Cofactor Genomics (YC S15) Pursues RNA Testing, Offers Better Diagnoses Than DNA
techcrunch.com
techcrunch.com
In blood cell cancers, Steve McCarroll's group has shown that oncogenic somatic DNA changes are readily discovered through routine sequencing, and these are prognostic of poor outcome.[1] If you do this on a pre-disease schedule based on the risk estimates from your first round of sequencing, you will be able to detect blood cell cancers at any stage you like.
In non-blood cell cancers (say, breast cancer), you don't expect to capture any of the tissue-specific cell of interest from a blood draw to determine if there are somatic mutations occurring. However, there is growing evidence that there is often enough circulating tumor DNA in the blood that it can be of diagnostic significance.[2]
In contrast, for diseases that do not involve somatic mutations (in other words, for diseases aside from cancer), an RNA-based assay could be quite interesting. For example, getting better characterization around non-dilated cardiomyopathies would be of broad interest.
In cancer, both DNA and RNA can be effective diagnostics, and there's been a lot of great work on the DNA side in cancer.
In essentially all other diseases, though, there are changes in RNA but not in DNA.
A group, perhaps yours or in concert with yours, could both define the disease subsets based on biomarkers and then diagnose/prognose/inform treatment. Surely the same is true for other diseases, this is just one high-impact example.
Is that true for autoimmune diseases like Type I Diabetes?
Great question.
We're developing tests around a recently discovered type of RNA called circular RNA. Tissue-specific circular RNAs are present in blood, and so that's how it's possible to use a blood test instead of having to go to tissue like you would with traditional mRNA-seq.
So you can detect circ. RNA that come from specific tissues and partition those reads out as expression for those tissues? What kind of coverage do you need to do that? Are mRNA circularization rates consistent among different genes?
So you can detect circ. RNA that come from specific tissues and partition those reads out as expression for those tissues?
In reality, we are detecting circRNA that arises or predominates during a specific disease state and then partition those reads out as a signal for the disease state. On a related note, the circRNA molecule resists degradation much more than linear RNA molecules, leading to a longer half-life and less variability in signal from tissue, plasma, and exosomes.
What kind of coverage do you need to do that?
Currently, 100's of million of reads need to be generated to just detect the highest expressed circRNAs. We have a patent pending circRNA enrichment technology (supported by a large NIH phase II grant) that increases the ratio of circRNA in the total RNA pool by logs, thus one could sequence logs less reads for the same level of detection. The coverage cutoff for detection can be "tuned" for assay sensitivity.
Are mRNA circularization rates consistent among different genes?
CircRNAs do not seem to be translated into proteins and probably perform multiple regulatory functions. Also, the level of a linear form does not correlate with the level of the circular form for the same gene. As with linear mRNA production, which is not consistent from gene to gene or tissue to tissue, we observe the same phenomenon with circRNA.
Hope this info helps.
We've filed patents on our work.
Is there any biotech patent landscape as bad as RNAi? :)
Good luck with your venture.
There's additional evidence shown here: "Using circular RNA as a novel type of biomarker in the screening of gastric cancer". http://dx.doi.org/10.1016/j.cca.2015.02.018
http://www.npr.org/programs/ted-radio-hour/
Soto is the CTO of Miroculus and they're using MicroRNA analysis to develop a cost effective way to provide early diagnosis for a variety of cancers.
So far they've made progress with pancreatic, breast and IIRC two others. This is huge because usually cancer is discovered when you become symptomatic which is usually stage three or worse and it's much harder to treat then.
If they can make this cost effective enough to be included in a regular doctor 'check up', then we may catch a large proportion of cancers early which makes treating them way easier.
Will your tests be available direct-to-consumer, or will patients have to go through health provider gatekeeping?
FTFY :)
In my understanding human cells have may different types of RNA, which one are you sequencing?
We are measuring circular RNAs.
I'm curious why you are going through doctors and not direct to consumers at the begging? I understand FDA might force you to limit your marketing claims, however you now need to convince both physicians and consumers of the benefits of these tests. No? Where as I would imagine there will be enough early-adopters in the consumer space who'd be happy to pay for a test like this.
You can later move to the physicians space and assuringly get insurance companies cover the costs, when you have been more stablished.
Would love to learn more about your thinking and strategy here.
We believe that our RNA test can become a routine part of a doctor's visit, both as an early indicator of disease and — if there is disease — as a means to monitor the effectiveness of treatment.