels can accurately distinguish cancer patients from control donors, suggesting a strong potential for exRNA measurements in cancer screening. More importantly, it is critical to monitor cancer patients who have been treated with surgery and/or chemotherapy. An effective and cost-efficient method for monitoring cancer recurrence is in great demand. In their 2019 PNAS paper, Genemo’s scientists showed that a simple artificial intelligence (AI) model using the exRNA levels can accurately predict cancer recurrence in a 5-year follow-up timeframe (ClinicalTrials.gov ID: NCT01197456) (DOI: 10.1073/pnas.190825211). This paper indicated that “The SILVER-seq technology can therefore lead the way to future in vitro diagnostics trials based on finger prick blood, which is more accessible for screening and frequent monitoring of human diseases.”

Early diagnosis of Alzheimer's Disease

One in nine people of age 65 or above in north America is living with Alzheimer's disease (AD). The hope is that if Alzheimer's disease can be diagnosed early, treatment can be applied before irreversible neural damage and cognitive decline happen. Genemo in collaboration with the Alzheimer’s Disease Research Center at UCSD measured the blood exRNA from a 15-year follow-up study of people aged 65 and above. This study identified a biomarker, i.e. the PHGDH exRNA. The exRNA of the PHGDH gene is significantly associated with Alzheimer’s pathology, based on the analysis of the postmortem brains. Supporting this result, PHGDH’s mRNA is increased in the AD patients’ brains in three independent patient cohorts at Mayo Clinic, Mount Sinai, and the ROSMAP multi-center study. Importantly, the blood level of PHGDH exRNA steeply increases approximately 2 years before anyone is clinically diagnosed as either mild cognitive impairment or Alzheimer’s Disease.

The blood level of PHGDH exRNA remains constant in those people who received “normal” diagnoses throughout the entire 15-year follow-up, and their postmortem brain confirmed that their brains were healthy.

Genemo and UCSD published a subset of our clinical data in the journal of Current Biology in 2020 (10.1016/j.cub.2020.02.084). These clinical data indicate that a blood-based measurement can identify AD patients before their symptoms appear.

Leveraging two other patient cohorts, the Genemo team reported that PHGDH protein level is only increased in AD patients but not patients with Parkinson’s disease (PD). Furthermore, the PHGDH levels are highest in AD-only patients, lowest in PD-only patients, and in the middle in AD-PD co-morbid patients. Thus, PHGDH’s expression increase is AD-specific, rather than promiscuously associated with any brain disorders. These data support PHGDH as an AD-specific biomarker.

The confirmation of PHGDH as a biomarker for AD from several independent cohorts inspired further studies on the underlying mechanism. Scientists at UCSD and University of California Irvine further revealed the specific cell types and brain regions that exhibit increased PHGDH levels in AD. They found that the astrocytes, a cell type that regulates brain blood flow, transfer mitochondria and supply nutrients to neurons, are the cell type in which PHGDH is particularly increased in the early stages of AD. The brain’s memory center, called hippocampus, is where PHGDH increases in AD. Most surprisingly, the PHGDH protein level in human hippocampus reversely correlates to this person’s cognitive functioning, i.e. the higher PHGDH, the worse a person's cognitive ability. These data establish that the expression level of a single gene correlates with a person’s overall cognitive functioning. These findings lend insights to the repeatedly validated correlation between PHGDH levels and AD. UCSD, UCI, and Genemo co-published these findings in the journal of Cell Metabolism in 2022 (DOI: 10.1016/j.cmet.2022.02.008). Taken together, PHGDH as an AD biomarker has been validated in two mouse models (Cell Metabolism, 2022) and 6 patient cohorts including Mayo Clinic, ROSMAP, Mount Sinai, UCSD and UCI, Baltimore, Amsterdam cohorts (Current Biology, 2020; Cell Metabolism, 2022).

Genemo is working with UCSD to expand their clinical validations to more than 1,000 patients. They are also expanding their assay types from blood serum and blood plasma to cerebral fluid and aqueous humor.

The accumulated data suggest the potential of using a single droplet of liquid biopsy for monitoring human health and early disease diagnosis. Genemo is on track to revolutionize the biotech space through its RNA detection technology, SILVER-seq.