Emma Yasinski

Stem cell therapy has been a far-reaching idea that has gradually grown closer to feasibility for multiple specialties. But it has often fallen short in being provided in a clinically viable manner, consistent with good manufacturing practice (GMP) standards. Problems with ensuring that pluripotent cells differentiate and organize properly, that the patients’ immune systems do not reject them, and that the cells do not become cancerous have been prevalent.

A team of investigators from the National Eye Institute recently published a study suggesting that they have developed a method for injecting specialized stem cells to regenerate damaged retinal epithelial cells in the eyes of patients with 

advanced dry age-related macular degeneration (dry AMD)

—and that it is ready for clinical trials in humans.

"If the clinical trial moves forward, it would be the first ever to test a stem cell-based therapy derived from induced pluripotent stem cells (iPSC) for treating a disease," Kapil Bharti, PhD, head of the NEI Unit on Ocular and Stem Cell Translational Research and lead author on the study, said in a 

The team harvested CD34+ cells from blood of 3 different human patients experiencing AMD, and turned them into induced pluripotent stem cells (iPSCs). They created a bank of iPSCs from these cells on which they tested and optimized methods for coaxing the cells to differentiate into functional cells that that could be safely inserted into the retinal pigment epithelia (RPE).

Those RPE cells then keep remaining photoreceptors healthy, allowing patients to theoretically maintain their sight. They then tested the methods which they developed to be clinical-grade manufacturing methods, both in vitro and in vivo.

For the in vivo tests, they seeded the cells on a biodegradable substrate that mimics their formation in the eye and then inserted them into rat and pig models, using a specialized tool developed for this purpose. The rats were immune-compromised or had RPE dysfunction-associated retinal degeneration, and the pigs had a laser-induced RPE injury. The substrate improved the integration of these cells into the animals’ RPE.

The models were assessed for 10 weeks, at which point imaging studies confirmed that the cells had properly integrated into the animals’ RPE and acted as normal RPE cells. Electrophysiological recordings showed normal activity in the transplanted cells. In controls without the transplants, photoreceptors had died.

Investigators noted the ten-week manufacturing process may make the therapy expensive. Nonetheless, an application was sent to the US Food and Drug Administration (FDA) to receive approval for the first human trials of the technology.

There may be hope yet, Bharti said, for previously untreated patients with AMD. 

“Induced pluripotent stem (iPS) cell technology has been around for over a decade,” said Bharti. “Cell replacement therapies are becoming a reality and in the near future will become a common practice.”

Clinical-grade stem cell—derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs

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FDA trial approval would make this trial the first ever to test a stem cell-based therapy derived from induced pluripotent stem cells for treating any disease.

Human Trials Could Begin for Macular Degeneration Stem Cell Therapy

 or hemiretinal vein occlusion (HRVO) do not respond to treatment with bevacizumab, they may be able to benefit from switching to aflibercept, according to a recently published secondary analysis of an ongoing clinical trial comparing the 2 treatments.

 set out in 2014 compare the effectiveness of aflibercept and bevacizumab, which is commonly used off-label to improve visual acuity in eyes with macular edema due to CRVO or HRVO, over the course of 6 months. A 

 published from the trial data in 2017 showed that the bevacizumab as non-inferior to aflibercept.

Still, not all patients respond well to these treatments. At the start of the study, Michael Ip, MD, Chief of the Vitreoretinal Surgery Service at University of California Los Angeles and lead author on the study, and his team planned this secondary analysis to see if patients who did not respond to their first treatment, but then switched to either from bevacizumab to aflibercept or from bevacizumab to steroid injections (dexamethasone) experienced improvements.

“We planned this analysis as we knew that some eyes would not respond well to initial therapy,” Ip said. “It is an outstanding question in our field if switching therapies has any benefit.”

A patient’s response was considered marginal or poor if their visual acuity letter score (VALS) was less than 58 or they improved less than 5 letters from the baseline and spectral-domain optical coherence tomography (SD-OCT) with central subfield thickness (CST) 300 μm or greater, presence of intraretinal cystoid spaces, or subretinal fluid.

Out of the 182 from the first study who were randomized to receive bevacizumab or aflibercept 14 patients who did not improve on aflibercept received an intravitreal injection of dexamethasone at month 6, with any necessary follow up injections between months 6 and 12. Thirty-five who had originally received bevacizumab and not responded were switched to aflibercept.

The patients who switched from aflibercept to the steroid injections did not experience imporvements in LAVS or CST over the next 6 months. However, those that switched from bevacizumab to aflibercept saw improvements in VALS of an average of 10.27, and a decrease of 125.4 μm on CST at the 12-month mark.

“If there is a poor response to initial therapy with Avastin that some eyes may achieve improvements in vision and anatomy of switched to Eylea,” Ip said. “Also, if an eye fails Eylea, the steroid implant does not seem to confer additional benefit.”

The trial was necessarily limited by the small number of patients who had poor responses to the initial treatment, as well as the lack of controls subjects.

The study is ongoing as Ip and his team intend to follow these patients for 5 years. They’ll publish data at the annual marks through 5 years, including long-term outcomes with anti-VEGF therapy for CRVO.

Month 12 Outcomes After Treatment Change at Month 6 Among Poor Responders to Aflibercept or Bevacizumab in Eyes with Macular Edema Secondary to Central or Hemiretinal Vein Occlusion

A new analysis of an ongoing clinical study offers insights for treating retinal vein occlusion in poor responders to bevacizumab.

Aflibercept Benefits Bevacizumab-Unresponsive Diabetic Retinopathy Patients

Signs and symptoms of diabetic retinopathy—the leading cause of vision loss in persons aged 20 to 74 years&mdash;are prevalent in about one-third of patients with type 2 diabetes (T2D), according to a 2015 study. Investigators estimate this rate will likely rise in the following years.

Individuals with diabetes are also prone to 

, which can be managed with the use of statins. These statins may be providing the unintended benefit of decreasing the risk of developing certain diabetes complications including retinopathy. Still, investigators wrote, “the effectiveness of regular statin therapy as the primary prevention of the development of retinopathy in patients with diabetes remains uncertain.”

To clarify the connection between the drugs designed to lower cholesterol levels and the development of diabetic retinopathy, Eugene Yu-Chuan Kang, MD, from the Chang Gung Memorial Hospital in Taiwan and his team turned to the National Health Insurance Research Database.

They found 1,648,305 patients with type 2 diabetes on the registry between January 1, 1998 and December 31, 2013. Of those patients, 219,359 were eligible for the study. Patients were randomized 1:1 to either receive statin or serve as control. They followed up with patients after at least 7 years (mean 7.6 years for the statin group; 7.3 years for the non-statin group).

By the end of the study, 4273 patients had developed diabetic retinopathy, including 10.6% of patients from the statin group, and 12.0% of the non-statin group. Patients in the statin group also had significantly lower rates of macular edema and required fewer surgical and laser interventions, suggesting statin therapy could also slow the progression of diabetic retinopathy in patients that did have it, as was suggested by previously by the 

The investigators found that the protective effects of statins were dose and adherence-dependent. They divided the statin patients into three groups based on the dose and frequency with which it was taken as recommended by the 2013 American College of Cardiology/American Heart Association guideline.

The groups included patients on a low-intensity, medium-intensity, or high-intensity statin regimen. Those with the high-intensity statins had only a 3.4% likelihood of developing diabetic retinopathy, where the medium a low-intensity groups had a 6.0% and 13.4% chance, respectively.

“We found that statins could delay all stages of diabetic retinopathy and decrease the number of invasive procedures needed,” investigators wrote. “This finding was associated with the intensity and duration of statin use.”

Therefore, Kang and colleagues noted, improved medical management could not only reduce diabetes complications but also decrease the supplemental cost of eventual invasive interventions, including retina laser treatment, intravitreal injections, and vitrectomies.

Association of Statin Therapy With Prevention of Vision-Threatening Diabetic Retinopathy

Statins are already a common therapy among patients with type 2 diabetes. Its cholesterol-lowering benefits may help retain patient vision longer.

Statins May Reduce Risk of Retinopathy in Diabetes Patients

A new intraocular injection gene therapy, QR-110, may be able to treat Leber congenital amaurosis (LCA) caused by a specific CEP290 mutation, according to early results of an ongoing phase 1/2 trial.

Lead author Artur V. Cideciyan, PhD, research professor of 

 at the University of Pennsylvania, told 

the preliminary findings come in the era of personalized medicines—particularly highlighted by the introduction of therapies for monogenic conditions like retinal degeneration.

“Our current work takes this gene-specific personalized medicine for inherited retinal disease one step further by making the treatment mutation-specific,” Cideciyan said. “Our positive results show for the first time that intraocularly-injected anti-sense oligos can improve vision by modulating aberrant splicing.”

The team, which has been studying inherited retinal degeneration for decades, decided to conduct an interim analysis of their study when they saw particularly dramatic results from one of the patients. Cideciyan noted a patient improved from only being able to differentiate light or dark at baseline, to reading multiple letters on an eye chart at 2 months-post first injection.

The trial of QR-110, developed by ProQR Therapeutics, is ongoing and designed to last 1 year. Ten patients aged 6 or older are receiving intraocular injections of the drug in their worse-seeing eye once every 3 months for a year. Vision in this eye is then compared to that of the untreated eye.

The most common CEP290 mutation is a single nucleotide change in intron 26 that reduces the amount of CEP290 protein. Low levels of this protein prevent patients’ photoreceptors from sensing light. QR-110 is an anti-sense oligonucleotide which is believed to block recognition of this mutation, and thus increase the amount of functional CEP290, improving patients’ eyesight.

Four of the participants had had their first injection 6 months prior to the interim analysis, and another 4 had had theirs 3 months prior. The team found no safety concerns—no adverse events and no intraocular inflammation.

At each visit, the researchers tested patients’ best-corrected visual acuity (BCVA) in both the treated and untreated eyes. One month after treatment, they found no changes, but after three months, the one patient saw a large improvement (2.7 log10 MAR), while 4 other patients had smaller, but still clinically significant, improvements. For those patients who had data up to six months, the improvements over baseline were retained.

The study is expected to conclude at the end of this year.

“This work opens the door to evaluating similar approaches in other inherited retinal degenerations where antisense gene therapy can modulate protein content in photoreceptors in order to improve vision or slow down progressive degeneration or both,” said Cideciyan.

Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect

University of Pennsylvania investigators conducted an interim analysis of a year-long study on intraocular injections of a mutation-specific gene therapy when one patient showed dramatic early improvements.

Emma Yasinski

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