Cheryl Guttman Krader, BS, Pharm

Cheryl Guttman is a medical writer based in Deerfield, Ill.

home

authors

cheryl-guttman-krader-bs-pharm

This article was reviewed by Peter A. Campochiaro, MD



Nanoparticles have been used to deliver gene therapy to treat 

, the Johns HopkinsUniversity (JHU) investigators used a uniquely engineered large molecule that facilitated compaction of large bundles of therapeutic DNA to be delivered into the ocular cells.

Regenxbio: Dosing of first patient in Phase 2 AAVIATE trial for wet AMD



This approach does not depend on viral vectors, as many of the gene therapies do, to transport the needed material into the cells. The downside of viral vectors is that an immune response is produced, and dosing cannot be repeated. 

In addition, the one used most often for ocular gene therapy cannot carry large genes, the investigators pointed out.

“Some of the most prevalent inherited retinal degenerations are due to mutations in large genes that simply cannot fit into the most commonly used viral vector,” said Peter A. Campochiaro, MD, the Eccles Professor of Ophthalmology at the JHU School of Medicine in Baltimore, Maryland.

In their research, Campochiaro and Jordan Green, PhD, used a biodegradable polymer that compacts long expanses of DNA to nanoparticles that can enter the cells, which transforms these ocular cells into “mini factories” for creating a therapeutic protein.

Contrast sensitivity shows potential for measuring visual function loss in early AMD

Green is a professor of biomedical engineering, ophthalmology, oncology, neurosurgery, materials science and engineering, and chemical and biomolecular engineering at the JHU School of Medicine.

In the first step of the research, Campochiaro and Green tested the visibility of the nanoparticles once they were in the eye by equipping them with a fluorescent protein gene. 

In this way, they could evaluate the location, amount, and duration of the gene expression that was possible. Remarkably, after 8 months most of the cells were visible, marking their places in the cells.

In the next phase of the experiment, the investigators loaded the nanoparticles with a gene for VEGF. This worked also. 

One month after the injection, abnormal blood vessels developed under and in the retinas of each of the 30 rats in the study, and at the 2- and 5-month evaluations, the blood vessels were more extensive as in untreated chronic AMD, they reported. These results indicate the durability of the genes in the cells.

Characterizing localized retinal layer changes in AMD

The next step was the test of the feasibility of delivery of a therapeutic to the cells to treat the disease in genetically engineered mice in which a form of 

was developed that is similar to the human form.

In the mouse model, Campochiaro and Green reported that there was a 60% reduction in the abnormal blood vessels compared to the control mice, and they reported seeing the same effect again 35 days later.

One potential benefit of this method of treatment is reduction of the number of times patients must return to clinics for reinjections of anti-vascular endothelial growth factor (VEGF) drugs, and a second one is that visual deterioration may be prevented. Jordan described these results as “extremely promising.” 


1. Johns Hopkins Medicine. Scientists use nanoparticle-delivered gene therapy to inhibit blinding eye disease in rodents. 

. July 7, 2020. sciencedaily.com/releases/2020/07/200707113210.htm

Articles

Investigators find that nanoparticles deliver gene therapy successfully in mice, rats.

Exploring novel gene therapy approaches to treat ocular disease


This article was reviewed by Jesper Høiberg Erichsen, MD



Results of a prospective randomized trial comparing 5 medication regimens for controlling inflammation early after uncomplicated surgery show that beginning monotherapy with a topical nonsteroidal anti-inflammatory drug (NSAID) the day of surgery offered the best outcome for efficacy and safety.

The findings, presented by Jesper Høiberg Erichsen, MD, revealed that adding a topical steroid to the NSAID provided no benefit but could adversely affect intraocular pressure. 


Improving surgical safety, efficiency, and outcomes for patients


Initiating topical treatment 3 days preoperatively also conferred no advantage for better inflammation control, whereas a dropless approach using a sub-Tenon corticosteroid injection proved inferior to topical treatment. 

“Controlling postoperative inflammation is important for achieving a successful outcome after cataract surgery. Surgeons generally prescribe an anti-inflammatory prophylactic regimen parallel to surgery, and recent meta-analyses have documented a beneficial effect of using a topical NSAID,” said Erichsen, a doctoral student in the Department of Ophthalmology at Rigshospitalet-Glostrup in Denmark. 

He added that several questions about inflammation prophylaxis require investigation.

“Based on our results, we recommend that cataract surgeons consider using NSAID monotherapy as anti-inflammatory prophylaxis in uncomplicated cases,” he said.

Patients with a senile cataract were eligible for enrollment in the study if they were undergoing uncomplicated surgery and had no history of diabetes, uveitis, glaucoma, retinal vein occlusion, epiretinal membrane, retinal detachment, or advanced age-related macular degeneration. 


Perioperative medications can eliminate postoperative drops after cataract surgery


A total of 470 patients were randomly selected in 5 equal groups to receive topical prednisolone and ketorolac started 3 days preoperatively, topical prednisolone and ketorolac started on the day of surgery, ketorolac started 3 days preoperatively, ketorolac started on the day of surgery, or a sub-Tenon depot of dexamethasone 2 mg/0.5 mL. 

All topical drops were to be administered 3 times daily and continued for 21 days after surgery.

After random selection, 14 patients were excluded, and 438 completed follow-up to the primary end point visit at postoperative day 3. The mean age of the 456 patients included in the baseline data analysis was 72 years, and almost two-thirds of the participants were women.

The primary outcome assessed change from baseline in anterior chamber flare measured on undilated pupils using a flare photometer (Kowa FM-600, Kowa Company). 

For statistical analyses, the group that received the combination topical regimen started preoperatively was used as the control group.



Dropless, hands-free regimen key for patients

Median flare was 10.1 photon counts per millisecond at baseline in all groups, and it increased significantly at postop day 3 in all groups. 

The greatest rise occurred in the dropless group, and the difference in change from baseline compared with the control group was statistically significant only in the dropless group.

“As another interesting result, we found that only a few patients in the topical treatment groups [1.1%-3.4%] needed additional intervention to control inflammation, whereas more than one-third of patients in the dropless group needed rescue anti-inflammatory treatment,” Erichsen said. “Minimizing the need for topical drops is desirable in older patients who may struggle with administration, but the dropless approach using the sub-Tenon injection did not seem effective for achieving that goal.”

Anterior chamber cell count at postop day 3 was investigated as a secondary outcome measure. The mean value was 3.4 in the control group, ranged from 3.8 to 4.1 in the 3 other topical regimen groups, and was 5.5 in the dropless group. 

Again, Erichsen noted that the only the difference between the dropless and control groups was statistically significant.


Research: Similar endophthalmitis rates for generic, branded topical antibiotics

Postop day 3 logMAR visual acuity measured with Early Treatment Diabetic Retinopathy Study charts was also evaluated as a secondary end point.

The results showed no significant differences between groups.

Intraocular pressure, another secondary outcome measure, was found to decrease significantly after cataract surgery in all groups. 

However, the drop was significantly less in the combination treatment groups that received a topical steroid compared with those receiving a topical NSAID alone and the dropless group.

Erichsen initially made his presentation at the virtual Association for Research in Vision and Ophthalmology 2020 annual meeting. 



Neither Erichsen nor any of his coauthors has any relevant financial interests to disclose.

Large randomized trial compares efficacy and safety of multiple regimens

Minimize inflammation after cataract surgery


This article was reviewed by Matthew S. Wieder, MD



Use of anxiety screening questionnaires in patients needing intravitreal anti-vascular endothelial growth factor (VEGF) injections may help to identify individuals at risk for elevated pain during the procedure, according to results of a study.

The 2-center, noninterventional, prospective study was designed to evaluate anxiety levels and sleep patterns as predictors of patient perceptions of pain following intravitreal bevacizumab injection. 

ASRS 2020: Diabetic retinopathy progression in anti-VEGF versus FA implant

In a regression analysis that controlled for potential confounders, anxiety score measured with the General Anxiety Disorder-7 (GAD-7) questionnaire was the only variable examined that independently predicted pain.

There were no statistically significant associations between intravitreal anti-VEGF injection pain and measured sleep parameters, age, gender, laterality, diagnosis, previous injections, or surgeon/site.

Intravitreal anti-VEGF injections are the most commonly performed in-office intraocular procedure, according to Matthew S. Wieder, MD

“Although generally well tolerated, some patients experience pain, and because many patients undergo these treatments on a regular basis for treatment of a chronic condition, pain during the injection could result in poor adherence to future treatment,” he said. “To identify strategies to combat the pain experienced by some patients, several studies have evaluated different techniques to decrease the pain, including changes in anesthesia and injection site.”

According to Wieder, a resident in the Department of Ophthalmology and Visual Sciences at the Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York:

“The findings of our study support future research of modifications that target anxiety to help address pain perception of intravitreal anti-VEGF injections.”

Evaluating the change in VA, CMT after early switch of anti-VEGF drugs

Wieder presented the study at the Association for Research in Vision and Ophthalmology (ARVO) 2020 virtual annual meeting.

Moshe Szlechter, MD, and Irene Rusu, MD, performed the injections. Szlechter is a retina specialist at KLM Eye Care, Brooklyn, New York, and Rusu is a retina specialist at Brooklyn Eye Center, also in Brooklyn. 

Both are assistant professors of ophthalmology and visual sciences at Albert Einstein College of Medicine, Bronx, New York.

Szlechter said the idea for the study occurred to him while he was lecturing in his community about ophthalmology procedures.

“I wound up speaking from the hip and said that I can predict based on a patient’s level of stress who will feel pain before I even administer the injection,” he noted. “I researched the idea after my lecture and found no good data to support my assertion.”

Szlechter added that it can be interesting to see how a psychological state influences a very physiological reaction.

“A patient’s heightened anticipation and anxiety of future pain will actually make the procedure more painful,” he said.

Anti-VEGF therapy may prevent/delay radiation maculopathy in choroidal melanoma


A standard technique was used at the two participating sites to control for potential confounding variables. Patients were given the GAD-7 (possible range 0-21) and Pittsburgh Sleep Quality Index (PSQI; possible range 0-21) to complete prior to their injection.

After the procedure, they were asked to rate the severity of pain after intravitreal injection as 0 to 10 with a visual analog scale.

A total of 154 patients were recruited, of which 140 met the inclusion criteria for analysis. The total cohort was equally distributed between the 2 sites. The patients included in the analysis had a mean age of approximately 72 years and 56% were women.

The 2 most common indications for the injections were wet age-related macular degeneration (40%) and diabetic macular edema (29%). 

Mean ± standard deviation scores were 4.9 ± 5.6 for the GAD-7, 6.3 ± 4.1 for the PSQI, and 3.69 ± 2.64 for pain. 

Mean ± standard deviation for overnight sleep was 6.7 ± 2.0 hours and was 7.6 ± 2.6 hours for sleep more than 24 hours.

What keeps you up at night in ophthalmology?

“Anxiety scores on the GAD-7 ranged from 0 to 21 and postprocedure pain scores ranged from 0 to 10, but most patients had low scores indicating mild to no anxiety and most experienced no or mild pain,” Wieder said.

A statistically significant positive correlation was found between the GAD-7 score and pain.

For the sleep measures, both previous night’s sleep and sleep over the previous 24 hours negatively correlated with pain, and there was a positive correlation between PSQI and pain scores (higher PSQI score indicates poorer sleep quality), although none of the correlations achieved statistical significance. In the regression analysis that controlled for confounding variables, each point increase in the GAD-7 score predicted a 0.11-point increase in procedural pain score, according to Wieder.


Wieder has no relevant financial interest to declare.


Szlechter has no relevant financial interest to declare.


Mbekeani has no relevant financial interest to declare.

Study points to possible role of addressing preprocedural anxiety


Improve patient comfort with intravitreal injections

DRY EYESSSS drops.jpeg

Even patients without pre-existing dry eye disease (DED) who are scheduled for cataract surgery can benefit from perioperative use of artificial tears, and particularly by starting the treatment preoperatively, according to the findings of a retrospective study conducted by Italian investigators.

The researchers analyzed data from the Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire, tear break-up time (TBUT) measurements, and corneal fluorescein staining (CFS) in three groups of patients comprised of those who did not use any artificial tears perioperatively (n = 140); patients who began to instill artificial tears one week preoperatively and continued for two months postoperatively (n= 139); and a cohort that used artificial tears postoperatively for two months (n = 140). The DED-related evaluations were performed preoperatively and at follow-up visits occurring at 1, 4, and 8 weeks after surgery. The artificial tear product was a commercially available lubricant formulation containing hydroxypropyl guar and hyaluronic acid, and all patients were treated with the same perioperative regimen of antibiotic and anti-inflammatory medications.

. 2020;14:1769-1775] showed statistically significant benefits of treatment with the artificial tears for mitigating surgically-induced signs and symptoms of DED. Statistically significant differences favoring the group that started using the artificial tears preoperatively compared with the group using the ocular lubricant only after surgery were seen in analyses of SPEED scores and TBUT.

Based on the findings, the investigators concluded that the artificial tear product was effective in protecting the ocular surface, particularly if initiated in the preoperative period. Noting that DED can lead to biometric errors and adversely affect patient comfort and vision after surgery, they stated that the findings highlight the importance of improving the homeostasis of the ocular surface not only in patients with established DED but also in those without frank disease or evident DED risk factors.

The study identified patients who had undergone unilateral cataract surgery across 17 centers in Italy. A total of 419 patients met the inclusion criteria that required eligible patients to be at least 50 years of age and have undergone an uncomplicated procedure with a clear corneal incision, IOL implantation in the capsular bag, and postoperative treatment with dexamethasone + tobramycin four times a day for ten days and nepafenac 0.1% three times a day for one month.

In addition, patients needed to have data from DED diagnostic tests conducted between 30 and 7 days before surgery and at 1, 4, and 8 weeks postoperatively. Patients were excluded if they had pre-existing DED, which was diagnosed based on a Schirmer test without anesthesia <7 mm/5 min, TBUT <10 seconds, SPEED score >4, and CFS score >1, or if they had any other findings that could confound the results.

Preoperatively, the three study groups were well-matched with respect to mean age (~72 years), mean Schirmer test score (~13 mm/5 min), mean TBUT (~12 sec), and percentage of eyes with a CFS score = 0 (65% to 76%). The postoperative data from all groups were consistent with previous reports showing that cataract surgery can induce signs and symptoms of DED.

Mean SPEED questionnaire scores did not change significantly in groups that were using artificial tears but increased significantly (worsened) at week 4 in the untreated patients. The differences in mean SPEED scores were statistically significant favoring both groups using the artificial tears versus the untreated group at all follow-up visits. The investigators noted that 25% of the patients in the untreated group had SPEED scores corresponding to mild-moderate dry eye symptoms at eight weeks after surgery.

In addition, a statistically significant difference favoring the group starting artificial tear use preoperatively compared with the group treated only postoperatively was noted at postoperative weeks 1 and 4.

The TBUT was significantly higher in both groups using the artificial tears compared with the controls at all follow-up visits, and mean TBUT fell to below 10 seconds postoperatively only in the control group. In addition, TBUT recovered faster in the group using artificial tears preoperatively compared with the group that was treated only after surgery. At the week 4 postoperative visit, the TBUT was higher in the group that started artificial tear use preoperatively compared with the group treated only postoperatively. The investigators noted, however, that while the difference was statistically significant, it was not clinically significant.

The results for CFS showed that patients using artificial tears had less corneal damage after surgery than their untreated counterparts. Among patients who used the artificial tears preoperatively and postoperatively, a small minority had CFS scores of 2 (7.2%) or 3 (0.7%) at the week 1 postoperative visit. In this same group by week 4, more patients had a CFS score of 0 compared with baseline, and the percentage was increased further at week 8.

A similar pattern of early worsening in CFS scores and subsequent progressive improvement was noted in the group that used artificial tears postoperatively only and in the untreated group. However, among patients who used the artificial tears after surgery, ~6% of patients had a CFS score >1 at week 4, while in the untreated group a CFS score >1 was found in 20% of eyes at week 1, 13% at week 4, and 6.4% at week 8.

Initiating the treatment preoperatively was associated with better outcomes than if the artificial tears were used only after the procedure.

Author | Cheryl Guttman Krader, BS, Pharm

Articles

Minimize inflammation after cataract surgery

Improve patient comfort with intravitreal injections

Optimizing the ocular surface in cataract surgery patients unaffected by dry eye

Exploring novel gene therapy approaches to treat ocular disease