(485d) Mechanistic Modeling, Optimization, and Control of in-Vitro Transcription for mRNA Production

The recent growth of mRNA-based therapeutics has opened new avenues for the treatment of disease. The mRNA in these therapeutics is generated by the cell-free in-vitro transcription (IVT) reaction, which offers the potential for rapid scale-up of mRNA-based vaccines and affordable mass production of gene therapies [1]. However, current practices are constrained by a reliance on batch production and heuristic-based reaction design systems [2]. Mechanistic modeling of the in-vitro transcription reaction offers an avenue for rational design and optimization of reaction schemes, including the design of continuous reactors. Past work in mechanistic modeling of in vitro transcription has been focused on constrained design spaces and has been limited by the datasets available [3][4].

This presentation describes results on mechanistic modeling, design, and control of the in-vitro transcription reaction used in the production of mRNA. Literature and industrial datasets are used to construct a comprehensive mechanistic model for the in-vitro transcription reaction, which explains inconsistencies in past literature efforts on mechanistic modeling of the IVT reaction. The mechanistic model is used for the optimal design and control of batch and continuous production of mRNA.

Refrences:

[1] Kis, Zoltán, et al. (2020). Resources, production scales and time required for producing RNA vaccines for the global pandemic demand." Vaccines 9.1, 3.

[2] van de Berg, Damien, et al. (2021) Quality by design modelling to support rapid RNA vaccine production against emerging infectious diseases. npj Vaccines 6.1, 65.

[3] Akama, Satoru, Masayuki Yamamura, and Takanori Kigawa. (2012). A multiphysics model of in vitro transcription coupling enzymatic reaction and precipitation formation. Biophysical Journal 102.2, 221-230.

[4] Arnold, Sabine, et al. (2001). Kinetic modeling and simulation of in vitro transcription by phage T7 RNA polymerase. Biotechnology and Vioengineering 72.5, 548-561.