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 suggest that SARS-CoV-2 may diffuse from the ocular surfaces to the patient’s body, and use of a conjunctival swab may be another method of diagnosing the virus, according to Claudio Azzolini, MD, from the Unit of Ophthalmology, Azienda Socio-Sanitaria Territoriale (ASST) dei Sette Laghi, Department of Medicine and Surgery, University of Insubria, Varese, Italy,

Azzolini and colleagues investigated the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detected in the tears of patients with COVID-19 based on the hypothesis that bodily fluids may serve as the conduits of viral spread, although thus far “insufficient information is available on the presence of the virus in human tears,” they pointed out.

The investigators used real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) to detect the virus in the tear samples from 91 patients in 2 intensive care units in northern Italy, between April 9 and May 5, 2020. 

COVID-19 had been clinically diagnosed using rRT-PCR performed on nasopharyngeal swabs and by radiology studies of these patients. 

Seventeen healthy volunteers who provided conjunctival swabs served as controls. The mean age of the 108 study participants was 58.7 years (55 women).

“SARS-CoV-2 was found on the ocular surface in 52 of 91 patients with COVID-19 (57.1%; 95% CI, 46.3%-67.5%), with a wide variability in the mean viral load from both eyes,” the investigators said.

They also evaluated a subset of 41 patients who had nasopharyngeal and conjunctival swabs performed on the same day or within 2 days and reported a “concordance of 63.0% (95% CI, 41.0%-81.0%) was found between positive conjunctival and nasopharyngeal swab test results when performed within 2 days of each other.”

Seven of 17 patients (41.2%; 95% CI, 18.0%-67.0%) in the subset had negative conjunctival and nasopharyngeal swabs, and the other 10 of these patients had negative nasopharyngeal swabs but positive conjunctival swabs.

This study showed that SARS-CoV-2 RNA was on the ocular surface in more than half of the patients in the COVID-19 cohort. 

“Because patients may have positive test results with a conjunctival swab and negative results with a nasopharyngeal swab, use of the slightly invasive conjunctival swab may be considered as a supplementary diagnostic test,” the investigators advised.



1. Azzolini C, Donati S, Premi E, et al. SARS-CoV-2 on ocular surfaces in a cohort of patients with COVID-19 from the Lombardy Region, Italy. JAMA Ophthalmol. Published online March 4, 2021. doi:10.1001/jamaophthalmol.2020.5464

Articles

Investigators suggest that SARS-CoV-2 may diffuse from the ocular surfaces to the patient’s body, and use of a conjunctival swab may be another method of diagnosing the virus.

SARS-CoV-2 populates ocular surfaces in COVID-19 patients in Northern Italy



This article was reviewed by Justine S. Paradis, PhD



The results of a preclinical study indicate there is hope for an effective treatment for the GNAQ-driven metastatic uveal melanoma, an aggressive form of the disease.

The treatment relies on 2 components, the MEK inhibitor trametinib or the second generation RAF/MEK inhibitor VS-6766 (Verastem Oncology) combined with defactinib, a focal adhesion kinase (FAK) inhibitor (Verastem Oncology), that work better together than apart for controlling uveal melanoma.



Light-activated agent novel option for uveal melanoma 

The importance of this potential treatment is underscored by the fact that uveal melanoma is the most frequently occurring ocular cancer in adults, and it becomes metastatic in 50% of patients in whom it develops. The survival rate currently is 2 years, with only 8% surviving following metastasis to the liver.

“To date there is no effective treatment for metastatic uveal melanoma, and there is an urgent need to identify novel precision therapies for advanced and metastatic uveal melanoma patients,” according to Justine S. Paradis, PhD, a postdoctoral fellow at the Moores Cancer Center at the University of California San Diego.


Trametinib is an inhibitor of MEK kinase activity, and VS-6766 is a second-generation RAF/MEK inhibitor blocking both the MEK kinase activity and the ability of RAF to phosphorylate MEK. 

The investigators explained that VS-6766 blocks MEK signaling without the compensatory activation of MEK, which differs from how other inhibitors work.

Defactinib (VS-6063) is an oral small-molecule inhibitor of FAK and PYK2 that is being evaluated as a potential combination therapy for various solid tumors.



Pearls for managing care of high-risk uveal melanoma patients

The combination of the 2 inhibitors induces apoptosis of the uveal melanoma cells, which in turn leads to rapid tumor regression in the uveal melanoma xenografts. When the 2 agents were used alone, the tumor growth was inhibited, but the size of the tumors did not shrink. 

In addition, this combination approach also decreased the tumor burden in models of uveal melanoma liver metastasis.

The investigators described that FAK and MEK inhibition combined showed “synergistic cytotoxic effects” in metastatic uveal melanoma cells.



The investigators used the combination of the MEK and FAK inhibitors in a xenograft mouse model in which the animals were treated for 20 days and found that the tumor volume decreased when the 2 were used together. 

In contrast, when used alone, the inhibitors only stabilized the tumor size, with a limited apoptotic response.



Conjunctival melanoma: Unlocking mysteries of disease

In a mouse model of liver metastasis, in which the animals were treated for 21 days, the investigators reported that the metastatic burden in the animals was reduced. The combination of the 2, they reported, very importantly “nearly eliminated all metastatic lesions.”

The team is evaluating residual disease and tumor burden progression after the treatments were stopped.

J. Silvio Gutkind, PhD, distinguished professor of pharmacology and associate director for Basic Science at Moores Cancer Center at the University of California San Diego, and senior investigator of the study, said results should lead to human trials.

“The study identified and reinforced FAK as a viable pathway to inhibit downstream from the GNAQ pathway, which is constitutively active in uveal melanoma,” he said. “We observed that cotargeting of FAK and RAF/MEK signaling led to tumor collapse in uveal melanoma xenograft and liver metastasis models in vivo.”



Liquid biopsies: Not yet ready for prime time in uveal melanoma 

Pharmacological inhibition of FAK and MEK inhibited the growth of uveal melanoma cells and had cytotoxic effects leading to tumor collapse in uveal melanoma xenograft and liver metastasis models in vivo.

The results emphasized the importance of cotargeting with FAK and RAF/MEK to provide a new network-based precision therapeutic strategy.

The signal-transduction-based precision therapy data support clinical testing of the combination inhibition in metastatic uveal melanoma.

VS-6766 and defactinib are also being studied clinically to treat low-grade serous ovarian and 

 mutant non–small cell lung cancers and colorectal cancer.

A phase 2 study of VS-6766 and defactinib in uveal melanoma is expected to commence in late 2020. 


Paradis has no financial interest in this subject matter.

Combining RAF/MEK signaling pathway inhibitor with FAK inhibitor raises bar

Options give 1-2 punch to metastatic uveal melanoma

A visual simulator (SimVisGekko, 2EyesVision) helps patients to choose how well multifocal IOLs function before surgical implantation and improve satisfaction with surgical outcomes.

) that provides patients the experience of vision with multifocal IOLs (mIOLs) before actual implantation may help to manage patient expectations, according to Susana Marcos, PhD.

This innovation arose out of the scaling down of technologies that originated in astronomy, i.e., adaptive optics, into a system useful to ophthalmologists for prescribing correction for presbyopia and simulating mIOLs.

Despite the availability of mIOLs, only 7% of patients opt for this correction modality after cataract surgery, noted Dr. Marcos, research professor, Instituto de Optica Daza de ValdÃ©s, Consejo Superior de Investigaciones CientÃ­ficas, Madrid.

The challenge may be the difficulty with explaining multifocality to patients.

In addition, it is difficult for patients to decide about mIOL implantation if they cannot visualize what their vision will be preoperatively, a scenario that leaves them with uncertainty about both their expectations and the actual surgical results.

A solution to this may be use of the mobile visual simulator that would ease their decision-making process.

“Visual simulators will help to sell more premium lenses and screen out prospective unhappy patients,” Dr. Marcos said. “This technology would be valuable for patients, clinicians, and IOL manufacturers.”

The device provides practical utility in the clinic, in that it improves patient satisfaction, facilitates comparison of corrective solutions, and saves time by providing an easy explanation of multifocality. It also provides business advantages by reducing patient complaints and refunds, provides a competitive advantage to doctors who adopt the device early, and increases the number of mIOL prescriptions.

Advanced toric IOL calculator improves refractive outcomes

The wearable, binocular, see-through device provides a 20-degree field of view, is programmable on a tablet, and simulates multifocal and extended-depth-of focus corrections and provides monovision or modified monovision correction.

“This facilitates testing a range of preoperative corrections,” she said.

The device contains optotunable lenses. Using a custom, high-speed electronic driver, the lenses can change focus rapidly by a process called temporal multiplexing.

“With periodic variations of the optical power at high speed, above 50 Hz, the static appearance of multifocal retinal images is provided by mapping spatial distribution in a lens into temporal distribution in the optotunable lens,” Dr. Marcos said.

She described this in a trifocal FineVision IOL. The map in the IOL is defined with a set of coefficients; the data show how much time the lens spends at the different power additions. With a trifocal lens the coefficients are at three different foci. This process can be performed with different coefficients and simulate extended-depth-of-focus lens types and different energy distributions.

“We also control for dynamic effects in the lens so that we can really map the true focus performance of the lens,” she said.

A comparison of the performance of an actual commercial IOL with the simulation showed how well the images of the two matched.

Performance of trifocal toric IOL highlighted in tests

When the mobile visual simulator was taken into the clinic, it performed well.

“We found that the device replicates mIOLs,” Dr. Marcos said. “We performed the test with a trifocal IOL in the SimVis preoperatively and the patient was ultimately implanted with the lens. We found that in patients with clear lenses and those with cataracts, the preoperative (with SimVis) and postoperative (with the implanted mIOL) defocus curved matched.”

In the presence of a cataract, there is a shift down because of the light distribution caused by the cataract, but the shape of the defocus focus curve is well captured, according to Dr. Marcos.

This technology is also useful for patients opting for multifocal contact lenses. An excellence replication of the contact lens performance on eye  was achieved with the SimVis simulation. For different lens designs with different power additions.

The device also was tested using different natural images at far and near distances under conditions during the day and at night.

When tested in a patient with corrected binocular far vision, for example, the scores at the far distance were high and the scores for near were low. When bilateral bifocal correction was provided the far vision decreased slightly and the near vision improved. This also can be applied to monovision and modified monovision.

When the patient is tested with different corrective options, surgery can proceed with much more certainty regarding the postoperative vision, Dr. Marcos noted.

The physician can choose the desired lenses and control the test on an iPad. The management of the mobile device allows connection of every iPad to the cloud, remote management of the devices, security management, remote app updates, monitoring and tracking, and remote troubleshooting.

Striving for perfection: Creating the perfect IOL

In addition, when new IOL designs become available the software is updated.

“This technology provides a powerful back-end,” Dr. Marcos said. “Over and above monitoring the use of the SimVis, we can monitor different patient lens preferences, the rates of actual implantations of those IOLs, and the conversion rate to multifocality.”

This is powerful information that is enabled by the fact that we can perform this preoperative clinical testing before surgery, she emphasized.

“We believe that SimVis represents a new paradigm in presbyopia correction that provides patient education, aid in lens selection, reduced uncertainty preoperatively, virtual clinical trials, the ability to test multiple lenses, and large data sets of patient preferences and usage,” Dr. Marcos concluded.

Innovative IOL power calculations gain accuracy

Susana Marcos, PhD
	E: susana@io.cfmac.csic.es
	Dr. Marcos is coinventor of the SimVis technology and co-founder and shareholder in 2EyesVision.

Simulator helps patients ‘see’ with multifocal IOLs before implantation

At the 22nd EURETINA World Congress, French researchers, led by Isabelle Audo, MD, reported that voretigene neparvovec used to treat patients with a RPE65-related inherited retinal dystrophy, showed good safety and efficacy at the 1-year time point of the LIGHT Study. (

French researchers, led by Isabelle Audo, MD, reported that voretigene neparvovec (VN) (Luxturna, Spark Therapeutics), used to treat patients with a RPE65-related inherited retinal dystrophy, showed good safety and efficacy at the 1-year time point of the LIGHT Study.

Audo is professor of ophthalmology in the Department of Genetics at Institut de la Vision, and coordinator of the National rare disease center at Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris. She presented data at the 22nd European Society of Retina Specialists (EURETINA) Congress in Hamburg, Germany.

 gene and loss of gene function causes photoreceptor dysfunction and degeneration, leading to blindness. VN is the first gene therapy for this patient population.

The LIGHT study, Audo described, is a descriptive, non-interventional study in which VN was administered at a dose of 1.5 x 1011 vector genomes that were delivered in a total subretinal volume of 0.3 ml.

Both eyes of the patients were treated on separate days and at least 6 days apart. Follow-up examinations were conducted at 1, 3, 6, 12 and 24 months following gene therapy in the second eye. At these time points, the investigators evaluated the treatment efficacy and safety and collected the patients’ postoperative experience.

The efficacy was assessed by measuring the visual acuity (VA), full-field stimulus threshold (FST), and visual fields (VF). A maze platform was used that showed a typical street that patients may encounter during daily activities. Patients were instructed to follow the path under four lighting conditions of 2, 7.5, 50, and 500 lux and avoid obstacles and walls. Their mobility was assessed using the percentage of preferred walking speed and the time to completion of the course completion time.

The investigators also collected patient/parent comments about the visual experience.


Twelve patients (6 adults, 6 children; age range, 4-35 years) were included.

Eleven had a diagnosis of Leber congenital amaurosis and one had retinitis pigmentosa. All have undergone bilateral surgeries.

At the 1-month evaluation, Audo noted that the FST had median decrease of -33.2 decibels (dB) (-33.7; -19.8) dB, which remained stable until the last assessment. The VFs and VAs did not change significantly.

Audo also reported that the percentage of preferred walking speed at 2 lux and at high speed, 1 month after surgery had a median increase of 63.9% (47.8%; 88.5%) and the course completion time decreased by 47.23% ( -58.50 %; -41.16 %). These improvements continued over time.

At least one adverse effect related to surgery occurred in all patients and only 1 was serious, i.e., a retinal detachment. Seven patients had at least one adverse effect related to VN, all of which were not serious and did not require treatment. Chorioretinal atrophy was observed in both eyes of 5 patients and was considered to be possibly related to surgery and VN.

The patients’ comments highlighted three categories described by Kay et al. 2021 mentioned by more than 50% of the patients: visual function symptoms, impact on vision dependent activities of daily living, and coping mechanisms and visual aids, providing more insight into their postoperative experience.

“This experience with VN showed significant post-treatment improvements in FST from month 1,” Audo explained. “Adding a mobility test to assess the evolution of functional vision in their routine follow-up protocol in addition to the FST allows this study to gain further insight into the efficacy of VN during the first postoperative year.”

Audo also pointed out that the patients’ mobility also improved from the first month after surgery for all patients.”

She also mentioned that in the 5 patients in which chorioretinal atrophy developed after VN treatment, the FST improved compared to baseline and remained stable over the long-term follow-up (between 12 and 24 months post VN treatment).

At the 22nd EURETINA World Congress in Hamburg, Germany,Isabelle Audo, MD, reported that voretigene neparvovec used to treat patients with a RPE65-related inherited retinal dystrophy, showed good safety and efficacy at the 1-year time point of the LIGHT Study. 


EURETINA 2022: LIGHT study offers first analysis of gene therapy for RPE65 inherited retinal dystrophies

The path that eye drops take to reach posterior ocular tissues of the eye.

A novel eye drop under development may provide neuroprotection to the retinal ganglion cells (RGCs). An added plus is that only once-weekly dosing is required, according to Laura Ensign, PhD, who headed up the research.

Ensign holds the Marcella E. Woll Professorship in Ophthalmology and is an associate professor of ophthalmology and vice chair for research at the Wilmer Eye Institute, Johns Hopkins Medicine in Baltimore, Maryland. This work is being conducted in collaboration with Justin Hanes, PhD, who is the Lewis J. Ort Professor of Ophthalmology and director of the Center for Nanomedicine at the Johns Hopkins University School of Medicine, and Donald Zack, MD, PhD, the Guerrieri Professor of Genetic Engineering and Molecular Ophthalmology and codirector of the Center for Stem Cells and Ocular Regenerative Medicine at the Wilmer Eye Institute.

Antiglaucoma eye drops are the mainstay of treatment for the disease, and they successfully and significantly lower the IOP. However, despite achieving a reduction of the IOP, glaucoma can continue to progress and threaten vision in many patients diagnosed with the disease. A therapy that protects the RGCs from damage was just a dream until recently. This new therapy developed by the Wilmer Eye Institute team is in the process of becoming a reality.

“The concept of delivering a drug to protect RGCs is not something that is currently done clinically, but as a complement to IOP lowering, may be an important glaucoma management tool,” Ensign said. “The fact that we can potentially protect the RGCs using an eye drop is unique and interesting, because this route is not typically used to deliver therapy to the retina.” The investigators reported their progress in Drug Delivery and Translational Research.

The drug, sunitinib (Sutent, Pfizer), was delivered in a novel gel-forming eye drop that remains in place for an extended period and provides increased intraocular drug absorption. In combination with the intrinsic melanin-binding properties of sunitinib, drug binding in the pigmented cells in the choroid and retinal pigment epithelium provided sustained, therapeutically relevant drug concentrations in the retina to protect the RGCs. “The process of binding to melanin serves as a reservoir for the drug—ie, it is a built-in sustained delivery system in the ocular cells,” Ensign said.

The 2-fold advantages of this therapeutic pathway are clear: (1) transport of the drug to the back of the eye in sufficiently high therapeutic concentrations, and (2) the sustained release of the drug over time from melanin. This capability allowed for once-weekly dosing that continues to provide a therapeutic effect in the retina, which has the potential to decrease the patient treatment burden.

Ensign and Hanes formed a start-up company under the umbrella of Johns Hopkins to develop the eye drop technology. The eye drop has not yet moved into clinical trials, but this is currently being considered. The ultimate goal is to have an eye drop available in a few years that is intended to treat retinal disease, according to Ensign.

In a previous publication,2 Ensign and colleagues in collaboration with Peter Campochiaro, MD, also from the Wilmer Eye Institute, used a porcine model to show that choroidal neovascularization was prevented by the sunitinib gel-forming eye drop in contrast to a saline eye drop version of the drug, which had no effect. “Our eye drop decreased the area of neovascularization by [approximately] half,” Ensign said.

The next step is to evaluate the effect of different doses of the sunitinib drop for glaucoma. In addition, for age-related macular degeneration, the investigators are considering a daily dose.

Ensign has a financial interest in this technology. She is one of the inventors listed on patents/patent applications related to this technology and is one of the cofounders of the start-up company planning to develop the eye drop technology for clinical use.

1. Kim YC, Hsueh HT, Shin MD, et al. A hypotonic gel-forming eye drop provides enhanced intraocular delivery of a kinase inhibitor with melanin-binding properties for sustained protection of retinal ganglion cells. Drug Deliv Transl Res. 2022;12(4):826-837. doi:10.1007/s13346-021-00987-6

2. Kim YC, Shin MD, Hackett SF, et al. Gelling hypotonic polymer solution for extended topical drug delivery to the eye. Nature Biomed Eng. 2020;4(11):1053-1062. doi:10.1038/s41551-020-00606-8

A novel eye drop under development may provide neuroprotection to the retinal ganglion cells.

Controlling glaucoma: Eye drop therapy reaches posterior ocular tissues

Investigators reported an important first step in a treatment approach for advanced dry age-related macular degeneration (AMD), which has until now had few options for millions of affected patients around the world.

The study showed that the California Project to Cure Blindness Retinal Pigment Epithelium (CPCB-RPE1, Regenerative Patch Technologies), a subretinal implant containing allogeneic human embryonic stem cell-derived retinal pigment epithelium (RPE) cells, was safe and well-tolerated by patients with this type of AMD.

Amir H. Kashani, MD, PhD, lead author of the study, principal investigator of the clinical trial at the University of Southern California, and currently an associate professor of ophthalmology at the Wilmer Eye Institute, Johns Hopkins University, Baltimore, reported results at the Bascom Palmer Eye Institute’s 19th annual Angiogenesis, Exudation, and Degeneration 2022 Virtual Edition conference.

The primary end-point was the safety of this approach at 1 year after implantation. Patients with dry AMD and severe vision loss secondary to geographic atrophy (GA) were included. The implant was delivered into the subretinal space of the worse-seeing eye of 15 patients using a custom subretinal insertion device in an outpatient surgery setting.

The median age of the 15 patients (9 women, 6 men) was 78 years (range, 69-85). The patients were all legally blind in the treated eye (best-corrected visual acuity [BCVA] ≤ 20/200). The patientswere divided into 2 cohorts: cohort 1 included 6 patients and cohort 2 had 9 patients.

All patients were evaluated postoperatively using optical coherence tomography and fundus photography. The implants remained pigmented and did not migrate postoperatively.

The investigators reported that no unexpected serious adverse events occurred in any study patients. Expected serious ocular adverse events did occur in cohort 1 subjects, i.e., retinal hemorrhage, edema, focal retinal detachment, or RPE detachment. Changes to the intraoperative procedure to improve hemostasis were implemented in cohort 2 subjects and prevented any serious ocular events in the second cohort.

No inflammation developed in any patient that was suggestive of an immune response directed toward the donor implant.

“It is encouraging that even though these implanted cells were not HLA-matched, there were no clinical signs of retinitis, vitritis, vasculitis, or choroiditis even in the absence of long-term immunosuppression in the phase 1/2a study,” Kashani said.

Although the study was not powered to detect efficacy, the BCVA improved in 4 treated eyes by more than 5 letters of vision (range, 6 to 13 letters). More treated eyes (27%) had a nonsignificant gain in vision of more than 5 letters compared to the untreated eye (7%) respectively. Conversely, more untreated eyes (47% vs 33%) lost 5 or more letters, a difference that did not reach significance.

One of the patients died of natural causes 2 years after the CPCB-RPE1 was implanted. The death was unrelated to this research. Both eyes were enucleated and analyzed histopathologically. The postmortem studies showed the presence of donor RPE cells 2 years after implantation by immunoreactivity for RPE65 and donor-specific HLA Class I molecules.Additional markers of RPE cell polarity and phagocytosis suggest that the donor RPE cells were functioning.

The authors speculated that the mechanism of action for the CPCB-RPE1 is the result of enhanced viability of surviving photoreceptor cells in the retina directly overlying or adjacent to the CPCB-RPE1 implant. However, they noted the need for additional data. They also theorized that dormant photoreceptors in the area of the GA may have been rehabilitated by the CPCB-RPE1 implant and stimulated to form outer segments.

Based on these results, they concluded that the implant procedure is feasible on an outpatient basis and that the implant was safe and well-tolerated in this patient population.

Kashani JS, Lebkowski JS, Rahhal FM, et al. One-year follow-up in a phase 1/2a clinical trial of an allogeneic RPE cell bioengineered implant for advanced dry age-related macular degeneration. TVST 2021;10(10):13; https://doi.org10.1167/tvst,10.10.13

In a presentation at the Bascom Palmer Eye Institute’s 19th annual Angiogenesis, Exudation, and Degeneration 2022 Virtual Edition, Amir Kashani, MD, PhD, discussed results that show the implant procedure is feasible on an outpatient basis and has a good safety and efficacy profile. 