Genome Editing to Inhibit Optic Nerve Cell Death in Glaucoma

Derek Welsbie, MD, PhD
University of California, San Diego (La Jolla, CA)


Donald J. Zack, MD, PhD
Johns Hopkins University (Baltimore, MD)
Year Awarded:
Grant Duration:
July 1, 2017 to June 30, 2020
Award Amount:
Grant Reference ID:
Award Type:
Award Region:
US Southwestern

Recipient of the Dr. Douglas H. Johnson Award

Derek Welsbie, MD, PhD

Novel AAV/CRISPR Therapeutic for DLK Inhibition


Nerve cells called retinal ganglion cells (RGCs) form the connection between the eye and the brain. In glaucoma, these nerve cells die and vision is permanently lost. We have previously shown that a protein called dual leucine zipper kinase (DLK) is critical for the death of these cells. Thus, this proposal seeks to develop a gene therapy vector that might interfere with DLK and prevent RGC death and accompanying vision loss.


Our lab is developing gene therapy strategies to treat optic neuropathies, potentially blinding diseases of the optic nerve. They are characterized by the loss of retinal ganglion cells (RGCs), the nerve cells that transmit visual information from the retina to the brain. The most common form, glaucoma, is a leading cause of worldwide blindness. Conventional therapy for glaucoma focuses on lowering the eye pressure, but this can be challenging in some while others worsen despite aggressive pressure-lowering. Thus, our lab has been interested in developing a novel neuroprotective strategy that directly interferes with the cell death process in RGCs.

To do this, we have screened through all of the genes in RGCs to identify those whose inhibition is the most effective at promoting RGC survival. This work led to the identification of dual leucine zipper kinase (DLK) as a key mediator of RGC cell death, and an exciting potential target for glaucoma neuroprotection. In this proposal, we are using a new technology called CRISPR editing to target DLK and prevent RGC cell death. In the first part of our study, we will validate that we can successfully target DLK in a rodent and that the strategy is effective at inhibiting DLK function. We will also test the safety of such an approach. In the second half of the study, we will test whether our gene therapy vector is effective at halting the progression of an optic neuropathy in rodents.

While CRISPR technology has the potential to revolutionize medicine, there are some limitations with respect to delivering this gene-editing machinery to cells. This work is based on a technology that solves some of these limitations. If successful, this would springboard the clinical development of this technology for glaucoma neuroprotection and potentially other diseases amenable to CRISPR-editing. 

About the Researcher

Dr. Welsbie is an assistant professor of ophthalmology at the Shiley Eye Institute of the University of California, San Diego. He has an active medical and surgical practice, specializing in the care of glaucoma patients. He completed his medical and graduate training at the University of California, Los Angeles and his residency and glaucoma fellowship training at the Wilmer Eye Institute of the Johns Hopkins University School of Medicine.

Dr. Welsbie’s laboratory focuses on the development of neuroprotective agents as a novel treatment strategy for glaucoma. Specifically, he uses high-throughput genetic screening to identify genes involved in the degeneration of retinal ganglion cells (RGCs), the nerve cells whose death defines glaucoma. Once these target genes are identified, he then uses a combination of gene therapy- and medication-based approaches to block the function of these genes and potentially halt the disease.

Personal Story

As a glaucomatologist, I regularly see patients who have exhausted our current repertoire of eye drops and need an escalation in therapy to prevent their glaucoma from progressing. Unfortunately, the current surgical options all have significant risk. It is clear that the field needs neuroprotective agents to complement our current pressure-lowering strategies. My background was in the identification of drug targets in prostate cancer, so working on developing new therapies in glaucoma was a natural progression. Brightfocus has generously funded our laboratory research over the last several years, allowing us to make significant progress towards the goal of developing a novel type of glaucoma therapy.

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