Research published in Frontiers in Neuroscience compared the therapeutic effects of using topical caspase-9 inhibition versus intravitreal injection of vascular endothelial growth factor (VEGF) antagonists to treat retinal vein occlusions (RVOs).
Give me some background first.
While anti-VEGF therapies have been the mainstay of treatment for RVOs, treatment response tend to be highly variable leading to less than favorable visual outcomes and treatment response in patients with significant retinal nonperfusion following RVO.
A previous study from the Columbia University research team determined that non-apoptotic activation of caspase-9 effectively could regulate edema, gliosis, and neuronal dysfunction during episodes of acute retinal hypoxia.
“We think the eye drops improve the health of blood vessels in the retina, which then decreases the toxic signaling that damages the retina’s neurons and leads to vision loss,” explained Maria Avrutsky, PhD, the study’s first author.
Now talk about this study.
Investigators used an image-guided laser system to create a localized occlusion to one or more branch retinal veins in the mice.
Adult male mice were randomized into RVO treatment cohorts, including:
- Vehicle
- Intravitreal injection of anti-VEGF antibody
- Topical administration of a selective caspase-9 inhibitor (Pen1-XBir3)
- Combination therapy
How was treatment efficacy measured?
Subsequently, the research team performed fundus retinal imaging and optical coherence tomography (OCT) scans on Days 1, 2, and 6 after the laser-induced RVO to evaluate retinal swelling, capillary nonperfusion, hyperreflective foci (HRF), and retinal atrophy.
On Day 7, focal electroretinography (ERG) measurements were taken, and from Day 8, investigators performed histologies on retinal sections.
Findings?
Both VEGF neutralization and caspase-9 inhibition demonstrated significant retinal protection from RVO compared to the vehicle treatment arm.
The study authors noted that retinal reperfusion of occluded veins was accelerated in eyes that received the caspase-9 inhibitor, but not to a significantly different degree than from the vehicle in the anti-VEGF group.
And compared to anti-VEGF monotherapy?
The combination of the two therapies was more effective than anti-VEGF monotherapy, but did not show improvement over the efficacy of Pen1-XBir3 alone.
What about the retinal edema?
Retinal edema was suppressed in all treatment groups, with roughly a 2-fold higher edema reduction with caspase-9 inhibition compared to VEGF neutralization.
What else?
Further observations on the therapeutic effects of topical caspase-9 inhibition included:
- HRF reduced similarly across all treatment groups compared to vehicle.
- Retinal detachment reduced only in eyes treated with caspase-9 inhibitor monotherapy.
- Caspase-9 inhibition reduced retinal atrophy and preserved ERG response, while VEGF neutralization did not prevent neurodegeneration following RVO.
Expert opinion?
According to Carol Troy, MD, PhD, co-author of the study, “Anti-VEGF therapy has helped a lot of people with RVO, but the fear factor—having to get a needle in the eye—causes many people to delay treatment, which can lead to retinal damage.”
“Finding the root cause of RVO is the holy grail, but if we can at least provide better symptomatic relief that doesn’t distress patients, it would be a really good start,” she added.
Take home.
The research team demonstrated that in a laser-induced mouse model of RVO, topical caspase-9 inhibition illustrated superior efficacy in all measures other than HRFs in comparison to anti-VEGF therapy.
Next steps?
Preparation is set to commence on further evaluation of Pen1-XBir3 in human clinical trials to potentially identify more therapeutic targets.