The small molecule YK-4-279 can help to treat premature babies and diabetic patients to reversing vision loss

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An Oklahoma Medical Research Foundation discovery could pave the way for therapies to reverse vision loss common in premature infants and adults.

In a new study appearing in the Proceedings of the National Academy of Sciences, OMRF scientists have identified a compound that could give birth to therapies for a host of eye diseases that include retinopathy of prematurity and diabetic retinopathy.

“Potentially, even patients with advanced disease progression could see their fortunes turned around,” said Courtney Griffin, Ph.D., the senior author of the study.

Several eye disorders occur when blood vessels grow out of control in the retina, the tissue that lines the back of the eye.

In these forms of retinopathy, a web of vessels blocks light from reaching the retina, which is how we see. The overgrowth causes vision issues that can advance to total blindness.

Retinopathy in premature babies—linked to high oxygen levels in NICU incubators that interrupts normal vessel development in the eye – often resolves naturally over time.

But not always. In those cases, and in adult diseases like diabetic retinopathy, vision damage can be irreversible.

Griffin and Chris Schafer, Ph.D., study the development of blood vessels. Schafer, a postdoctoral researcher, thought there might be clues to thinning this tangle of vessels if they analyzed a different set of vessels that naturally regress and disappear in mice soon after birth.

When they studied newborn mice, the OMRF researchers found that levels of a specific class of cellular proteins crashed as the mice experienced normal blood vessel loss in the eye.

“Dr. Schafer hypothesized that these cellular proteins might be an important ‘off switch’ to eliminate these vessels in a neonatal model,” said Griffin, who holds the Scott Zarrow Chair in Biomedical Research at OMRF.

“This is a new way of approaching these diseases. The current methods—invasive surgeries or life-long injections into the eye—only prevent the disease from advancing and often have serious complications.”

Schafer identified an experimental compound that disables the proteins. It allowed him to flip the switch and test the idea.

“We wanted to trick blood vessels in diseased mice into thinking they were supposed to be regressing and naturally dying off,” said Schafer. “This appears to be what happened.”

Even more encouraging, Griffin said, the compound only impacted abnormal blood vessels with slow blood flow. The normal vessels needed in a healthy eye were spared.

The findings open the door to tailored therapies to reverse vision loss. It may also have implications in shrinking tumors that contain abnormal blood vessels in other parts of the body.

“We’ve shown that once these abnormal vessels have formed in the young eye, they’re susceptible to being treated,” said Griffin. The research team will now study the compound in models of adult eye diseases.

“More research is needed, but this could be a major advance in treatment for vision loss in patients of all ages,” Griffin said.


Abstract

During the progression of ocular diseases such as retinopathy of prematurity and diabetic retinopathy, overgrowth of retinal blood vessels results in the formation of pathological neovascular tufts that impair vision.

Current therapeutic options for treating these diseases include antiangiogenic strategies that can lead to the undesirable inhibition of normal vascular development.

Therefore, strategies that eliminate pathological neovascular tufts while sparing normal blood vessels are needed. In this study we exploited the hyaloid vascular network in murine eyes, which naturally undergoes regression after birth, to gain mechanistic insights that could be therapeutically adapted for driving neovessel regression in ocular diseases. We found that endothelial cells of regressing hyaloid vessels underwent down-regulation of two structurally related E-26 transformation-specific (ETS) transcription factors, ETS-related gene (ERG) and Friend leukemia integration 1 (FLI1), prior to apoptosis.

Moreover, the small molecule YK-4-279, which inhibits the transcriptional and biological activity of ETS factors, enhanced hyaloid regression in vivo and drove Human Umbilical Vein Endothelial Cells (HUVEC) tube regression and apoptosis in vitro.

Importantly, exposure of HUVECs to sheer stress inhibited YK-4-279–induced apoptosis, indicating that low-flow vessels may be uniquely susceptible to YK-4-279–mediated regression.

We tested this hypothesis by administering YK-4-279 to mice in an oxygen-induced retinopathy model that generates disorganized and poorly perfused neovascular tufts that mimic human ocular diseases. YK-4-279 treatment significantly reduced neovascular tufts while sparing healthy retinal vessels, thereby demonstrating the therapeutic potential of this inhibitor.


The ETS Inhibitors YK-4-279 and TK-216 Are Novel Antilymphoma Agents

The erythroblastosis virus E26 transformation specific (ETS)-transcription factors family comprises 28 proteins sharing a conserved DNA-binding domain (1). Altered ETS gene expression levels are often observed in many different tumors, including lymphomas (2–6). ETS1 and FLI1 are recurrently gained in approximately 25% of the cases of diffuse large B-cell lymphoma (DLBCL; ref. 3).

SPIB is overexpressed as a consequence of translocation of the IgH locus to chromosome 19 (4) or recurrent DNA gains in about 25% of activated B-cell–like (ABC) DLBCL (5). Silencing experiments have shown that SPIB is indeed an essential gene for the ABC-DLBCL, while SPI1 is necessary for the survival of germinal center B-cell–type (GCB) DLBCL (5–7).

Transcription factors have been widely considered difficult to target due to their nonenzymatic mechanism of action. They often complex with RNA helicases; these enzymes have emerged as key regulators of cellular transformation in cancer (8).

One example is RNA helicase A (DHX9 or RHA), an enzyme with many functions including translation and splicing. EWS-FLI1 is an Ewing sarcoma (ES) specific fusion oncogene that requires DHX9 for neoplastic transformation (9, 10). YK-4-279 is a small molecule that binds to EWS-FLI1 and blocks its interaction with DHX9, resulting in growth arrest and apoptosis in ES cells (9).

This disruption of protein interaction rather than inhibition of a relatively ubiquitous enzyme is believed to provide relative specificity for cancer cells. YK-4-279 can also affect other ETS transcription factors, such as ERG and ETV1 in prostate cancer cells (11–14).

TK-216 is a derivative developed for clinical trials with demonstrated in vitro and in vivo antitumor activity in ES models (15). TK-216 is a first-in-class inhibitor of the ETS family that is currently in phase I trials for patients with relapsed/refractory ES (NCT02657005; ref. 16).

Although the mechanism of action of YK-4-279 and TK-216 has been studied in ES, nothing is known about their efficacy and mechanism of action in lymphoma. In this study, we investigated the activity and the molecular mechanisms of these compounds as potential novel antilymphoma agents as single agents and in combination.

reference link : https://clincancerres.aacrjournals.org/content/25/16/5167


More information: Christopher M. Schafer el al., “An inhibitor of endothelial ETS transcription factors promotes physiologic and therapeutic vessel regression,” PNAS (2020). www.pnas.org/cgi/doi/10.1073/pnas.2015980117

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