Take-home message: The class of molecules called “neurotrophic factors” has been demonstrated to reduce the rate of photoreceptor cell loss during retinal regeneration.
By Laird Harrison; Reviewed by Martin Friedlander, MD, PhD
La Jolla, CA—Neurotrophic molecules may prove useful in treating macular telangiectasia type 2, according to research.
“While we don’t have statistically significant efficacy results yet, data from the phase I trial show that the safety with encapsulated cell-based delivery of ciliary neurotrophic factor (CNTF) is good, and anecdotally, outcomes appear better in treated eyes than untreated eyes,” said Martin Friedlander, MD, PhD.
The possibility arises from an 11-year-old collaborative research effort—the MacTel Project—encompassing natural history, genetics, imaging, and laboratory studies of the disease, said Dr. Friedlander, chief of retinal services, Scripps Clinic, and professor, Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA.
An administrative interim analysis of the phase II clinical trial will take place in May. If there are no safety concerns, final analysis of the phase II trial will take place 1 year later. If the results of this trial and a subsequent phase III trial demonstrate efficacy, CNTF could become the first treatment for macular telangiectasia type 2, he noted.
Research into the proposed treatment stems from recent discoveries that the disease results from deterioration of photoreceptor cells in addition to the vascular changes, and that the cells may be damaged rather than destroyed and, thus, might be revived.
“It’s really a game-changer in terms of treating this disease,” Dr. Friedlander said. “You’re talking about restoration rather than resurrection.”
More about the disease
A degenerative condition of the macula, macular telangiectasia type 2 affects both eyes and may cause progressive loss of central vision. It afflicts about one person in 22,000.
The condition was described in 1982, and until recently, physicians knew little about it.
“It’s often misdiagnosed as macular degeneration,” Dr. Friedlander said.
Macular telangiectasia is classified as three types, but the diseases are not related.
In type 2, the most common type, leakage occurs during fluorescein angiography with manifest retinal capillary dilatation but without retinal thickening. Patients are typically diagnosed in their 40s or 50s. As the disease progresses, intraretinal pigment plaques and intraretinal or subretinal neovascularization may develop.
Lowy Medical Research Institute
Research into macular telangiectasia type 2 took off in 2005, when funding by the Lowy Family Group, owners of the Westfield Corp., initiated the MacTel Project.
The project has since grown, taking the form of the Lowy Medical Research Institute (LMRI), which is devoted to full-time investigation of the disease and related neurological, vascular, and glial degenerative disease of the retina. LMRI resides next to the campus of The Scripps Research Institute in La Jolla.
In addition to its own full-time staff, the institute supports the activities of macular telangiectasia-related research through grants to about a dozen laboratories and 22 clinics worldwide. Along with basic preclinical basic research, it has sponsored programs in adaptive optics, OCT, metabolomics, visual psychophysics, and genetics.
In its early days—under the direction of Emily Chew, MD, of the National Eye Institute, and Alan Bird, MD, of University College London and Moorfields Eye Hospital—the project undertook a multicentered, international natural history study of MacTel type 2 and identified several key features:
Loss of luteal pigment centrally comes as one of the first signs, and changes from this loss can be imaged using fundus autofluorescence with a confocal laser ophthalmoscope. Abnormalities in this and blue light reflectance were shown by Frank Holz, MD, University of Bonn in Germany; Daniel Pauleikhoff, MD, medical faculty of the University of Duisburg in Essen, Germany, and Alain Gaudric, MD, at the University of Paris.
Abnormalities in photoreceptors—visible on optical coherence tomography (OCT) early in the disease—often comes with significant loss of scotopic and photopic function beginning nasal to fixation. It can lead to pre-fixational blindness.
Cone loss also characterizes the early disease, and is visible with adaptive optics imaging. The photoreceptor loss may be functional rather than structural, with two independent studies from Austin Roorda, PhD, and Brandon Lujon, MD, University of California, Berkeley; Jacque Duncan, MD, University of California, San Francisco; and Joseph Carroll, PhD, Medical College of Wisconsin in Milwaukee, showing that affected cones may lose their outer segments but preserve inner segments.
Anti-vascular endothelial growth factor (VEGF) treatment reverses the blood vessel changes but does not influence progression of photoreceptor cell loss or functional loss.
The retina is thinner than normal unlike other macular conditions such as diabetic retinopathy.
Dye leaks during fluorescein angiography of eyes with macular telangiectasia type 2. Opacification of the retina occurs very early in disease but is not due to retinal edema. Histopathological examination of several post mortem eyes taken from patients with MacTel shows the presence of sub-retinal deposits and an abnormality of Müller glia.
In one recent study conducted by Ferenc Sallo, MD, PhD, and Tunde Peto, MD, PhD, of Moorfields Eye Hospital, London, visual field defects assessed by microperimetry were closely associated with defects in the ellipsoid zone measured by OCT. This shows that there is a good correlation between vision loss and retinal pathology, most likely at the level of photoreceptor functional loss, Dr. Friedlander said.
The current evidence has convinced Dr. Friedlander that photoreceptor cell loss is intrinsic to the disorder rather than directly resulting from blood vessel changes, although we know that there is extensive “crosstalk” between vessels, photoreceptors, and glia, he said.
In animal models, a class of molecules known as neurotrophic factors has proved effective in reducing the rate of photoreceptor loss during retinal degeneration, Dr. Friedlander said.
CNTF, which belongs to this class, has slowed vision loss from photoreceptor cell death in 12 animal models of outer retinal degeneration, including in rats, cats, and dogs.
Treating the outer retina of mice with phenotypic macular telangiectasia type 2 characteristics has shown profound functional and anatomic photoreceptor cell rescue without correcting associated vascular abnormalities.
One obstacle to the therapy is the blood-retinal barrier, which prevents the penetration of a variety of molecules to the neurosensory retina from plasma, much as the blood-brain barrier prevents most molecules from passing between the central nervous system and systemic circulation.
Encapsulated cell technology (ECT) (Neurotech USA) can deliver controlled, sustained delivery of therapeutic agents directly into the vitreous humor, thereby providing direct access to the retina while limiting leakage of the growth factor outside the eye.
ECT consists of cells encapsulated within a semi-permeable polymer membrane. The devices can be surgically retrieved, providing an added level of safety.
The MacTel Project collaborated with Neurotech, which is sponsoring the current clinical trial, to assess the safety and efficacy of using ECTs to deliver CNTF to patients with macular telangiectasia type 2.
The phase I trial has been ongoing for 4 years, and shows that the device and CNTF are well tolerated without any significant adverse events. A 2-year phase II study is under way, and has enrolled 68 participants with macular telangiectasia type 2.
Other potential treatments
Though this approach is perhaps the most promising so far, the MacTel Project is also working on other potential treatments, Dr. Friedlander said. It is hoped its genetic studies—conducted by Rando Allikmets, PhD, Columbia University, New York; Melanie Bahlo, BSc Hons, PhD, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; and Paul S. Bernstein, MD, PhD, and Mark F. Leppert, PhD, University of Utah School of Medicine, Salt Lake City—reveal more about the underlying etiology.
In the meantime, “we have other things coming down the line,” Dr. Friedlander said. “If preliminary studies by Daniel Palanker, MSc, PhD, and Daniel Lavinsky, MD, PhD, then at Stanford University in California, are further validated, it may be that with subthreshold laser you may be able to get stabilization by inducing production of endogenous neuroprotective molecules.”
LMRI is also working on developing stem cells and differentiating them into retinal cells.
Although no treatment is yet available, Dr. Friedlander urged ophthalmologists to be on the lookout for patients with the following:
· leakage on fluorescein angiography
· right angle vessels
· superficial crystalline deposits
· pigment migration
· abnormal fundus autofluorescence
· loss of retinal transparency, OCT abnormalities
· inner segment/outer segment break
· cavities, loss of macular pigment
· blue light reflectance abnormalities,
· selective cone outer segment loss
· Müller glial death
· subretinal deposits
General ophthalmologists should refer such patients to the MacTel Project (www.lmri.net), Dr. Friedlander said. These patients might benefit by being enrolled in clinical trials or being notified quickly if a treatment becomes available.
Martin Friedlander, MD, PhD
This article was adapted from Dr. Friedlander’s presentation at Retina Subspecialty Day during the 2015 meeting of the American Academy of Ophthalmology. Dr. Friedlander has no financial interest in the subject matter.