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CONAN II - COmplete Nucleic acid ANalysis at genome scale at ultra-high throughput Phase 2

Periodic Reporting for period 2 - CONAN II (CONAN II - COmplete Nucleic acid ANalysis at genome scale at ultra-high throughput Phase 2)

Reporting period: 2019-11-01 to 2020-10-31

Depixus is developing an innovative new biotechnology for ‘complete nucleic acid analysis’ called SIMDEQ (SIngle molecule Magnetic DEtection and Quantification). SIMDEQ is being developed not only for standard DNA sequencing, but to also reveal previously undecipherable layers of information contained within the many subtle chemical signatures (epigenetic base modifications) that are found on both DNA and RNA. The emerging picture is that these base modifications form a ‘second genome’ that plays many vital roles in biology – from early embryonic development, to pathogenic defence mechanisms, and the evolution of many cancers. Current sequencing technologies have very limited abilities to read these modifications. The current Covid-19 pandemic has been an important reminder that there are significant gaps in our current state of knowledge about viruses (and in particular RNA viruses. SIMDEQ technology can analyse individual nucleic acid molecules (DNA or RNA) and will be an important tool in defending society against the ongoing threat of emerging contagious diseases.
This CONAN 2 proposal describes an ambitious project that focusses on the development of a high-throughput system, known as ‘SIMDEQ Digital’, based on a CMOS chip (like those in digital cameras) on which many millions of electronically addressable micron-scale wells are fabricated. The basic concepts underpinning SIMDEQ Digital have been well validated during the H2020 SME Phase 1 project, and the goal of CONAN 2 is to industrialise advanced MEMS and CMOS technologies to develop a fully-functional system suitable for commercialisation. The release of SIMDEQ technology will not only allow Depixus to compete in the existing sequencing industry, but also to open new markets for genetic and epigenetic analysis, EU-wide and globally. Early access to this technology will provide great business opportunities especially for European SMEs, who will help pioneer an entirely new “complete genomics” ecosystem.
Most aspects of the project proceeded according to schedule during the first year of activity. A project this complex requires careful planning and design work, and thus a great deal of the early efforts were devoted to hiring staff and completing basic planning and design tasks. During the first year of this project, we closely monitored and amended the project risk register, and while the project has experienced some mild to moderate delays, these were largely anticipated in the register, and mitigation strategies were deployed when possible.
The second year of the project brought serious challenges that ultimately required a complete restructuring of the project. Firstly, we determined that our commercialization plan, developed several years ago, was no longer viable, and that in order to launch a successful product, we would need to greatly increase the capabilities of the chip we were planning to manufacture and sell. The original plan called for 3 generations of chip: Chip 0, Chip 1 and Chip 2, each with increasing numbers of features. The plan was that we would complete Chip 1 by the end of the project (November 31st, 2020) and that this would be our first product. Chip 2 would then be a second-generation product financed by additional fundraising. However, ongoing work on our commercialization strategy led us to understand that in fact this mid-range Chip 1 would not meet the specifications required for a minimum viable product in an intensely dynamic and competitive field. During this time, progress with Chip 0 was excellent, and we were able to validate the design and send it out for manufacturing with our CMOS manufacturing partner. Additional delays were incurred, however, due to the Covid-19 pandemic, as critical microfabrication facilities were shut down for extended periods of time, preventing critical outsourced tasks to be completed on schedule. Fortunately, we were able to use this time to advance our Chip 2 design efforts, and we ultimately adapted a strategy to jump directly from Chip 0 to Chip 2. In October 2020 we applied for, and were granted, a 1-year extension of the project. The new plan will enable us to launch a product with improved capabilities shortly after the completion of the project in November 2021.
In our original proposal we pointed out that while DNA sequencing has become increasingly efficient, accurate and cheap, advancement in this field is stalling, with users lacking the fundamental capability to uncover deeper layers of information from their genomics samples. We identified this as a large untapped future market, and we still believe this to be the case. Regarding the specific markets for RNA sequencing and DNA/RNA epityping, we have every reason to believe that their growth trajectories will be similar to that of DNA sequencing over the last 20 years. The recent Covid-19 pandemic, caused by the novel RNA virus SARS CoV2, has accentuated the need for better tools to understand complex biological systems.

The scope and timeline of the project have been expanded, but the expected results by the end of the project remain largely unaltered since the commencement of the project:
*The project has focussed on the development of a digital high-throughput SIMDEQ system (SIMDEQ Digital) based on detection using a complementary metal–oxide–semiconductor (CMOS) chip.
*This project has been a major catalyst for Depixus to receive significant further equity funding support of the company’s wider activities (we are currently in the process of securing this financing, and expect to complete the current fundraising round by Q1 2021).
*The project has directly created more than 10 new jobs already as well as supporting the work of a team of more than 20 R&D staff throughout the company. We expect an additional 75-100 new employees to join the company within the next 24 months.

In addition to the user benefits discussed above, we proposed that SIMDEQ Digital will also have the following wide-ranging societal and environmental benefits
* There will be a major impact on advances in medical sciences and, subsequently, on health. In particular, we think the investigation of RNA viruses, such as influenza and Coronaviruses, will benefit from the ability to read modified bases.
* The novel data generated by SIMDEQ Digital will also have the capacity to improve public health surveillance and infectious disease outbreak investigation.
* Enabling epigenetics technology will accelerate advances in environmental sciences.
* SIMDEQ Digital dispenses with large inefficient detection systems, and thus uses considerably less energy, requires less expensive laboratory space, and consumes lower amounts of chemical reagents and plastic consumables.
Conclusions.
Although 2020 poses unique challenges, and the commercial landscape continues to be extremely competitive, we have responded and adapted our project by making some course corrections to our original R&D plan. We anticipate that at the end of the project, we will be well positioned (both financially and from the perspective of TRL) to enter immediately into the commercialization phase of this innovative technology platform.
h financially and from the perspective of TRL) to enter immediately into the commercialization phase of this innovative technology platform.
Innovative microwell strcuture is the key to our digtial approch