Nanomedicine Development Center (NDC) for Optical Control of Biological Function
Ehud Isacoff, Ph.D., Lawrence Berkeley National Lab/University of California, Berkeley
John Flannery, Ph.D., University of California, Berkeley
Russell Van Gelder, M.D., Ph.D., University of Washington
The NDC for Optical Control of Biological Function aims to treat the blinding disease retinitis pigmentosa (RP) by introducing synthetic light-sensitive molecules into retinal cells.
This center began by developing new methods to use light to noninvasively control proteins in cells, with the ultimate goal of treating human disease. They have now synthesized several rapid and reversible light-gated signaling proteins and peptides, including those that block and open K+ channels, block an enzyme, and act as agonists and antagonists of glutamate receptors, including both channels and G-protein coupled receptors. They have already shown that engineered photoswitches function in vivo in model systems, for example, controlling cardiac function in zebrafish, silencing pain-sensing neurons in rat, and restoring pupillary response in mice. The center has focused on treating blindness by restoring light sensitivity to retinas with non-functioning photoreceptors.
The NDC for Optical Control of Biological Function aims to restore vision initially in animal models of the blinding disease retinitis pigmentosa (RP), in which photoreceptor cells in the retina degenerate but cells in other cell layers of the retina remain functional. Their approach is to synthesize chemical photoswitches which can be delivered directly to the retina via intravitreal injection. Incorporation of photoswitches into retinal cell membranes will confer light sensitivity and may offer some vision for previously blind individuals.
The center is pursuing two strategies:
One-component approach. The photoswitch enters the surviving cells, associates with the ion channels of those cells so that channels open and close in response to changes between light and dark. Changes in membrane ion flow generate neural activity. Although the photoswitches may enter all of the surviving cell types of the diseased retina, they appear to selectively impact the firing of the output cells of the retina, the retinal ganglion cells (RGCs).
Two-component approach. The photoswitch is covalently attached to a specific amino acid of a receptor on the exterior of the cell. The receptor is introduced into a specific retinal cell type via a viral gene delivery. The AAV virus was chosen as the delivery vehicle for its flexibility, cell-specific targeting and because it is best established for clinical use. In this case, the identity of the light-receptive protein is defined as is the cell type in which it resides. This makes it possible to select whether to target the RGCs or, alternatively, other retinal cells such as bipolar cells. Being able to test different cell types could provide advantages of neural processing that occurs in normal vision as information flows through the retinal circuit. Moreover, it makes it possible to select either ion channel receptors whose activation directly generates currents, or to select G-protein coupled receptors (GPCRs), which activate ion channels through a cascade that could result in signal amplification. This approach depends on both the small chemical compound and the viral introduction of the gene encoding the modified receptor (even though the receptor comes from the organism).
CLINICAL CONSULTING BOARD (CCB)
Jon Levine, M.D., University of California, San Francisco
Martin Friedlander, M.D., Ph.D., Scripps Research Institute
David Sretavan, M.D., Ph.D., University of California, San Francisco