Engineered sensor actuator modulator as aqueous humor outflow actuator for gene therapy of primary open-angle glaucoma.

Glaucoma, a blinding eye disease with optic neuropathy, is usually associated with elevated intraocular pressure (IOP). The currently available pharmacological and surgical treatments for glaucoma have significant limitations and side effects, which include systemic reactions to medications, patient non-compliance, eye infections, surgical device failure, and damage to the eye. Here, we present Sensor-Actuator-Modulator (SAM), an engineered double mutant version of the bacterial stretch-activated mechanosensitive channel of large conductance (MscL) that directly senses tension in the membrane lipid bilayer of cells and in response, transiently opens its large nonspecific pore to release cytoplasmic fluid.

Response of heterologously expressed pressure sensor-actuator-modulator macromolecule to external mechanical stress.

Cells from different organs in the body experience a range of mechanical and osmotic pressures that change in various diseases, including neurological, cardiovascular, ophthalmological, and renal diseases. Here, we demonstrate the use of an engineered Sensor-Actuator-Modulator (SAM) of microbial origin derived from a mechanosensitive channel of large conductance (MscL) for sensing external mechanical stress and modulating activities of mammalian cells. SAM is reliably expressed in the mammalian cell membrane and acts as a tension-activated pressure release valve.

MscL: channeling membrane tension.

Mechanosensitive channels are integral components for the response of bacteria to osmotic shock. The mechanosensitive channel of large conductance (MscL) responds to extreme turgor pressure increase that would otherwise lyse the cellular membrane. MscL has been studied as a model mechanosensitive channel using both structural and functional approaches.