The need for DNA throughout the world, particularly plasmid DNA, has skyrocketed in recent years. A rise fueled mainly by the development of cell and gene treatments, at least up to the emergence of the Covid-19 epidemic. Modern remedies exist in many forms, and they are revolutionizing the way many deadly diseases are treated. But the mass synthesis of DNA is essential to creating and operating all of these technologies.
At first, plasmid DNA was primarily utilized at research institutions and universities. In the pharmaceutical business, plasmids were first used to express foreign genes in bacteria or mammalian cells to manufacture therapeutic proteins. As a result, many service providers sprang up to meet this need. However, the rapidly expanding cell and gene therapy sector has altered the size and quality of DNA demand.
DNA is employed by hundreds of biopharmaceutical firms in clinical research, and it is also present in several drugs that have recently been granted distribution licenses. According to data from the Food and Drug Administration, the number of IND applications for cell and gene therapy products has increased.
There has been an unexpected and pressing need for high-capacity, high-quality DNA manufacturing since the business has swiftly migrated toward the commercial realm.
The DNA industry is experiencing a bottleneck due to the difficulty in increasing the production capacity for plasmid DNA. Contract manufacturers have significant backlogs and waiting lists that can provide GMP-grade plasmid DNA. The industry risks damaging market and future patient expectations if it cannot produce quality DNA within tight timescales. DNA producers have the onus of figuring out how to up production without sacrificing quality.
How plasmid DNA gained popularity
The spread of COVID-19 has made an already bad situation much worse. For the SARS-CoV-2 coronavirus, the biopharmaceutical industry has been moving at breakneck speed this year to create safe and effective vaccinations. Attempts to solve the enormous public health issue have sparked parallel efforts by over 200 business and academic entities working on vaccine candidate projects. Time being of the essence, production has commenced “at risk” even though none of these vaccinations have received regulatory permission for use. This will allow for speedy distribution once approval is received. Therefore, there are several initiatives aiming to increase vaccine production above historical norms at the same time.
Researchers are exploring a wide range of vaccine delivery mechanisms to increase the likelihood of creating at least one vaccination that can make a safe and effective countermeasure to Covid-19. Many nucleic acid vaccines, including messenger RNA (mRNA) and DNA, are produced using plasmid DNA. Nucleic acid vaccines deliver a portion of the virus’s genetic code in an attempt to evoke an immunological response, as opposed to standard vaccinations, which try to elicit an immune response by introducing antigens via a weakened virus or protein. SARS-CoV-2, specifically its “spike” protein, is encoded by these sequences and is translated once within the body to create viral proteins that induce an immunological response.
The rapidity of manufacture is the most significant benefit of nucleic acid vaccines over conventional vaccinations in the event of a pandemic. In the case of traditional vaccinations, Phase I clinical testing can take up to two years after initial research [3]. Covid-19 mRNA vaccines, on the other hand, have made it to clinical trials only a few months after the SARS-CoV-2 genetic sequence was made public. The current rate of progress suggests that the vaccine against Covid-19 may be the first nucleic acid vaccine authorized in humans. Furthermore, nucleic acid vaccines have specific benefits in combating emerging viral diseases as they appear due to the speed with which they may be developed.
Pharma giants like Pfizer, GSK, and Sanofi, cutting-edge biotechs like Biotech, Moderna, Curevac, Inovio, and Touchlight, and academic institutions like Imperial College London are all interested in developing and marketing Covid-19 nucleic acid vaccines. Moderna [4] and BioNTech/Pfizer [5] are the current frontrunners in the development of mRNA vaccines. Both companies have advanced to the Phase III stage with their respective projects.
With clinical trials well underway, the focus has shifted to expanding production capacity to produce the billions of doses required if these vaccines gain regulatory clearance and authorization. Production of mRNA and DNA vaccines calls for large amounts of DNA, either as the final result in a DNA vaccine or as the template for an enzymatic process. Producing more than 1 kilogram of DNA, for instance, may be necessary to manufacture enough mRNA vaccine to deliver 1 billion doses. This will be a massive undertaking if we stick with our existing methods of producing plasmid DNA. We’ll need cooperation from companies worldwide in the biotech, pharmaceutical, and contract development and manufacturing sectors to pull it out (CDMOs). One Covid-19 mRNA vaccine will require more than half of the world’s plasmid DNA production capacity, according to Aldevron, the market leader in plasmid DNA manufacturing [6].
Due to rising demand from the cell and gene therapy industry and the vaccine industry’s need for nucleic acids, DNA production capacity has far outstripped demand. The production of plasmid DNA has stalled the advancement of genetic medicine; thus, the industry has to act swiftly and efficiently.
Why it’s preferred over other DNA manufacturing
However, the foundations of plasmid DNA manufacturing render it incapable of allowing the future of genetic medicine. The time and cost investment needed to develop this additional capacity are becoming increasingly apparent. Large stainless steel bioreactors are used in fermentation to create plasmid DNA from E. coli. The procedure is inefficient due to its inherent high cost, low throughput, and high propensity for failure in batches. Delays in third-party manufacture of the product candidate can have detrimental consequences on clinical development, as was demonstrated in 2018 when Editas Medicine postponed filing the IND application for its LCA10 program to account for the manufacturing delay [10].
Similarly, the purifying process is high-priced, time-consuming, and challenging to scale. DNA manufacturing will remain a significant bottleneck as long as the business depends on this outmoded technology. Global regulators also worry that the final product may include antibiotic-resistant genes, which compounds the problems of long lead times, and expensive capital and labor costs.
Because of these formidable obstacles that might derail the progress of the genetic medical revolution, businesses and research facilities are exploring new methods of DNA manufacture. With the title “COVID-19: Accelerating vaccine research and global manufacturing capacity to end the pandemic,” the UK’s Coalition for Epidemic Preparedness Innovations (CEPI) is now accepting suggestions to overcome the difficulties of rapidly scaling nucleic acid vaccine manufacture.
