(504f) Tunable Thermal Bioswitches for in vivo Control of Biological Therapeutics

Tunable
thermal bioswitches for in vivo control of biological therapeutics

Keywords:
Protein engineering, Medicine

Temperature
is a unique input signal that could be used by therapeutic agents, including engineered proteins
and cells, to sense
and respond to patient conditions or spatially targeted external triggers such
as focused ultrasound. A critical capability for many envisioned applications
is the ability to control the function of such therapies in situ to
enable spatially and temporally specific activation at anatomical and disease
sites such as the gastrointestinal tract or tumors. However, among existing
control methods, systemic chemical administration typically lacks the spatial
precision needed to modulate activity at specific anatomical locations, while
optical approaches suffer from poor light penetration into tissues. On the
other hand, temperature can be controlled both globally and locally—at
depth—using technologies such as focused ultrasound, infrared light and magnetic
particle hyperthermia. In addition, body temperature can serve as an indicator
of the patient’s condition. Here, we describe the development of
temperature-dependent protein actuators for therapeutic applications, ranging from
transcriptional regulation of engineered microbial therapeutics to generalized
control of protein-protein interactions.

To
enable the design of temperature-responsive therapeutic agents, we developed
two orthogonal families of high-performance transcriptional repressors with
tunable thresholds within the biomedically relevant range of 32–46 °C (Figure
1). We demonstrated the potential utility of these devices in several in
vivo scenarios relevant to mammalian microbial therapy, including spatially
selective activation within a mammalian host using focused ultrasound (Figure
2) and response to a host’s fever (1). Based on these results, we envision the
use of our thermal bioswitches to control a wide variety of functions in
engineered cellular therapeutic agents.

We
further demonstrate that the temperature-sensing components of these transcriptional
repressors can be isolated and repurposed in a generalized strategy to exert direct
and rapid control over protein function in the context of both bacterial and
mammalian cells. This technology can be utilized to engineer a broad range of
biological therapies with modular, non-invasive actuation and response to host
conditions.

1.           Piraner, D.I., Abedi, M.H., Moser, B.A., Lee-Gosselin, A. & Shapiro,
M.G. Tunable thermal bioswitches for in vivo control of microbial therapeutics.
Nature Chem Biol 13, 75-80 (2017).

Figure 1: Transcriptional responses of gene circuits
utilizing a panel of thermal bioswitch variants.

Figure 2: Spatiotemporal thermal control via focused
ultrasound heating.