PHOTORECEPTOR TRANSPLANTATION HAS LONG-TERM POTENTIAL

In a recent issue of Progress in Retinal and Eye Research, researchers from the Center for Regenerative Therapies, Dresden, Germany, reviewed the state of efforts to combat degenerative retinal diseases through photoreceptor transplantation.

A few highlights of the study:

• Loss of light-sensing photoreceptors due to retinal degeneration is, thus far, irreversible, but photoreceptor transplantation represents a potential therapeutic approach for such diseases.
• Retinal organoids are a potentially unlimited source of donor photoreceptors, while cytoplasmic material transfer must be considered in further studies of visual function recovery by cell transplantation.
• Immune reaction to the graft needs to be properly understood prior to clinical translation.

SUPRACHOROIDAL SPACE STUDIED FOR GENE TRANSFER

The two companies currently conducting clinical trials for continuous gene-derived anti-VEGF expression are using different routes to administer the genetically coded material. RegenxBio uses subretinal administration, while Adverum employs an intravitreal injection. Now, Clearside Biomedical in preclinical testing is demonstrating the potential advantages of suprachoroidal administration.

At this Spring’s ARVO meeting, multiple posters were presented utilizing a suprachoroidal approach to deliver gene therapies in non-clinical models. Overall, the data presented at ARVO suggests that suprachoroidal administration has the potential to offer targeted delivery of gene therapies without risks of vitrectomy and subretinal surgery. Clearside said it looks to optimize the procedure for gene therapy delivery using its proprietary suprachoroidal (SCS) injection platform in this setting.

Glenn Chung-Wing Yiu, MD, PhD, assistant professor of ophthalmology, UC Davis, presented at ARVO “Suprachoroidal injection of AAV8 for ocular gene delivery in the nonhuman primate.”

Although the sample size of eyes undergoing SCS injection of AAV8 expressing green fluorescent protein was small, Dr. Yiu concluded that suprachoroidal injection of AAV8 (developed/licensed by RegenxBio) may be a feasible mode of ocular gene delivery with transduction of mostly retinal pigment epithelium rather than photoreceptors and in peripheral rather than macular regions. In the studies, maximal expression was seen at 1 month and additional studies are recommended to optimize the extent and duration of viral transduction.

NEW SUSTAINED-RELEASE CONCEPT FOR DRUG DELIVERY

A multi-discipline team at Ohio State University has developed an injectable, biodegradable, bi-layered (IBB) capsule that has proven in preclinical testing that it is effective in delivering anti-VEGF drugs into the eye continuously for 6 to 12 months.

The researchers, who presented their findings at this year’s ARVO meeting, said the novel IBB capsule showed no cytotoxicity, excellent injectability, and maintained the high potency of anti-VEGF during long-term release. By meeting the needs of high drug payload and long-term sustainable release, the device may represent a promising evolution in the treatment of AMD as well as other ocular diseases and injuries.

GENETIC VARIATION SEEN AS A CAUSE OF AMD

A study published in the journal Stem Cell Reports focused on the importance of a specific genetic variation that affects expression of the VEGFA gene. The product of this gene, the VEGFA protein, is known for supporting new blood vessel growth — a process that goes awry in AMD.

Using this new model of AMD, the researchers determined that a specific genetic variation in a region of the genome that regulates expression of the VEGFA gene reduces the amount of VEGFA produced and directly contributes to AMD.

“We didn’t start with the VEGFA gene when we went looking for genetic causes of AMD,” said senior author Kelly A. Frazer, PhD, professor of pediatrics and director of the Institute for Genomic Medicine at UC San Diego School of Medicine. “But we were surprised to find that, with samples from just six people, this genetic variation clearly emerged as a causal factor.”

The researchers said they were surprised that the causal variant results in decreased VEGFA expression prior to AMD onset, and this finding could potentially be relevant for the treatment of AMD using anti-VEGF therapeutics.

The genetic variant most closely associated with AMD was rs943080, a specific genetic variation that affects expression of the VEGFA gene by altering activity of a distant region of the genome. Five of the six participants had one copy of rs943080 and one person had two copies of the gene variant.

LONG-ACTING STEROID IMPLANT COMBATS MAR

In a groundbreaking effort, researchers from the University of Surrey and Royal Surrey County Hospital, UK, supported by the electrophysiology department of Moorfields Eye Hospital, initiated a new approach in treating melanoma-associated retinopathy (MAR), a rare autoimmune syndrome occurring in patients with cancer, which can cause night blindness and progressive vision loss.

Working with a 73-year-old patient with MAR, researchers injected long-acting steroid implants into the eye. The implants slowly release fluocinolone acetonide, which prevent anti-retinal antibodies from attacking proteins in the organ. Current therapies to treat patients with MAR are limited in their effectiveness and may be harmful to some.

After 1 week of treatment, improvements in vision were detected, and detailed examination of the patient’s eye revealed that abnormalities previously observed, such as reduced electroretinogram recordings, had partly resolved, which is consistent with improved inner retinal cell function. Monitoring the patient over a 3-year period, researchers found that vision remained stable with visual acuity remaining at 20/20.

Simon Taylor, professor of ophthalmology at the University of Surrey, said: “To our knowledge, this is the first time the vision of a patient with melanoma-associated retinopathy has been treated and significantly improved with long-acting steroid implants. This offers a possible alternative option to patients whose quality of life is significantly reduced due to the symptoms of this debilitating ailment.”

ASTHMA MEDICATION MAY BE EFFECTIVE IN DIABETIC RETINOPATHY

Physician-researchers from University Hospitals Rainbow Babies and Children’s Hospital and Case Western Reserve University School of Medicine found that the asthma medication montelukast (Singulair), can inhibit early changes in diabetic retinopathy in a mouse model of type 1 diabetes.

The study was published online in the journal Diabetes.

“We found that montelukast was able to disrupt the signaling of inflammatory molecules called lekotrienes. This disruption significantly reduced small blood vessel and nerve damage that we see in the early stages of diabetic retinopathy,” said Rose Gubitosi-Klug, MD, PhD, senior author of the study and chief of pediatric endocrinology at UH Rainbow and the William T. Dahms professor of pediatrics at CWRU School of Medicine. “While most therapies target the late stages of the eye disease in diabetes, these findings offer a much-needed approach to treat the disease much earlier.

“The re-purposing of a medication already FDA-approved for use in children and adolescents sets the stage for rapid translation of these animal model findings to human subjects,” said Dr. Gubitosi-Klug. “The daily dose equivalent used in the current study is similar to the once daily dose used in the treatment of asthma. Reassuringly, in our diabetes model, as in asthma studies, this dose allows effective suppression of chronic inflammation, which can prevent pathology, but avoids complete inhibition of inflammation, which can compromise innate immunity.

“Moreover, montelukast was efficacious in both prevention and delayed intervention approaches, which implies relevance to patients with newly diagnosed diabetes as well as individuals living with diabetes of longer duration,” she said. “Thus, there is promise that a safe treatment that effectively stabilizes airways in asthma may also preserve small blood vessels and nerve cells in diabetes.” NRP