Cross-sectional images of retina from retinoschisin-deficient mice, untreated and treated with XLRS gene therapy.
The National Eye Institute (NEI) recently launched the first-ever human gene therapy trial for the vision disorder X-linked retinoschisis (XLRS). Researchers are conducting the trial at the National Institutes of Health Clinical Research Center in Bethesda, Maryland.
XLRS is a genetic disorder that causes splitting through the layers of the retina, the light-sensitive neural tissue in the back of the eye. XLRS gene mutations are inherited from mother to child; however, typically only males develop symptoms. Vision loss usually is evident by early grade school age and slowly worsens over the next several decades as cells in the retina lose function and die.
The causative gene was identified in 1997 and named Retinoschisin 1 (RS1). The gene codes for the retinoschisin protein, which normally works like double-sided tape, providing lateral adhesion that holds retinal cells together. RS1 gene mutations alter the protein and thereby interfere with the ability of cells to maintain proper structure of the retina.
The XLRS gene therapy technique employs an adeno-associated virus (AAV) as a carrier, or vector, to shuttle normal RS1 DNA into cells of the retina. This virus does not cause human disease. In preclinical studies, the NEI team successfully demonstrated use of the vector to deliver the RS1 gene into an XLRS mouse model. When treated, the mouse eyes showed improvements in retinal structure and visual function. A similar treatment strategy with an AAV vector, loaded with a different gene, was used in the groundbreaking gene therapy trials for Leber congenital amaurosis (LCA), another degenerative retinal disease. The XLRS gene therapy trial is one of the first ever at NIH to use the AAV vector.
While the XLRS study seeks to optimize the gene therapy dose, as a phase I/IIa clinical trial it is primarily designed to address safety. “This is the first clinical trial of gene therapy for XLRS, and our first priority is to ensure it is safe,” said Dr. Paul A. Sieving, who is leading the trial. “An important secondary goal is also to look for benefit to vision.”
The first participant has been treated and is being monitored closely. Results from the trial are expected in 2016.
Further information about this trial is available at https://clinicaltrials.gov/(link is external).
Most patients with retinoschisis will remain asymptomatic without treatment. It is important to know when and how to intervene.
Although degenerative retinoschisis is usually benign, vision-threatening complications can occur. It is important to appropriately manage these complications, which include:
When a patient is found to have posterior retinoschisis (Figure 1), it is easy to get concerned because of the following logic:
This logic has led to attempts to halt progression of retinoschisis using a wide array of techniques.1 However, the temptation to lay down a strong chorioretinal scar with some “low risk” laser, for example, should be resisted. The natural history of retinoschisis suggests that it almost never progresses significantly more posterior from where it is first observed.1 In fact, most cases of posterior retinoschisis will not progress beyond 3 disc diameters from the macula. Only a handful of cases of degenerative retinoschisis involving the macula have been reported.2-5
Additionally, no treatment, including laser, has been shown to halt the progression of retinoschisis. One possible explanation for this phenomenon is that retinoschisis, unlike retinal detachment, is multifocal in nature.6 Cases in which the disease appears to have progressed through laser scars may in reality be retinoschisis arising de novo in previously unaffected areas of the retina. Finally, although retinoschisis causes an absolute scotoma, patients are almost invariably asymptomatic, even with very posterior retinoschisis. Treatment for these patients should be observation.
Occasionally, a patient with retinoschisis will be referred for laser prophylaxis before cataract surgery. However, neither cataract surgery1 nor posterior vitreous detachment (PVD)6 have any adverse effect on retinoschisis. This makes sense, as the pathology is within the retina, not at the vitreoretinal interface.
Outer wall breaks are usually large (greater than 3 disc diameters), round, and posterior, often with rolled edges. If they are chronic, a cuff of subretinal fluid may create a ring of pigmentation (Figures 2 and 3). This appearance is in contrast to inner wall breaks, which are typically small and round, reminiscent of atrophic holes. Outer wall breaks are common, found in 11% to 24% of retinoschisis cases.1,7,8 The large size and posterior location increase the perceived threat of outer wall breaks, and their amenability to laser prophylaxis increases the temptation to treat9,10; however, studies suggest that outer wall breaks usually remain stable.1
The worst typical outcome of outer wall breaks is the development of an asymptomatic schisis detachment. Byer found that schisis detachment occurred in 58% (14 of 24) of patients with outer wall breaks during long-term follow up.1 Fortunately, the subretinal fluid does not typically extend beyond the borders of the schisis cavity itself, likely due to the highly viscous nature of the intraschisis fluid and its high mucopolysaccharide content.6 None of the patients in Byer’s natural history study received treatment or developed symptoms due to retinoschisis complications over an average of 9 years of follow-up.1 However, until more comprehensive data is available, surgeons’ judgments and patients’ wishes should guide discussion over whether to barricade outer wall breaks and localized schisis detachments.
Rarely, the subretinal fluid of a schisis detachment will leak into the macula and cause symptomatic vision loss (Figure 4).9,11,12 However, even very posterior subretinal fluid may remain stable for years.13 For example, despite the juxtafoveal fluid in Figure 4, the vision remained 20/50 over 4 years of follow-up without treatment. Because cases of posterior extension of schisis detachment are rare, surgeons must use their best judgment on a case-by-case basis. Laser barricade can be attempted in asymptomatic patients, but vitreoretinal surgery may be required. The principles of vitreoretinal surgery in the setting of retinoschisis are discussed below.
Progressive RRD associated with retinoschisis occurs when breaks in both the inner and outer layers permit vitreous fluid into the subretinal space (Figure 5A). Outer wall breaks will be evident, although inner wall breaks may be difficult to find.14 In contrast to the smooth, immobile surface of retinoschisis, progressive RRD associated with retinoschisis will feature opacified and often corrugated retina. Also, the patient will be symptomatic due to the progressive scotoma. Fortunately, this complication is rare, occurring in only 0.05% of patients with retinoschisis.1
Treatment of progressive RRD associated with retinoschisis follows the same principles as treatment of any RRD, but with a few special considerations. First, the primary surgical goal is to close the outer wall breaks; treating inner wall breaks and collapsing the schisis cavity is optional.14 If the schisis cavity is collapsed intraoperatively, it will likely recur postoperatively. Even if the schisis cavity remains collapsed, the scotoma from this area is not reversed.15,16
Pars plana vitrectomy and/or scleral buckle may be used to fix the RRD. Factors favoring pars plana vitrectomy include posterior location of outer wall breaks and presence of PVD. Anterior location of outer wall breaks and absence of PVD favor scleral buckle.17 When performing pars plana vitrectomy, a drainage retinotomy in the inner wall overlying the outer wall break may be created to drain subretinal fluid (Video).14 Alternatively, the inner wall of the schisis cavity may be resected entirely (Figure 5B).
Apart from posterior extension of schisis detachment and progressive RRD, in the majority of cases the complications of degenerative retinoschisis require observation only. Surgical treatment of posterior schisis detachment and progressive RRD requires closing the outer wall breaks using vitreoretinal surgical techniques. n
Sunir J. Garg, MD, is an associate professor of ophthalmology at Thomas Jefferson University Retina Service and Wills Eye Hospital in Philadelphia, Pennsylvania, and a vitreoretinal surgeon at Mid Atlantic Retina Consultants in Pennsylvania and New Jersey. Dr. Garg may be reached at email@example.com.
Omesh P. Gupta, MD, MBA, is an associate with Mid Atlantic Retina. Dr. Gupta may be reached at firstname.lastname@example.org.
S. K. Steven Houston III, MD; Ehsan Rahimy, MD; and David C. Reed, MD, are second-year vitreoretinal fellows at Wills Eye Hospital in Philadelphia, Pennsylvania, and are members of the Retina Today Editorial Board. Dr. Houston may be reached email@example.com. Dr. Rahimy may be reached at firstname.lastname@example.org. Dr. Reed may be reached at email@example.com.
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