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Cellular and Molecular Bioengineering

Applications in Cellular and Molecular Bioengineering

A Cell-Based Bioelectric Drug Factory with Time and Dosage Control for Regulation of the Circadian System

Friday, October 13, 2023

4:30 PM – 4:45 PM PDT

Location: 322

Presenting Author(s)

SF

Samantha Fleury

Ph.D. Candidate
Rice University, United States

Co-Author(s)

Cody Fell, MS, MPhil

Graduate Student
Rice University
Houston, Texas, United States
JG

Jacob Goell

Rice University Department of Bioengineering, United States
JL

Jing Li

Rice University Department of Bioengineering, United States
MP

Matthew Parker

Rice University Department of Electrical and Computer Engineering, United States
SB

Scott Beard

Northwestern University Department of Biomedical Engineering, United States
MH

Martha Hotz Vitaterna

Northwestern University Center for Sleep and Circadian Biology, United States
JR

Jonathan Rivnay (he/him/his)

Professor of Biomedical Engineering
Northwestern University, Illinois, United States
JR

Jacob Robinson, PhD

Rice University Department of Electrical and Computer Engineering, United States

Primary Investigator(s)

OV

Omid Veiseh, PhD

Professor
Rice University, United States

Introduction:: Circadian rhythms are vital regulators of cyclical biological functions including metabolism and endocrine signaling. Dysregulation of the circadian system is a common problem faced by shift workers and travelers among others. Beyond the immediate detrimental impact to cognitive and physical function, circadian disruption is associated with negative health outcomes including increased risk of metabolic diseases, mental health disorders and some cancers. Light is a powerful regulator of the central circadian clock, however, alternative cues including endocrine signals also play a role in regulating the circadian clocks. An important challenge for regulating the circadian system is the need for a precisely timed therapy to influence the dynamic biologic process. Interfacing cell-based therapeutics with bioelectronic devices can enable timing and dosage control in addition to cell health maintenance and monitoring. We utilized cells’ innate ability to produce bioactive peptide therapeutics in combination with advances in synthetic biology to create a cell-based drug factory capable of producing circadian rhythm modulating therapies on demand.

Materials and Methods:: We engineered a clinically relevant epithelial cell line to express endocrine signals demonstrated to regulate the circadian rhythm (leptin, and adrenocorticotropic hormone (ACTH)) under the control of a light-responsive optogenetic system. We then validated therapeutic secretion from these cells in vitro via ELISA and further characterized the productivity of the engineered cells in response to varying light intensity and time. Engineered cells were then encapsulated in silicone and hydrogel-based devices to isolate the therapy from the immune system and implanted in mice to evaluate in vivo therapeutic production.

Results, Conclusions, and Discussions:: Our results demonstrate that a clinically relevant cell line can be engineered to secrete therapeutically relevant peptides on demand. Engineered cells increased production of ACTH 34-fold and leptin 324-fold in response to light exposure. Further testing demonstrated this induction level is tunable based on light intensity and duration allowing for titratable therapeutic dosing. We determined that engineered cells can be turned on repeatedly over the course of days without a decrease in ACTH or leptin production, which allows for repeated, long-term therapeutic dosing from a single engineered cell dose. When implanted in a mouse model, engineered cells remained viable and productive and were able to deliver the peptide therapeutic in vivo.
In summary, we demonstrated that clinically relevant cells can be used as cell-based drug factories to produce peptide-based circadian regulators on demand. Therapeutic production can be timed and tuned based on user-defined light input enabling precise dosing control. These cells have the potential to advance therapeutic circadian rhythm modulation. Additionally, due to its potential to produce any peptide-based therapeutic this technology can function as a platform for the treatment of a wide array of indications.

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