The Lethbridge iGEM team has a history of developing novel targeted delivery methods. In 2014, the Lethbridge team began development of an innovative cell therapy platform designed to non-invasively deliver a therapeutic genetic construct to neural scars to promote functional recovery from stroke, traumatic brain injury, and neurodegenerative disease (for more information, see the 2014 Lethbridge Wiki). Since the 2014 season, two members of the current 2018 Lethbridge team, Aubrey and Zak, have been committed to patenting and commercializing this technology under the start-up, Nomadogen Biotechnologies Inc., which was incorporated in February of 2015.

Nomadogen’s foundational technology, a combination genetic and cellular therapy dubbed “Nomadocytes”, is a patented platform that utilizes patient-derived cells to non-invasively deliver therapeutic signals to brain cells specifically affected by stroke, traumatic brain injury and neurodegenerative disease. These signals reprogram neural scar tissue that prevents natural regeneration and rehabilitation into functional neurons, which are predicted to restore lost functionality and facilitate recovery.

Specifically, Nomadocytes are a genetically modified type of microglia. Microglia, the mobile immune cells of the brain, have three characteristics that make them excellent candidates for delivery of therapies targeting neural injuries and scar tissue: (1) they have been shown to migrate across the blood-brain barrier and travel specifically to sites of neuron death when injected intravenously (Haney et al., 2013); (2) they produce nanoparticles called exosomes, which have been previously demonstrated to have significant potential in trafficking brain disease therapies (Alvarez-Erviti et al., 2011); and (3) microglia can be derived from patient bone marrow cells (Hinze & Stolzing, 2011).

The therapeutic process itself involves the introduction of a novel exosomal protein to microglia that enhances both the targeting of therapeutic DNA to exosomes (a process that would also have widespread scientific applications) and the uptake of these exosomes by specific cells in the central nervous system. The therapeutic DNA, a cellular reprogramming gene called NeuroD1, has been previously shown to reprogram specific scar tissue cells into neurons, which are predicted to integrate into existing neural networks, restore lost functionality, and facilitate recovery (Guo et al., 2014).

Nomadocytes are currently in preclinical trials.

Figure 1: Two confocal images of cultured cortical astrocytes transfected with a DNA vector containing the coding region for NeuroD1 linked to that of Green Fluorescent Protein (GFP) via an internal ribosome entry site (IRES). Untransfected astrocytes express an astrocyte-specific marker, Glial Fibrillary Acidic Protein (GFAP; red). After six days, transfected astrocytes (expressing GFP; green) no longer express GFAP and begin to exhibit a neuronal phenotype. Nuclei are counterstained with 4′,6-diamidino-2-phenylindole (DAPI; blue).

The method for generating Nomadocytes is now patented in the USA and patent-pending in Canada:

Wong SA, Stinson ZK, Demchuk AM, Caton EA (2017) Methods and compositions for the packaging of nucleic acids into microglial exosomes for the targeted expression of polypeptides in neural cells.
A) United States Patent and Trademark Office Patent Publication No. 9,840,542. Filed on September 8, 2016; issued on December 12, 2017.
B) Canadian Intellectual Property Office Patent No. CA2903933. Filed on September 11, 2015.

The University of Lethbridge, unlike many universities, requires no assignment of intellectual property (IP) and so Nomadogen remains the sole owner of these patents. Moreover, the University of Lethbridge offers many resources to encourage student entrepreneurism. For example, to verify that the technology did not infringe on other companies’ patents, a preliminary patentability search was conducted on behalf of Nomadogen by the University-Industry Liaison Office.

The critical factor for future marketing success will be the demonstrated applicability, safety, and efficacy of the preclinical Nomadocyte technology through peer review and scientific publication. As such, Nomadogen has developed strong, reciprocal relationships with scientific advisors from the University of Lethbridge for the duration of preclinical development. Since 2014, Dr. Bruce L. McNaughton and Dr. Aaron J. Gruber have continued to generously provide access to specialized laboratory equipment and resources to facilitate ongoing research and development at the Canadian Centre for Behavioural Neuroscience. Thus, Nomadogen has no overhead costs for laboratory and equipment use, liability insurance, or further preclinical development of the technology.

In addition, there is a strong culture of innovation and entrepreneurship both at the University of Lethbridge and in Southern Alberta as a whole. The local small business support network (including organizations such as RINSA, Tecconnect, and Community Futures) have provided numerous funding resources, entrepreneurial guidance, and networking opportunities. Mostly notably, an Alberta Innovates Technology Advisor (Mr. Bill Halley) has been instrumental to our current success.

To fund intellectual property protection within the brief one-year grace period following disclosure of the technology at the 2014 iGEM Jamboree, Nomadogen pursued capital through business plan competitions. First, a business plan was submitted to the small institutional Canadian Centre for Behavioural Neuroscience Business Plan Competition (where we finished in Second Place). Nomadogen then used the feedback from that competition to revise the business plan and went on to win both the Technology and Student streams of the regional 2015 Chinook Entrepreneur Challenge:

The funding received from the Chinook Entrepreneur Challenge was then leveraged towards the Alberta Innovates Micro Voucher program, which together enabled the rapid initiation of intellectual property protection following the iGEM Jamboree.

Taking a medical biotechnology through human clinical trials is a multimillion dollar endeavour. Once Nomadocytes have been demonstrated as safe and effective through sufficient preclinical testing, Nomadogen has three main options:

1) License the patented technology to established biotechnology companies for all phases of clinical development. This option has little financial risk (as the established company would be responsible for all associated development costs) and Nomadogen would receive a licensing fee for the patent, milestone payments, and future royalties from successfully developed and marketed treatments. This revenue would then be used to pursue development of additional therapies (and patents) and to further grow and establish Nomadogen as a strong competitor in the industry.

2) Proceed through Phase I clinical trials independently with the assistance of an angel investor or as an academic venture. This strategy would require greater financial investment, a longer timeline for investment return, and collaboration with appropriately equipped research facilities and experienced personnel. While this option poses the greatest financial risk to the company and investors, further maturation of the intellectual property as it progresses through clinical trials exponentially increases the technology’s market value.

3) Sell the company (or patent) to a larger biotechnology company that is capable of overseeing both clinical development of the technology and the business. This option would yield the smallest return but is a profitable and viable exit strategy.

Nomadogen’s product is the patent covering the process of manufacturing Nomadocytes. So, Nomadogen’s primary target market is larger biotechnology or pharmaceutical companies who are interested in supplementing their own development pipelines by acquiring smaller companies with promising drugs and treatments that are not currently approved for market sale. Nomadogen aims to license its patented therapy to these companies who will then bring the technology through clinical trials and, ultimately, to the healthcare market. In exchange, Nomadogen will negotiate a licensing fee, milestone payments, and royalties from sale of the validated final product. Alternatively, the company can sell its intellectual property to a larger corporation who will assume ownership of the design. Potential companies in this target market include Johnson & Johnson, Sanofi-Genzyme, Merck, Pfizer, Roche, and many more.

Early market research and investor engagement provides an opportunity to inform further biotechnology product design to best ensure success during the transition from preclinical to clinical trials. As such, Nomadogen has been meeting with potential investors and gaining feedback at events such as SynBioBeta, TEC Edmonton Industry Day (with Johnson & Johnson, Sanofi-Genzyme, and Blueline Bioscience in attendance), Accelerate South50 (at which Nomadogen was an invited speaker), and a pitch event with Bloom Burton & Co. Nomadogen has also recently started exploring international collaborations and partnership opportunities through the German-Canadian Centre for Innovation & Research (GCCIR) Matchmaking program.

Some notable feedback that we have incorporated into our current stategy includes:

1) Clinical trials for acute stroke treatments are especially challenging due to the rapid onset and instability of motor or cognitive deficits. However, chronic stroke is a much better clinical target and will be of significantly more interest to potential investors.

2) Autologous (patient-derived) cells have obvious benefits to the patient but their use has not been widely established in clinical settings. A universal cell-line, produced at a specialized manufacturing facility, is a more profitable and realistic avenue at this time.

3) Animal results are critical before investment for clinical trials will be considered.

There is a massive, unmet market need for therapies that facilitate neural regeneration and functional recovery after stroke, traumatic brain injury, or neurodegenerative disease onset. The Nomadocyte technology directly addresses this need, can be adapted to treat a wide range of injuries and diseases, and offers distinct advantages over conventional drugs and analogous cell therapies (see below chart for a comparison of Nomadocytes to other stroke treatments). These advantages include a non-invasive method of administration, low patient immune response, a broad timeline of application, regional and cellular specificity in delivery, as well as a reduction and replacement of inhibitory scar tissue with functional neurons.

Nomadogen’s revenue will be based on licensing fees for contractual use of the Nomadocyte patent by larger corporations, milestone payments, and the royalties from sales of the commercialized therapy to the public health sector. The negotiated terms will be largely influenced by intellectual property valuation and current industry trends at the time of purchase. Combined licensing and milestone payment deals for discovery and preclinical biotechnologies have historically ranged from $1.2 - $62 million (USD) with upfront licensing fees ranging from $0.04 – $7.5 million (USD; Borshell & Ahmed, 2012).

In addition to licensing and milestone payments, Nomadogen can also expect royalties from the Nomadocyte technology when it is successfully commercialized and reaches the market (though this will likely be 5-10 years from the onset of clinical trials). Drugs that reach Phase II and Phase III clinical trials tend to have associated 5% and 9% royalty rates, respectively, according to the 2012 Royalty Rate Report (Cartwright & Borshell, 2012). Thus, Nomadogen anticipates a modest 1-2% royalty (in addition to licensing fees) for the preclinical Nomadocyte technology.

Altogether, Nomadogen offers a product with enormous market and profit potential and an exciting opportunity to enhance Southern Alberta’s contribution to the global biotechnology market. The success of this iGEM-inspired company would not only foster the prestige of the supporting University of Lethbridge (and attract future scientific professionals to the community), but also has the potential to provide employment opportunities for business management professionals and scientists in Alberta.

For more information, please contact Aubrey (aubrey@nomadogen.com) or Zak (zak@nomadogen.com) directly.

• Alvarez-Erviti, L., Seow, Y., Yin, H., Betts, C., Lakhal, S., & Wood, M.J.A. (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nature Biotechnology, 29, 341-347.
• Borshell, N., & Ahmed, T. (2012) Approaches to Valuation of Pharmaceutical Licensing Deals. Available at: http://files.pharmadeals.net/contents/Sample_Valuation.pdf
• Cartwright, H., & Borshell, N. (2012) The Royalty Rate Report 2012: A Comprehensive Assessment of Valuation in the Pharmaceutical Sector. Available at: http://files.pharmadeals.net/contents/toc_rrr2012.pdf
• Guo, Z., Zhang, L., Wu, Z., Chen, Y., Wang, F., & Chen, G. (2014). In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer's disease model. Cell Stem Cell, 14, 188-202.
• Hinze, A., & Stolzing, A. (2011). Differentiation of mouse bone marrow derived stem cells toward microglia-like cells. BMC Cell Biol, 12, 35.
• Haney, M. J., Zhao, Y., Harrison, E. B., Mahajan, V., Ahmed, S., He, Z., Suresh, P., Hingtgen, S. D., Klyachko, N. L., Mosley, R. L., Gendelman, H. E., Kabanov, A. V., & Batrakova, E. V. (2013) Specific transfection of inflamed brain by macrophages: a new therapeutic strategy for neurodegenerative diseases. PLOS ONE, 8, e61852.