When innovative microfluidics and MEMS silicon technology combine to enable new opportunities in biotechnology – An interview with Basilard BioTech
October 22, 2020
Biotechnology and Cell and Gene Therapy (CGT) offer many possibilities through the delivery of life-changing treatments to a large number of patients. This is the objective that biotechnologists are pursuing whole-heartedly. While all biopharmaceutical companies have been affected by the COVID-19 pandemic, the race to efficient and reliable biotechnological tools has gained ever more importance, and genetic engineering has taken center stage. Many biotech companies have been hit particularly hard because of their complex manufacturing and delivery model as well as their funding model, though some of them are differentiating themselves using innovative unconventional ways.
Indeed, thanks to the combination of advanced microfluidics and mature MEMS technology, Basilard BioTech offers a mechanical approach for the delivery of virtually any gene to a cell nucleus, opening new beachheads to genetic engineering.
This is a great example of the increased use of microfluidic technologies in biotechnology applications. In its recent Status of the Microfluidics Industry 2020 report, Yole Développement expects the microfluidic product market to grow at a CAGR2019-2025 of 14.0% to reach $24.5B in 2025.
Yole Développement’s analysts, Sébastien Clerc and Eric Mounier, PhD. had the opportunity to interview Brynley Lee, CEO of Basilard BioTech, to discover his view on its technology, and how silicon-based technology can be a gamechanger in gene therapy.
Sébastien Clerc (SC): Can you please introduce Basilard BioTech, where does it come from?
Brynley Lee (BL): Basilard BioTech was incorporated on July 1, 2019 as a spin out from the University of California Riverside (UCR) by myself and my co-founder Professor Masa Rao. The company’s foundational technology, SoloPore, is covered by IP the company has exclusively licensed from the UC Regents for all fields of use. It was invented by Dr. Rao and developed over the course of a decade of NIH-funded research in his lab at UCR. The company is actively undertaking an aggressive commercialization strategy to further build upon this foundational IP.
SC: Can you explain to our readers what Cell and Gene Therapy (CGT) are, and in which context Basilard Biotech’s technology was developed?
BL: Cell and Gene Therapy (CGT) is a revolutionary new approach for treating devastating illnesses such as cancer, genetic disorders and degenerative diseases, among others. Its differentiation results from focusing on reengineering cells to enhance them with new capabilities, then deploying those cells to better treat, and even cure disease. In many CGT applications, this reengineering process is performed ex vivo, meaning the cells are first removed from the body, then genetically reprogramed to achieve the desired new functionality (e.g., better tumor recognition), and then returned to the body to treat the disease.
Basilard BioTech’s disruptive technology was developed to address one of the most critical bottlenecks in this ex vivo process, the challenges associated with effective delivery of those reengineered genes into the cells in order for them to successfully perform the genetic modification step. We developed a novel, IP protected non-viral (ex-vivo) mechanical poration based gene delivery technology platform (which we have named SoloPore) that allows for much better transfection performance at a lower cost and with the ability to scale to the number and types of cells required to make the therapy clinically viable across all therapy types. It is a disruptive solution we believe to be superior to other ex-vivo techniques currently available.
SC: How is gene delivery usually done and what is the advantage of SoloPore compared to these solutions? Which bottleneck is it solving?
BL: Viral vectors are currently the most common method used for gene delivery in ex vivo CGT applications. However, there is widespread recognition that they will not be able to meet this need in the future due to their well-documented limitations, such as high cost, lag time, supply chain challenges, etc., and most importantly, their inability to scale with the rapid growth of the CGT market. Consequently, this is driving the industry to look more closely at non-viral options for answers.
However, prevailing non-viral approaches (e.g., electroporation, shear poration, chemical poration, etc.) also come with their own limitations. For example, they typically suffer from poor uniformity and they often force users to choose between either high delivery efficiency or high cellular viability. They also rely on inherently random poration mechanisms, which can harm the cells and reduce their ultimate therapeutic efficacy. Finally, these approaches have not been shown to be able to consistently breach the nuclear envelope of each cell in the targeted population. Opening a pathway for delivery into the nucleus is critical to success for many applications. These are the bottlenecks that Basilard BioTech’s SoloPore technology solves.
SC: How does SoloPore work?
BL: SoloPore is a new, mechanical approach for delivering virtually any gene (or other payload) to the nucleus of cells, en masse, while achieving high transfection efficiency and high cell viability. You can view our brief HD animation video showing how it works here.
Essentially, SoloPore uses fluid flow to drag each cell in suspension into its own well in a vast site capture array, where the plasma and nuclear membranes are then precisely porated by a dedicated needle. The cells are then pushed off the needles by the reversing flow, after which gene delivery occurs by diffusion of the constructs through the single transient hole produced in each cell. Poration of every cell in the same manner across the site capture array ensures high uniformity, while limiting poration to a single, precision incision in each cell minimizes damage to the cell and provides a path for delivery to the nucleus, which as we know is crucial. The absence of moving parts on-chip minimizes complexity and enables massive parallelization, thus ensuring the opportunity for scaling to the throughputs required for CGT applications.
From our perspective, we think that SoloPore provides an exceedingly simple, elegant and better solution to a critical need in the industry.
Please see our recently published data for more information.
SC: SoloPore is based on MEMS technology. Can you explain to what extent it is a MEMS device, what is its size, and what is the added value of using MEMS for this application?
BL: At its heart, SoloPore is a microfluidics platform that leverages miniaturization and massive parallelization to provide the ability for engineering ex vivo CGTs with greater safety, efficiency, scalability, and versatility than prevailing gene delivery techniques. As shown in the above figures, it relies upon a unique device architecture consisting of a large array of hemispherical wells that are similar in size to the cells being manipulated (e.g., 10 – 30 um for most cells of interest in CGT). Within each well lies a single, submicrometer-scale needle, as well as a multiplicity of vias, which collectively enable the rapid capture, poration, and release of cells solely via fluid flow. The animated video that I mentioned earlier does a nice job illustrating how this works.
Poration of every cell in the same manner ensures high uniformity, while limitation of poration to a single site in each cell minimizes damage and provides a path for delivery to the nucleus. The absence of moving parts on-chip minimizes complexity and facilitates high-density massive parallelization, thus ensuring opportunity for scaling to the throughputs required for CGT applications. Without MEMS, and microfabrication more specifically, none of this would be possible.
SC: How was the development carried out, from device design to prototyping and through to beginning of production? Did Basilard BioTech manage the whole process or were partners involved at some point?
BL: The published proof of concept data was generated using an early prototype developed by Dr. Rao and his team at UC Riverside. Working with our product development and manufacturing partners, we have since advanced the device design and scaled it up to produce a minimum viable product (MVP) – commercial prototypes to be specific.
Concurrently, we are building (with support from our partners) a system kit containing the control systems and syringe pumps to operate the device containing the SoloPore chip.
While our partners have provided valuable engineering support for our efforts via their technical capabilities, facilities and product development best practices, the entire MVP development effort has been wholly managed by Basilard executives, on time and on budget!
Eric Mounier (EM): Cell and Gene Therapies are still in their infancy. What do you think is the market potential for SoloPore? How many SoloPore devices per year does that represent?
BL: Our technology is of great interest to companies in the ex vivo CGT space, companies whose therapies, as I’ve mentioned, offer the best hope for finding cures to deadly diseases affecting millions, but who struggle with the current gene delivery limitations. While it may still be relatively new, the CGT industry is growing quickly, and to that point, I think it’s fair to say that this market has moved well beyond infancy.
Consider that three genetically-modified ex vivo cell therapies were recently approved for use in the U.S. (i.e., Kymriah ™ & Yescarta™ in 2017, and Tecartus™ earlier this summer, all of which are chimeric antigen receptor T cell (CAR-T) cancer immunotherapies), and many others are in the pipeline soon to follow. Globally, the number of new therapies in clinical trials numbers over 1,000 (2018), and there are now over 900 cell therapy companies (2018) with more launching each year. The current valuation of the industry is $3 billion globally, projected to nearly triple by 2025 to reach $8.21 billion for a CAGR of 14.9% generally, and 58.5% for CAR-T specifically.
Leading therapy types where we can have a big impact include: CAR-T, TCR-T and NK-CAR cancer immunotherapies, HSC gene therapies, and iPSC regenerative medicine therapies.
Many of these companies developing and launching these new therapies face the problems and challenges I’ve described in terms of the challenges associated with both prevailing viral and non-viral gene delivery and how to most efficiently and cost effectively transfect the cells. While it’s too early to project production estimates for the number of devices we will send to market – that will depend on our traction in co-development with early cell therapy company partners/adopters – we intend to eventually become the gene delivery mechanism of choice for ex vivo CGT companies.
EM: SoloPore delivers genes into cells: how is this combination between MEMS and DNA molecules done? Are DNA strands pre-loaded into the device? Is it carried out at the manufacturing level, or later by SoloPore’s users?
BL: The intended genetic constructs are simply added to the cell suspension by the user. Once the cells have been porated, they are released from the wells. Delivery then occurs by diffusion of the constructs through the single transient pore produced in each cell – straight through to the nucleus.
EM: Overall, is it a complex MEMS device? Does it include exotic content and materials beyond silicon?
BL: Not at all. Elegant simplicity has always been the primary principle guiding the development of SoloPore, ever since its inception in Dr. Rao’s lab. This remains our guiding ethos in commercialization. For example, this has driven our use of conventional MEMS materials and fabrication techniques, to facilitate the transfer of the process to a commercial foundry (a project now completed with our Solopore MVP}, a process now easily repeatable. Furthermore, this ethos has driven the design of the microfluidic chip as a fully passive component, to further simplify fabrication and maximize device density, and thus, ensure scalability.
EM: Who will be the users of the technology? What does it cost, and how does it compare with other technologies used for gene delivery?
BL: The primary users will be biotech and big pharma companies who are seeking to engineer innovative new cell therapies with freedom to operate around existing gene delivery techniques. It’s conceivable that a significant number of those 900+ cell therapy companies I mentioned could some day be potential partners for Basilard BioTech – both to enable their market-facing commercial strategies for current therapies in their pipeline, and to enhance their R&D efforts – with our tool helping them to discover and develop new therapies not yet imagined.
More specifically to the present though, we are currently working to engage a selected set of initial therapeutics partners in technology evaluation agreements, with the ultimate goal of extending these into longer-term strategic co-development partnerships. That is when our first phase of monetization achievements will occur, resulting from long-term licensing and royalties, even before we hit the commercial markets with co-developed product(s). We predict that SoloPore’s superior performance and versatility will allow us to offer a much more competitive cost basis – i.e. much lower Total Cost of Goods – and we expect that these differentiators will resonate with our future partner/customers.
Consider that it costs a lot of money to put an expensive genetic construct into a cell that is destined to be lost due to irreparable damage. It costs even more as you can imagine when the numbers of those failed cells can represent a significant percentage of the total population of cells being transfected. We posit that our technology, with its better efficiency and cell viability results in less loss of cells and their expensive cargo, resulting in better results for the patient and the bottom line of the company. This in turn we hope will drive down the overall price point across the spectrum and, we believe, aid in making these therapies more affordable, and therefore more available to those in need.
EM: The pharmaceutical industry is usually conservative and takes time to adopt and validate new technologies. Isn’t that a threat for Basilard BioTech and the adoption of SoloPore? Does the technology have some users already?
BL: It is well understood in this industry that viral vectors, while they are effective to a point today, cannot be scaled to meet the needs of, or keep up with, the fast arriving future. So therefore, everyone is looking to non-viral gene delivery for the answers to the question of what new technology the industry will lean on to meet those increasingly imminent demands. That market reality is already here and those questions are already being asked. We don’t need to create the case or convince anybody of the need. We just need to get the word out and be ready and able to position our technology as the best solution with the highest upside, in order to take advantage of the current opportunity.
Early versions of our technology have been used as the basis for our published data, in the labs of City of Hope, a premier cancer research hospital in Southern California. We have plans under way to introduce the new prototype chips to several initial cell therapy company partners under technology evaluation agreements.Any therapy company or R&D institution requiring better solutions to meet their gene delivery needs (and we propose that will ultimately be most or all of them) will eventually face a critical decision point about what they do next, even if they’ve already invested heavily in one current solution or another. Smaller, newer companies will be better positioned to be early adopters of our technology and we will grow with them. However, we are also convinced that even larger, more established companies will eventually come to the realization that from a long-term cost-benefit perspective they will need to adapt to compete effectively.
EM: Is SoloPore commercially available? If not, what is your timeline for commercialization? Does it need any regulatory approval beforehand?
BL: SoloPore will initially only be available to select partners, first under technology evaluation agreements, and then under longer-term co-development agreements. In parallel, we will continue to ramp up our internal R&D, product development, and validation efforts over the coming years. We will also scale up the technology for commercial rollout under a combination product model (i.e., engineered cell therapies fundamentally enabled by SoloPore) in collaboration with our strategic partners(s). Our most optimistic estimates on the timeline to a commercially available, co-developed combination product point to a minimum of five years, but this is only an estimate as the actual timeline is wholly dependent on market factors and partner priorities out of our direct control. While these eventual combination products will certainly require regulatory approval, SoloPore itself will not, since it is classified as a manufacturing tool. We are, however, preparing a SoloPore master file that will be used to support our CGT partners’ future regulatory applications.
EM: Anything else you would like to add for our readers?
BL: We thank you for giving us the opportunity to discuss our company and our disruptive SoloPore technology with your readers. Those interested in getting in touch are welcome to email me at brynleylee@basilardbiotech.net. Those interested in learning more can also visit our website or our LinkedIn page.