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14 Pharmaceutical Technology ® The Real Message Behind Commercial mRNA Products April eBook 2023 PharmTech.com mRNA TReNds Scholz states that, while DNA is harder to deliver than RNA, DNA does offer many advantages over RNA, such as durability of expression, reduced man- ufacturing costs, increased stability, and contextual control of expression. "DNA-based vaccines are in clinical trials now, and Oisin Biotechnologies has a pipeline of candidates targeting indications includ- ing chronic kidney disease, metabolic diseases, and sarcopenia, to name a few," says Scholz. "As these technologies are currently being evaluated in human clinical trials, we expect it will not be long before pharmaceutical companies broadly adopt this tech- nology to deliver DNA payload." Scholz explains that the key to delivering DNA is to have a non-toxic delivery system that can easily get into cells without causing damage. "These technologies are in humans now, and we expect it won't be long before more pharmaceutical companies adapt this technol- ogy to deliver DNA payloads," he states. DNA payloads permit an additional layer of selective expression, thus paving the way for encoded therapeutics that not only target and kill tumor cells while sparing healthy cells, but also deliver key immune modulators to healthy cells, including immune cells, which can enable multi- pronged therapeutic approaches, he adds. Becraft also notes that there are a number of DNA- based approaches currently in development, including T-cell therapies, genome editing and writing, and clus- tered regularly interspaced short palindromic repeats (CRISPR). Becraft adds that viral-based gene therapies that use adeno-associated virus (AAV) for diseases such as muscular dystrophy use a DNA-based pay- load. "While DNA and RNA-based therapeutics have similarities, the main difference is that DNA needs to be delivered further into the nucleus. This presents a lot of challenges to overcome due to the strength and defense of the nuclear membrane," says Becraft. DNA offers a variety of benefits compared with RNA, remarks Lewis. Benefits from using DNA include more durable expression, the ability to design a single DNA therapy that expresses multiple therapeutic molecules, and less complex supply chain management. "To date, a challenge in realizing the f ull potential of DNA- based therapies has been developing safe and highly effective delivery systems," says Lewis. Lipid-based systems, for example, are associated with liver toxicity while viral delivery systems trigger immune responses (which can result in serious ad- verse events) that limit repeat dosing, Lewis explains. He f ur t her adds t hat, whi le t he DNA-based gene therapies approved to date have shown promising long-term data, it remains to be seen if a single-dose provides life-long therapy or if repeat dosing will be needed following longer periods of time. "Given the enormous potential of DNA-based ther- apies, there are many academic and industry efforts to develop new deliver y strategies, either through innovation of novel deliver y systems or improved approaches to mitigating the safety and efficacy lim- itations of current approaches," says Lewis. Larry Pitcher, senior director and general manager, microbial manufacturing ser vices, Thermo Fisher Scientific also emphasizes the fact that plasmid DNA (pDNA)-based vaccines have been around since the dawn of recombinant DNA technology. He also notes that pDNA is increasingly being used as a raw mate- rial or therapeutic agent in gene therapies and certain vaccines, and that its use is driven by the growth and transformational benefits of cell and gene therapies as well as the expanded application of mRNA. "Its [pDNA's] advantages, including weak immuno- genicity, increased safety, and ease of manufacture, have dramatically increased demand for materials and manufacturing capacity globally. Investments in state-of-the-art manufacturing ensure [that clients] have reliable access to the high-quality materials and capabilities that have become vital for the production of these new lifesaving medicines and the patients in need," says Pitcher. Development challenges Among the key challenges for developers of nucleic acid-based therapeutics will be the need to scale up to meet current demand and to evolve as market needs change, highlights Serena Fries Smith, director of Market Development & Strateg y, mRNA Vaccines and Therapeutics, Thermo Fisher Scientific. Smith explains that, to meet current demand and evolve with the market, developers need a reliable supply of high-quality, good manufacturing practice (GMP)- grade raw materials. Without reliable materials supply, developers can encounter manufacturing disruptions, including de- viations, that can result in costly delays. "Another challenge is the need for in-region manu- facturing capacity and distribution to improve global access, including for people in lower income regions. To help address barriers such as lack of a cold sup- ply chain, we are seeing smaller facilities popping up globally," Smith says. "Stability and shelf-life are also challenges, but researchers have learned to alter chemical features of the mRNA transcript to improve the stability. In addition, improvements in delivery can protect mRNA against degradation." Historical and current challenges to nucleic ac- id-based therapy development include the production process itself, in terms of scalability, standardized quality metrics, and deliver y, emphasizes Jordana Henderson, associate director of Research and Devel- opment at TriLink Biotechnologies (part of Maravai LifeSciences), a contract development and manufac- turing organization specializing in the synthesis of