Pediatrics: Genetics and Pharmacology Provide Fertile Ground for Therapeutic Initiatives

Genetics and Pharmacology Provide Fertile Ground for Therapeutic Initiatives

Current concepts in diagnosis, management and prevention are changing the landscape of
pediatric retinal disease.

Advances in understanding the molecular genetic basis of disease are increasingly being translated into therapeutic initiatives. This understanding will drive the future of pediatric retina disease management, according to Antonio Capone, Jr., MD, of Associated Retinal Consultants, Royal Oak, Mich. "Future potential therapies include pharmacologic and immunologic interventions, of course, but I think most promise lies in either DNA- or RNA-directed therapies," Dr. Capone said.


Dr. Capone used congenital retinoschisis (CRS) as an example of the future applicability of genetic intervention, while pointing out that DNA/RNA-related therapies will be just as applicable to retinopathy of prematurity (ROP), familial exudative vitreoretinopathy (FEVR), Coats' disease, persistent fetal vasculature or Norrie's disease.

Prior assumptions about X-linked retinoschisis are being replaced by new information made possible by optical coherence tomography (OCT), which is dovetailing with advances in molecular biology and molecular genetics. "OCT has helped us refine our understanding of the anatomy of this disease without having to look at autopsy eyes," he said.

Dr. Capone referred to a series of 19 eyes with CRS in which OCT was performed on both the foveal and the extrafoveal retina. "The OCT images show what we might expect in the fovea, but they also show cystic changes in the retina outside of the fovea, not just in the nerve fiber layer," he said. "What we've learned from OCT is that schisis may be seen in an ophthalmoscopically normal retina, not just in the fovea or the bulla; that schisis is always limited to the nerve fiber layer, and in fact, the retina may be diffusely abnormal. Based on OCT, there are patients who have only foveal involvement, and then there are those — up to 80% — who have Type 3 or the complex type of involvement."

Further clarity has been provided via a mouse model, which demonstrated a possible neurotransmission function to retinoschisin. Dr. Capone pointed out that the primary mechanism of X-linked retinoschisis is reduced or absent secretion, with intracellular retention of the majority of mutant proteins. According to Dr. Capone, this may explain why, in spite of more than 130 identified mutations, severity is usually mutation-specific because the mutations are intertwined with regard to the inability to secrete protein. "But that is not the only mechanism," Dr. Capone said. "Other potential mechanisms will affect oligomerization — where secretion and oligomerization occur — but function at the level of the receptor is abnormal."

Current treatment would entail using a retinectomy laser and silicone oil to collapse the threatening bullae, according to Dr. Capone. "Many of these children, when they present, will have a bulla obstructing the visual axis," he said. "So simply clearing the visual axis by eliminating the bullous area often provides them with a nice visual outcome."

The most promise for future therapies for CRS, as well as most pediatric retinal disease, lies in either DNA or RNA-directed therapies, according to Dr. Capone. "One of the potentials for DNA therapy will require a 'boutique approach,' where each child's mutation is addressed, and then the repair is directed toward that specific mutation," he said. "Compare this to the advantage of an RNA approach, which allows you to target multiple mutations and using a 'hairpin RNA,' initiate a repair and basically fix everything downstream."

While the potential for genetic intervention is a certainty, questions remain. "Will the aberrant protein still inhibit function if it's left in the eye? How much of the RNA do you need to fix to obtain function, and how long will the fix last, among other things?" Dr. Capone said.

Figure 1: Exudate threatening the center of the macula with some proliferative component.


Another exciting future therapy lies in stem cells. "We typically have entered these eyes, retinectomized the inner wall, and used silicone oil and laser. In the future, it may be that we will be preserving the inner wall in the hope of then introducing stem cells to re-integrate the inner and outer leaflet," Dr. Capone said. "It sounds like a tall order for stem cells, but I have been surprised at the direction of stem cell research that demonstrates the capacity for these cells to integrate and then differentiate in the direction that one would hope they would. My bias initially was that it was too much to ask in terms of integration and differentiation, but I think I will be proven wrong."

Beyond stem cell intervention is the concept of 'pre-implantation,' which entails genetic diagnosis of a disease and then in vitro fertilization attempts for selective implantation of a disease-free embryo to eliminate the disorder from a family's lineage.


Until genetic and/or stem cell intervention becomes a clinical reality for pediatric retinal disease patients, there's pharmacologic management. Michael Trese, MD, also of Associated Retinal Consultants, addressed the use of pegaptanib sodium (Macugen, [OSI] Eyetech) to treat FEVR and ROP.

FEVR is a lifelong, potentially active retinal vascular disease that can lead to a combined exudative and tractional retinal detachment, which Dr. Trese pointed out, is, at least in part, driven by unopposed VEGF. "We began treating FEVR patients with one intravitreal injection of pegaptanib in February 2005 and have since treated more than 20 eyes that had failed laser treatment. We now have more than 11 months of follow-up in patients age 8 to 25, who had exudation that threatened the center of the macula (Figure 1). All of the eyes showed reduced exudation at the 4-week visit with continued reduction beyond that time point," Dr. Trese said. We also saw a recognizable pattern of exudate involution and resolution in these patients and no evidence of toxicity. "We did, however, see a rather longer-lasting increase in IOP, more so than we've seen in AMD eyes, and one of the eyes even required a paracentesis."

Two of the FEVR eyes treated with pegaptanib required a second injection after 6 months, and three of the first four eyes had small-to-large vitreous hemorrhages. Two of these eyes required vitrectomy, and the mechanism of the vitreous hemorrhage was such that the exudate resolved so much that there was traction on preretinal vessels, and the preretinal vessels bled, according to Dr. Trese.

"Interestingly, after we performed vitrectomy, the vision improved, and in two of these eyes, the vision became better than it ever had been, one improving to 20/60, the other to 20/200. We did not see any involution of preretinal vessels, but we did see a very dramatic reduction in exudates," Dr. Trese said. "Both of those eyes had been followed for lengthy periods — one for 6 years, one for 8 years."

According to Dr. Trese, this series suggests pegaptanib is very helpful in reducing existing exudate. "Currently, if there are moderate preretinal vessels present, we perform vitrectomy and inject pegaptanib," Dr. Trese said. "One thing to keep in mind is that in vitrectomized eyes, it's very likely that pegaptanib or any other chemical placed inside the vitreous cavity may not last as long, but so far, we've not seen the need to reinject these vitrectomized eyes."

Exploring Anti-VEGF Therapy for Coats' Disease

Seen less often than ROP or FEVR, Coats' disease (exudative retinitis) tends to develop subretinal exudate, and the temporal periphery is usually involved first but not exclusively. Anti-VEGF treatment is being explored here, as well. "If we do get some 'punch' out of using an anti-VEGF agent, I think angiography can explain why," said Antonio Capone, Jr., MD. "With Coats' you don't just get leakage from the small telangiectatic areas, you also get leakage from the vessels and the microvasculature bordering the areas of capillary non-perfusion. We don't typically think of this as an ischemia-driven disease, but we may be wrong."

Angiography is absolutely essential in determining how extensive the disease is and in managing these children, Dr. Capone pointed out. "Hopefully in the near future I'll have some information regarding how we can use anti-VEGF agents to try to mitigate the hyperexudative response to retinal vascular ablation," he said.

ROP is another pediatric disease that is driven in large part by VEGF. It is off-regulated by endogenous TGF-beta, which is produced at the mother's due date. According to Dr. Trese, this shows there is an endogenous biochemical system to downregulate VEGF and bring the disease to an end.

"When you're dealing with a child with ROP, and you're trying to determine whether or not they need either laser treatment or other kinds of pharmacologic treatment, you know help is on the way if you're close to the due date in terms of downregulation," he said. "TGF-beta is also a potent scarring agent, which is why they end up with very fibrotic retrolenticular membranes if they are left alone — hence the older name, retrolental fibroplasias."

The VEGF and ROP connection is simple: VEGF promotes permeability, supports neovascularization and suppresses genetically programmed endothelial apoptosis, particularly of the hyaloid system and the tunica vasculosa lentis, resulting in a cell bolus, which contributes to a tractional retinal detachment. According to Dr. Trese, there may be a rebound that occurs after getting an anti-VEGF drug, and this, he said, may have something to do with why recurrent injections are often necessary.

Drs. Trese and Capone as well as Kimberly Drenzer, PhD, recently conducted a study to evaluate VEGF levels in the vitreous cavities of 10 ROP eyes at the time of vitrectomy. They compared them to 12 eyes that were vascularly active and five congenital cataract controls.

"We saw that in children who had vascularly active eyes, there were extremely high levels of VEGF of around 3800 picograms/mL; in vascularly inactive eyes, it was about 660 picograms/mL; and in eyes with congenital cataract, it was about 330 picograms/mL," Dr. Trese said. "So there was a vast difference between the eyes with ROP and those with congenital cata-racts, but it seems these levels are consistent with diabetic disease." Further study of a small series of eyes suggests that pegaptanib will quiet the eye vascularly, although it does not seem that it will effectively reduce the chances of the child going on to retinal detachment.

It appears a single injection of pegaptanib may reduce subretinal exudates in FEVR patients, but preretinal neovascularization in this disease is less responsive to this treatment. While Dr. Trese and colleagues originally considered pegaptanib as rescue therapy for ROP, that now appears not to be the right approach.

"We do think anti-VEGF therapy, if timed appropriately and relative to the involution of the tractional detachment cells, can be a better alternative to destruction of two-thirds of the retina by laser," Dr. Trese said. "We believe further study is needed to look at both selective and nonselective blockage of VEGF-A to see if that's something that will improve our outcomes."