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1 From the Laser Research Laboratory, Retina Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School; and the 2 Department of Dermatology, Wellman Laboratories of Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Abstract
PURPOSE. To study the long-term effects of photodynamic therapy (PDT), using liposomal benzoporphyrin derivative (BPD) or Verteporfin, on experimental choroidal neovascularization (CNV) and on normal retina and choroid (with no CNV) in the cynomolgus monkey eye.
METHODS. Photodynamic therapy was performed in 8 cynomolgus monkey eyes with experimental CNV induced by laser injury. The effect of PDT on normal retina and choroid (with no CNV) was studied in 9 monkey eyes. Liposomal BPD was administered intravenously (0.375 mg/kg) either as a bolus, as a slow infusion over 32 minutes, or as a fast infusion over 10 minutes. Photodynamic therapy was performed using light at a wavelength of 689 or 692 nm, with an irradiance of 600 mW/cm2 and fluence of 150 J/cm2. Follow-up studies, including fundus photography and FA, were performed at 24 hours after PDT and then weekly. Indocyanine green and BPD angiography were performed in selected cases. Tissues were examined with light and electron microscopy at the end of follow-up.
RESULTS. Twenty-three of the 32 areas of CNV treated with PDT showed absence of angiographic leakage at 24 hours. Twenty-eight areas of CNV were followed for 4 weeks; 22 of 28 showed absence of angiographic leakage at 2 weeks; and 20 of 28 at 4 weeks of follow-up. Forty spots on the normal retina and choroid were treated with PDT and were followed for 4 to 7 weeks. These spots showed pigment-laden cells in the outer retina, variably pigmented retinal pigment epithelium (RPE) in the treated area, intact neurosensory retina, and reperfusion of the choriocapillaris.
CONCLUSIONS. Photodynamic therapy leads to absence of angiographic leakage for at least 4 weeks in experimental CNV in the monkey model. In the normal monkey eye the RPE and choriocapillaris show generalized recovery with preservation of the neurosensory retina 7 weeks after PDT.
Photodynamic therapy (PDT) is a developing treatment modality. It involves intravenous injection of a photosensitizer that accumulates in the neovascular and tumor tissue. This photosensitized tissue is then irradiated by light at the absorption maximum of the dye leading to cytotoxicity.1 2 Previous work in our laboratory has shown effective treatment at 24 hours after PDT, of experimental choroidal neovascularization (CNV), using a liposomal preparation of benzoporphyrin derivative (BPD) or Verteporfin.3 4 5 Optimal treatment parameters were identified that led to an absence of angiographic leakage and histologic occlusion of CNV. In normal areas of the fundus treated at these parameters, PDT caused choriocapillaris closure with minimal damage to the outer retina. This included disruption of the retinal pigment epithelium with minimal pyknosis of the outer nuclear layer and swelling of the outer segments.4 5 6 Verteporfin is a safe drug for human use and has been used in clinical trials in dermatology.7 Therefore, this treatment modality offers the potential of selective closure of CNV with minimal damage to the overlying retina.
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the western world.8 Choroidal neovascularization causes 90% of the visual loss in AMD.9 Currently, the only established management of subfoveal CNV is laser photocoagulation, with inherent drawbacks including the risk of a sudden decrease of vision, and significant recurrence of CNV after the treatment. Additionally, only 13% cases of neovascular AMD are eligible for laser treatment under the present guidelines.10 Therefore, there is a need for alternative treatment modalities for this condition. Other treatments under investigation include low-dose external beam and proton irradiation, systemic thalidomide and other antiangiogenic agents, and PDT.
Before starting the clinical trials of photodynamic therapy for AMD, we investigated the "long-term" (4 to 7 weeks) effect of the treatment on tissues surrounding the CNV, namely the neurosensory retina and choroid, and the persistence of CNV closure. We performed the studies with Verteporfin in cynomolgus monkeys, in eyes with experimental CNV, and on normal eyes without CNV.
Materials and Methods
Animals
Twelve Maccaca Fascicularis cynomolgus monkeys were used in
accordance with the ARVO Statement on the Use of Animals in Vision and
Ophthalmic Research, and in compliance with the guidelines developed by
the Animal Care Committee of the Massachusetts Eye and Ear Infirmary.
Eight eyes of 7 monkeys were used to study the effect on CNV, and 9
eyes of 5 monkeys were used for the study of normal retina and choroid.
Monkeys (3 to 5 kg) were anesthetized for all procedures using ketamine
hydrochloride (20 mg/kg), acepromazine maleate (0.25 mg/kg), and
atropine sulfate (0.125 mg/kg), as previously
described.3
4
5
At the end of the experiment enucleation
was performed under deep anesthesia, and animals were euthanatized
using pentobarbital (50 mg/kg), as previously
described.4
5
Induction of CNV
Choroidal neovascularization was created in 8 monkey maculae, as
previously described, by inducing damage to the outer retina using
high-intensity argon laser.3
4
5
11
12
The monkeys were
followed weekly with fundus photography and FA to detect the
development of CNV.
Liposomal BPD Verteporfin Administration
Liposomal BPD or Verteporfin was provided by QLT Phototherapeutics
(Vancouver, British Columbia, Canada). The Verteporfin was handled,
reconstituted and stored according to the guidelines provided by the
manufacturer, and protected from light at all times as previously
described.4
5
The Verteporfin was infused as an
intravenous bolus (0.375 mg/kg or approximately 6
mg/m2) over 30 seconds followed by a
flush4
in 3 animals for PDT of CNV and in 1 animal for PDT
of normal retina and choroid. The Verteporfin was infused (0.375 mg/kg)
over 31.9 minutes (slow infusion) via an infusion pump (IVAC 70 syringe
pump; IVAC, San Diego, CA),5
in 3 animals for PDT of CNV
and in 3 animals for PDT of normal retina and choroid. One of the
animals in the slow infusion group received a Verteporfin dose of 0.75
mg/kg. The Verteporfin was infused intravenously over 10 minutes (fast
infusion)5
in 1 animal for PDT of CNV and in 1 animal for
PDT of normal retina and choroid. The infusion rates were selected from
ongoing trials of PDT using Verteporfin for dermatology trials and from
trials proposed for AMD.
Lasers
Laser irradiation was performed in initial experiments with laser
light at 692 nm using Argon/Dye laser (Coherent 920; Coherent Medical
Laser, Palo Alto, CA) and subsequently at 689 nm using an Ocular
Photoactivation Diode Laser (Coherent Medical Laser). The laser light
was delivered via slit lamp using an adaptation of the ophthalmic
delivery systems called the Laser Link Photoactivation Slit Lamp
delivery system (patent No. 5336216, Coherent Medical Laser).
Photodynamic Therapy
The light parameters were selected on the basis of previous
investigations4
5
and were kept constant for all
experiments at an irradiance of 600 mW/cm2 and
fluence of 150 J/cm2. Light was focused on the
retina using a plano contact lens (OGFA; Ocular Instruments, Bellevue,
WA) producing either a 1250-, 1875-, or 4000-µm spot, which was
centered on the area to be treated. Areas of CNV were identified using
a fluorescein angiogram done within 48 hours before the planned PDT.
Areas of normal retina and choroid were selected in the posterior pole,
in areas that could facilitate identification during histologic
preparation. Irradiation was performed 10 to 71 minutes after the start
of the intravenous dye injection. The follow-up at 24 hours and at 2
and 4 weeks was done by fundus photography and FA, and the findings
were confirmed at 4 to 7 weeks by histopathology.
Eight monkey eyes with experimental CNV were treated with PDT (Table 1) . Photodynamic therapy was performed in 4 eyes with CNV using a bolus administration of Verteporfin and followed for 4 weeks. Photodynamic therapy was done in 3 eyes with CNV, using a slow infusion of Verteporfin and followed for 1 to 4 weeks. Photodynamic therapy was done in 1 eye with CNV, using a fast infusion of dye and followed for 5 weeks. The effect of PDT on the normal retina and choroid was studied by performing PDT on 9 normal monkey eyes (Table 1) . Photodynamic therapy was done in 2 eyes of 1 animal after bolus injection of Verteporfin and was followed for 7 weeks and 5 days after PDT. Photodynamic therapy using a slow injection of Verteporfin was done in 5 eyes of 3 animals, with follow-up for 3 or 4 weeks. Photodynamic therapy was performed in 2 eyes of 1 animal using a fast (10-minute) infusion of Verteporfin and a larger treatment spot size of 4000 µm, with follow-up for 2 or 5 weeks.
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Histology
All eyes were enucleated at the end of the experiment. The
enucleated eyes were bisected and placed in modified Karnovsky’s
fixative at 4°C overnight then transferred to 0.1 M cacodylate buffer
at pH 7.4. Tissues were postfixed in buffered 2% osmium tetroxide,
dehydrated in graded ethanols, and embedded in Epon.
One-micrometer-thick sections were stained with 0.5% toluidine blue in
borate buffer for light microscopy and examined using a Zeiss
photomicroscope (Axiophot, Oberkochen, Germany). Thin sections were
stained with uranyl acetate in methanol, and Sato’s lead stain, and
examined with a Phillips CM 10 transmission electron microscope
(Eindhoven, The Netherlands).
Results
Efficacy of PDT
The efficacy of CNV closure was demonstrated by the absence of
angiographic leakage with FA. Typically the CNV did not perfuse, and
there was hypofluorescence in the early phase of the angiogram, with no
leakage from CNV as the angiogram progressed. Hyperfluorescence was
noted in the PDT treatment spot starting from the periphery of the
treated area in the late phase of the angiogram. Figure 1 demonstrates CNV before PDT, which shows hyperfluorescence in the early
phase of the angiogram, followed by leakage of the dye in the late
phase. Figure 2
demonstrates an absence of angiographic leakage from the CNV, 24 hours
after PDT.
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Follow-up at 2 weeks after PDT of CNV (n = 28) demonstrated the following observations by angiography. Choroidal neovascularization irradiated within 20 minutes of the beginning of dye infusion continued to show an absence of angiographic leakage in 5 of the 6 CNV that were treated and followed. Choroidal neovascularization irradiated 20 to 50 minutes after the beginning of Verteporfin injection continued to show absence of angiographic leakage in 12 of the 14 CNV that were treated and followed. However, CNV irradiated more than 50 minutes after the beginning of Verteporfin injection showed a lack of angiographic leakage in 5 of the 8 CNV treated and followed.
Follow-up at 4 weeks after PDT of CNV (n = 28) demonstrated the following observations by angiography. Choroidal neovascularization irradiated within 20 minutes of the beginning of Verteporfin injection showed an absence of angiographic leakage in 5 of the 6 treated CNV. Choroidal neovascularization irradiated 20 to 50 minutes after the beginning of Verteporfin injection showed an absence of angiographic leakage in 10 of the 14 CNV that were treated and followed. Choroidal neovascularization irradiated more than 50 minutes after the beginning of Verteporfin injection showed a lack of angiographic leakage in only 5 of the 8 treated CNV.
Light (Fig. 4) and electron microscopy of the experimental CNV that showed an absence of angiographic leakage at 4 weeks of follow-up demonstrated envelopment of the CNV by proliferating hypopigmented retinal pigment epithelium (RPE). These proliferating RPE cells were seen connecting to the native RPE at the margin of the treated CNV. Rare open capillaries were seen. There were pigment-laden cells in the subretinal space as well as within the CNV. The treated experimental CNV also contained RPE cells and fibroblasts. Acinar structures were seen in the RPE cells, as previously described.13 The overlying neurosensory retina and retinal vessels appeared mostly undamaged, although the laser injury used to create the experimental CNV caused some disruption of outer and inner nuclear layers, similar to that in lesions examined 24 hours after PDT as previously reported.4 5
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ICG and BPD (Verteporfin) Angiography after PDT
Indocyanine green angiography at 24 hours after PDT of CNV
demonstrated hypofluorescence of the treated area with no perfusion of
CNV, and late-phase angiography showed staining of the treatment spot.
Indocyanine green angiography 5 weeks after PDT showed hypofluorescence
of the treated area in the early phase of the angiogram (Fig. 8
A), with perfusion of the retinal and large choroidal vessels. The late
phase of the angiogram showed persistence of hypofluorescence in the
treated area with some fluorescence in the area of treated CNV
(Fig. 8B)
.
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Discussion
Photodynamic therapy using Verteporfin offers a potentially selective treatment for CNV due to AMD and other diseases. Previous studies have demonstrated that by adjusting the light and dye doses, and the timing of irradiation after dye administration, vascular occlusion can be achieved in the choriocapillaris and CNV, with minimal disruption to the neurosensory retina. However, the long-term efficacy and the recovery of normal structures after PDT using Verteporfin have not been studied so far, and this is the first demonstration of the "longer-term" (4 to 7 weeks) effects of PDT on both CNV and normal retina and choroid.
The laser injury model of CNV in the primate is not ideal, because it is a wounding model and may not mimic the pathogenesis of CNV in AMD. Nevertheless, it provides a model of neovascularization originating from the choroid in the primate eye, with features common to clinical CNV, including angiographic and histologic features. More recently, studies have demonstrated that CNV in this model expresses growth factors and cell surface molecules such as vascular endothelial growth factor14 and integrins,15 which are also seen in CNV due to AMD. The model differs from clinical CNV in its tendency to regress, evidenced by a loss of angiographic leakage and envelopment by RPE cells.12 16, This may limit the ability of the model to assess long-term effects of CNV treatment. However, the changes that occur in the first few weeks after PDT assessed by FA, ICG, and BPD(Verteporfin) angiography, and light and electron microscopy may provide some useful information to predict and compare the effects in patients.
Fluorescein angiography early after PDT demonstrates hypofluorescence with perfusion of retinal vessels. BPD (Verteporfin) and ICG demonstrate deeper vasculature with most of the ICG fluorescence emanating from large choroidal vessels, and BPD (Verteporfin) fluorescence emanating from smaller choroidal vessels. The spectral characteristics of BPD (Verteporfin) are intermediate between fluorescein and ICG. Both ICG and BPD (Verteporfin) demonstrate hypofluorescence in the area treated with PDT, although larger choroidal vessels are perfused. This hypofluorescence with BPD (Verteporfin) and ICG angiography resolved to some extent with follow-up but was still evident at 5 to 8 weeks after PDT. The hypofluorescence may be caused by PDT-induced choriocapillaris occlusion or retinal pigment swelling leading to blocked fluorescence. Follow-up at 2 to 5 weeks after PDT of CNV demonstrated staining of the irradiated CNV by ICG and BPD (Verteporfin) angiography and may represent staining of the remaining fibrovascular tissue.
More intriguing are the findings of recovery of normal structures after PDT. The dye and light and dosing parameters of PDT can be adjusted to minimize effects on surrounding tissues, but the cells that are affected in the mildest treatments are the capillary endothelium and the RPE cells. Increased intensity of treatment results in increasing effects in the neurosensory retina, with disruption of the outer segments and pyknosis of the outer nuclear layer. At the parameters required for closure of CNV, one sees choriocapillaris occlusion, RPE cellular necrosis, and mild pyknosis of the outer nuclear layer; at 4 to 7 weeks after PDT these lesions show generalized recovery. The RPE repopulates the treated area, even when larger areas (4 mm) are treated. Although it has not been demonstrated in this study whether this repopulation is due to proliferation or migration or both, Smiddy et al.17 has shown that in adult primate retina proliferation of RPE can occur.
The RPE cells lining the treated areas in our study were found to be variably pigmented with basal infoldings and lysosomes, indicating some recovery of normal function. Similar recovery of the RPE has been described after surgical debridement of the RPE in primate eyes,18 in porcine eyes,19 and after laser injury to the RPE cells in rabbit eyes.20 In our study, pigment-laden cells with phagocytic activity were seen overlying the RPE, and the significance of these is unknown. These cells have been previously reported in the literature and are proposed to be derived from histiocytes21 or RPE cells.22 In our study the choriocapillaris was reperfused and showed reduplication of basement membrane on electron microscopy, suggesting recanalization by migrating and proliferating endothelial cells after PDT. There also appeared to be some minimal loss of photoreceptors 4 to 7 weeks after PDT. The recovery of healthy RPE and choriocapillaris in the monkey eye may differ from the recovery in the elderly eye with AMD. The visual significance of PDT on normal structures will await the results of clinical trials.
The treatment parameters used in this study were based on previous studies of PDT using Verteporfin to treat experimental CNV.3 4 5 The present study and the previous preclinical studies in monkeys were used to select the initial parameters used in the phase 1 and 2 clinical trials of PDT for CNV using Verteporfin. These included the Verteporfin dose of 6 or 12 mg/m2, irradiance of 600 mW/cm2, fluence of 50 to 150 J/cm2, and irradiation applied 10 to 40 minutes after the start of Verteporfin infusion.23 24 25 Subsequently the fluence was reduced to 50 J/cm2 in the phase 3 trials when nonselective effects with damage to retinal vessels was observed at the highest fluence of 150 J/cm2.24 25
Studies of PDT using Verteporfin in monkeys demonstrate that CNV can remain without angiographic leakage for 4 weeks and that the RPE and choriocapillaris show generalized recovery with preservation of the neurosensory retina over 4 to 7 weeks. The long-term efficacy and visual implications await the results of clinical trials.
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Supported in part by QLT Phototherapeutics (Vancouver, British Columbia, Canada).
Submitted for publication March 4, 1998; revised February 18, 1999; accepted March 16, 1999.
Proprietary interest category: C5.
The Massachusetts Eye and Ear Infirmary is an owner of a patent covering the use of verteporfin. Should the Massachusetts Eye and Ear Infirmary receive royalties or other financial renumeration related to that patent, Drs Joan W. Miller and Evangelos S. Gragoudas would receive a share of same in accordance with the Massachusetts Eye and Ear Infirmary’s institutional patent policy and procedures, which includes royalty sharing provisions.
Corresponding author: Joan W. Miller, Laser Research Laboratory, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114. Email: jwmiller@meei.harvard.edu
References
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