Targeting the Right Cells: Human MiniPromoters for Restricted Gene Expression in Specific Cells of the Eyes

Challenge: Diseases of the eye, sometimes leading to blindness represent an enormous burden in terms of human suffering and economic cost. New gene therapies where promoters act as switches to modulate gene expression could offer cures, but such expression is difficult to target to the appropriate diseased cells. Due to their size, complexity and regulation, endogenous promoters can rarely be used for gene therapy. New cell-specific and minimized promoters are thus needed to generate the success of this new therapeutic approach.

Solution: The goal of this project was to generate a toolkit of human MiniPromoters with restricted expression, suitable for targeting different diseases of the eye. The team had to design and engineer such promoters for each individual reporter gene to be tested. The selected promoters needed to target expression with high specificity and fidelity, so that they could eventually be used to treat macular telangiectasia type 2, stationary night blindness, or glaucoma. Selectivity of these MiniPromoters was evaluated upon injection into specific cells of the eye, first in mice and then validated in primates.

Achievements/Impact: From the 46 MiniPromoters designed by the team, intravenous injections demonstrated that 35 of them showed restricted expression in the target cell type of the eye for which they were developed (76%). When injected into the eye of mice, 27 out of the 30 MiniPromoters retained their specific expression pattern. The team further demonstrated that the MiniPromoter derived from the NEFL (neurofilament protein light polypeptide) gene showed strong and cell-specific expression in retinal ganglion cells upon intravitreal injection into the eye of adult primate. Since the death of these cells is associated with glaucoma, specific expression of gene that could slow the death process, under the regulation of the NEFL MiniPromoter, could be a great benefit to the patients afflicted by the disease. The team also discovered that a subset of MiniPromoters showed restricted expression in the brain and spinal cord.

Principal Investigator:

Elizabeth M. Simpson
University of British Columbia


Adriana Di Polo
Université de Montréal

Completed Project
$1,497,000 / 3 years
Supported by CQDM through:
• Merck
• Pfizer
And by co-funding partner:

• Brain Canada