A Novel Approach to Treating Glaucoma by Inhibiting Dual Leucine Zipper Kinase, a Key Mediator of Nerve Cell Death

Derek S Welsbie, MD, PhD
Johns Hopkins University, School of Medicine (Baltimore, MD, United States)
Year Awarded:
2014
Grant Duration:
July 1, 2014 to June 30, 2016
Disease:
Glaucoma
Award Amount:
$100,000
Grant Reference ID:
G2014119
Award Type:
Standard
Award Region:
US Northeastern
Derek S Welsbie, MD, PhD

Developing Dual Leucine Zipper Kinase Inhibitors for Glaucoma

Summary

Nerve cells called retinal ganglion cells (RGC) 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 to glaucoma’s progression as a key mediator of nerve cell death. Thus, our project seeks to identify a drug that might block or interfere with DLK and prevent RGC death.

Details

Nerve cells called retinal ganglion cells form the connection between the eye and the brain. In glaucoma, these nerve cells die and vision is permanently lost. The only treatment for glaucoma has been to lower eye pressure. However, this can be difficult to achieve in some patients, while in others, the disease may progress despite pressure-lowering. A complementary approach is called neuroprotection, whereby drugs directly target the cell death pathways in retinal ganglion cells and make them more resistant to injury. Unfortunately, no neuroprotective agent has yet made it to the clinic.

In order to develop such a neuroprotective strategy, we previously screened genes to find those that would be the best drug targets. We showed that a protein called dual leucine zipper kinase (DLK) is critical for the death of retinal ganglion cells. Moreover, we identified two drugs originally created as anti-cancer agents, tozasertib and foretinib, that are reasonably effective inhibitors of DLK. Indeed, when these inhibitors were given to rats with glaucoma, there was a significant reduction in the amount of retinal ganglion cell death. While promising, both compounds, at their therapeutic doses, inhibit numerous other unrelated targets, leading to toxicity and undesired side effects.

We are currently working with medicinal chemists to modify the structures of tozasertib and foretinib in such a way that we improve their ability to target DLK and reduce their ability to target other gene products. If successful, this work will lead to the generation of compounds with improved selectivity for DLK. Since we and others have already used genetic approaches to show that DLK is an excellent neuroprotective target (i.e., the ""protected"" cells remain alive for extended periods of time and appear to be functional), these compounds could become the prototype for glaucoma neuroprotectives.

About the Researcher

Dr. Welsbie is an Assistant Professor of Ophthalmology at The Johns Hopkins University School of Medicine in Baltimore, MD. He completed his medical and graduate training at the University of California, Los Angeles and then came to the Wilmer Ophthalmological Institute for his residency and glaucoma subspecialty training. His group is interested in the use of functional genomic screening in retinal ganglion cells—the cells that are injured in glaucoma—to identify new therapeutic targets.
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